Protocol. This trial protocol has been provided by the authors to give readers additional information about their work.

Transcription

1 Protocol This trial protocol has been provided by the authors to give readers additional information about their work. Protocol for: Powers SW, Coffey CS, Chamberlin LA, et al. Trial of amitriptyline, topiramate, and placebo for pediatric migraine. N Engl J Med 2017;376: DOI: /NEJMoa

2 This supplement contains the following items: 1. Original protocol, final protocol, summary of changes. 2. Original statistical analysis plan, final statistical analysis plan, summary of changes.

3 The Childhood and Adolescent Migraine Prevention Study Study Chairs: Andrew D. Hershey, MD, PhD, FAHS Associate Director of Research, Division of Neurology Professor of Pediatrics and Neurology University of Cincinnati College of Medicine Co-Director, Headache Center Cincinnati Children s Hospital Medical Center Cincinnati, Ohio Scott W. Powers, PhD, ABPP, FAHS Director of Clinical and Translational Research Cincinnati Children s Research Foundation Professor of Pediatrics and Psychology University of Cincinnati College of Medicine Co-Director, Headache Center Director, Center for Child Behavior and Nutrition Research Cincinnati Children s Hospital Medical Center Cincinnati, Ohio Supported by: The National Institute of Neurological Disorders and Stroke (NINDS) Grant # 1U01NS Amitriptyline and Topiramate in the Prevention of Childhood Migraine Investigational Drug Application (IND) Holder: Andrew D. Hershey, MD, PhD, FAHS IND # 112,220 Any modification to the protocol should be annotated on the change control memo. The annotation should note the exact words that are changed, the location in the protocol, the date the modification was approved by the Study Chairs and the date it became effective. CHAMP DSMB Approved Version 1 March 23, 2012

4 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean TABLE OF CONTENTS CLINICAL SITES PARTIPATING IN THE STUDY 6 PRIMARY STUDY TEAM MEMBERS 11 PRÉCIS STUDY OBJECTIVES Primary Objective 15 PAGE 2. BACKGROUND Rationale for Study General Issues Supporting Data - Previous Evidence STUDY DESIGN Overview of Study Design Overview of Study Procedures Study Visit and Procedure Schedule SELECTION AND ENROLLMENT OF SUBJECTS Inclusion Criteria Exclusion Criteria Study Enrollment Procedures STUDY INTERVENTIONS Interventions, Administration, and Duration Double Blind Treatment Phase 35

5 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 5.3 Titration Period Maintenance Period Weaning Period Concomitant Interventions Prohibited Interventions Handling of Study Intervention Adherence Assessment Option for Future Re-contact of Subjects CLINICAL AND LABORATORY EVALUATIONS Informed Consent Evaluations Titration Adjustment Visit, Unscheduled Visits and Discontinuation Evaluations Special Instructions and Definitions of Evaluations MANAGEMENT OF ADVERSE EXPERIENCES Adverse Event Expected Adverse Reactions Dose Modification Guidelines and Procedures Serious Adverse Events (SAE) Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs CRITERIA FOR INTERVENTION OR DISCONTINUATION Subject Termination 71

6 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 8.2 Site Termination Study Termination STATISTICAL CONSIDERATIONS Specific Aims and Hypothesis Outcomes Data Monitoring Data Management and Statistical Analysis Plan DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORTING Records to be Kept Document Retention Electronic Case Report Form (ecrf) Missing Data Role of Data Management Data Management by the Data Coordinating Center (DCC) Case Report Forms Training for Study Data Entry Quality Assurance Adverse Experience Reporting HUMAN SUBJECTS Ongoing Review of Potential Risks Adequacy of Protection Against Risks Institutional Review Board (IRB) Review and Informed Consent 102

7 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 11.4 Subject Confidentiality Subject Compensation Study Modification/Discontinuation PUBLICATION OF RESEARCH FINDINGS REFERENCES 103

8 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean CLINICAL SITES PARTICIPATING IN THE STUDY Site: Akron, OH Site: Amherst, NY Maria Christina Victorio, MD Laszlo Mechtler Akron Children s Hospital Dent Neurological Institute One Perkins Square 3980 Sheridan Drive, Suite 200 Akron, OH Amherst, NY Phone: Phone: Fax: Fax: mvictorio@chmca.org lmechtler@dentinstitute.com Site: Ann Arbor, MI Site: Atlanta, GA Joel Saper Frank Berenson Michigan Head Pain & Neurological Clinic Atlanta Headache Specialists 3120 Professional Drive 5887 Glenridge Drive, Suite 140 Ann Arbor, MI Atlanta, GA Phone: Phone: Fax: Fax: mwinters@mhni.com fberenson@atlantaheadachespecialists.com Site: Aurora, CO Site: Baltimore, MD Sita Kedia Jack Gladstein Children s Hospital Colorado Univ. of Maryland School of Medicine East 16 th Avenue, Box West Lombard St, Room 195-A Aurora, CO Baltimore, MD Phone: Phone: Fax: Fax: Kedia.sita@tchden.org jgladstein@peds.umaryland.edu Site: Bethlehem, PA Site: Birmingham, AL Robert Coni J. Ivan Lopez St. Luke s Neuroscience Center University of Alabama at Birmingham 826 Delaware Avenue th Avenue South, RWUH, Room 226 Bethlehem, PA Birmingham, AL Phone: Phone: Fax: Fax: conir@slhn.org jilopez@uab.edu

9 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Site: Chicago, IL Site: Chico, CA Alma Bicknese Stephen Forner Dept. of Pediatrics, Clinical Sciences Bldg. Stephen Forner, MD 840 South Wood Street 1405 Magnolia Drive, Suite B Chicago, IL Chico, CA Phone: Phone: Fax: Fax: bicknese@uic.edu sdfornermd@comcast.net Site: Cincinnati, OH Marielle Kabbouche Cincinnati Children s Hosp Med Center 3333 Burnet Avenue, MLC: Euclid Avenue Cincinnati, OH Cleveland, OH Phone: Phone: Site: Cleveland, OH* A. David Rothner Children s Hospital, The Cleveland Clinic Fax: Fax: marielle.kabbouche@cchmc.org rothned@ccf.org Site: Columbus, OH Site: Colorado Springs, CO Anne Pakalnis Randall Bjork Nationwide Children s Hospital Colorado Springs Neurological Associates 700 Children s Drive 175 S. Union Blvd, Suite 310 Columbus, OH Colorado Springs, CO Phone: Phone: Fax: Fax: Ann.Pakalnis@nationwidechildrens.org christenkutz@yahoo.com Site: Dallas, TX Site: Flint, MI Steve Linder Ahmad Kaddurah Dallas Pediatric Neurology Associates Hurley Research Center 7777 Forest Lane, Suite B116 One Hurley Plaza Dallas, TX Flint, MI Phone: Phone: Fax: Fax: DPNASusanne@aol.com akaddur1@hurleymc.com

10 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Site: Houston, TX Diana Lebron Texas Children s Hospital 6621 Fannin Street, MC East Stop 11 Road, Suite 26 Houston, TX Indianapolis, IN Phone: Phone: Site: Indianapolis, IN Keith Ridel Josephson Wallack Munshower Neurology Fax: Fax: dlebron@bcm.edu ridelkands@gmail.com Site: Kansas City, KS Site: Los Angeles, CA Jennifer Bickel Victoria Wexley Children s Mercy Hospital Wexley Headache and Medical Clinic 2401 Gillham Road Kansas City, KS N. Fairfax Avenue Phone: Los Angeles, CA Fax: Phone: jlbickel@cmh.edu Fax: Victoria.wexley@wexleymedical.com Site: Louisville, KY Site: Marshfield, WI Michael K. Sowell Hema Murali University of Louisville Health Sciences Marshfield Clinic Center Department of Neurology 1000 North Oak Avenue Room 113A, HSC Marshfield, WI Louisville, KY Phone: Phone: Fax: Fax: murali.hema@marshfieldclinic.org Michael.sowell@louisville.edu Site: Miami, FL Site: Mineola, NY Elza Vasconcellas Vijaya Atluru Miami Children s Hospital Winthrop University Hospital 3200 SW 60 th Court, Suite First Street Miami, FL Mineola, New York Phone: Phone: Fax: Fax: evasconcellos@nnpmd.com vatluru@winthrop.org

11 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Site: New York, NY Josh Cohen The Headache Institute, St. Luke Roosevelt Site: New York, NY M. Richard Koenigsberger Children s Hospital of New York at New York-Presbyterian Hospital Columbia University Medical Center 425 West 59 th Street, Suite 4A 180 Fort Washington Ave. Room 542 New York, NY New York, NY Phone: Phone: Fax: Fax: joscohen@chpnet.org Sd2489@mail.cumc.columbia.edu; Nar9018@nyp.org Site: Norfolk, VA Site: Phoenix, AZ L. Matthew Frank Marcy Yonker Eastern Virginia Medical School Phoenix Children s Medical Group 850 Southampton Ave., 3 rd Floor 1919 East Thomas Road Norfolk, VA Building B, 3 rd Floor Phone: Phoenix, AZ Fax: Phone: Fax: myonker@phoenixchildrens.com Site: Pittsburgh, PA Site: Plymouth, MN Nathan Bennett Gary Berman Preferred Clinical Research Clinical Research Institute, Inc. 140 Curry Hollow Rd, Suite Campus Drive, Suite 435 Pittsburg, PA Plymouth, MN Phone: Phone: Fax: Fax: nbennett@ppcp.org gdb@allergy-asthma-docs.com; cri@criminnesota.com Site: Rochester, MN Site: San Francisco, CA Kenneth Mack Peter J. Goadsby Mayo Clinic Pediatric Center University of California-San Francisco 200 First Street SW 1701 Divisadero Street, Suite 480 Rochester, MN San Francisco, CA Phone: Phone: Fax: Fax: mack.kenneth@mayo.edu GoadsbyP@neurology.ucsf.edu

12 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Site: Savannah, GA Eric Pearlman Children s Memorial University Medical Center 4700 Waters Ave 1401 Union Street Savannah, GA Schnectady, NY Phone: Phone: Site: Schenectady, NY Richard J. Simmons Schnectady Neurological Consultants, PC Fax: Fax: PearlEr1@memorialhealth.com Neuroresearch1401@yahoo.com Site: Seattle, WA Site: Seattle, WA Sheena Aurora Heidi Blume Swedish Medical Center Seattle Children s Hospital 747 Broadway 4800 Sandpoint Way, MS:B-5552 Seattle, WA Seattle, WA Phone: Phone: Fax: Fax: Danna.reyes@swedish.org Heidi.blume@seattlechildrens.org Site: St. Louis, MO Site: West Palm Beach, FL Deepa Arun Paul Winner Saint Louis University Premiere Research Institute 1438 South Grand Boulevard, Rm N. Congress Avenue, Suite 200 St. Louis, MO West Palm Beach, FL Phone: Phone: Fax: Fax: darun@slu.edu Pwinner777@aol.com Site: Worcester, MA Herbert G. Markley New England Regional Headache Center 85 Prescott Street, Suite 101 Worcester, MA Phone: Fax: markleyh@nerhc.org

13 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean STUDY STUDY TEAM MEMBERS* * Roster of additional study team members and their contact information is included in the Manual of Operations Clinical Coordinating Center Scott Powers, PhD, ABPP, FAHS Principal Investigator Cincinnati Children s Hospital Medical Center 3333 Burnet Ave, MLC Burnet Ave, MLC 2015 Cincinnati, OH Cincinnati, OH Phone: Phone: Andrew Hershey, MD, PhD, FAHS Principal Investigator Cincinnati Children s Hospital Medical Center Fax: Fax: Scott.Powers@cchmc.org Andrew.Hershey@cchmc.org Leigh Ann Chamberlin, RD, MEd Project Manager Cincinnati Children s Hospital Medical Center 3333 Burnet Ave, MLC Burnet Ave, MLC 2015 Cincinnati, OH Cincinnati, OH Phone: Phone: Susan LeCates, MSN, FNP Lead Coordinator Cincinnati Children s Hospital Medical Center Fax: Fax: LeighAnn.Chamberlin@cchmc.org Susan.LeCates@cchmc.org Leslie Korbee, BS, SI(ASCP) Regulatory Manager 3333 Burnet Ave, MLC 3015 Cincinnati, OH Phone: Fax: Leslie.Korbee@cchmc.org Data Coordinating Center Christopher Coffey, PhD Principal Investigator Clinical Trials Statistical and Data Management Center Department of Biostatistics University of Iowa 2400 University Capitol Centre 2400 University Capitol Centre Iowa City, IA Iowa City, IA Phone: Phone: Dixie Ecklund, RN, MSN, MBA Associate Director, DCC, Co-Investigator Clinical Trials Statistical and Data Management Center Department of Biostatistics University of Iowa Fax: Fax: christopher-coffey@uiowa.edu dixie-ecklund@uiowa.edu

14 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Research Pharmacy Denise LaGory, RPh Lead Investigational Pharmacist Cincinnati Children s Hospital Medical Center 3333 Burnet Ave, MLC 1011 Cincinnati, OH Phone: Fax: Denise.LaGory@cchmc.org Independent Medical Monitor David Dodick, MD Professor of Neurology, Mayo Clinic E. Shea Boulevard Scottsdale, AZ Phone: Fax: dodick.david@mayo.edu

15 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean PRÉCIS Study Title: The Childhood and Adolescent Migraine Prevention (CHAMP) Study Objectives: The global objective is: To determine the optimal medication for the prevention of migraines in children and adolescents. The primary objective is: To test if amitriptyline (AMI) and topiramate (TPM) are superior to placebo in reducing migraine frequency* in children and adolescents, ages 8 to 17 years old, inclusive, and to conduct a comparative effectiveness study of the two therapies. Specifically, we will determine if there is a difference in the proportion of subjects with a 50% reduction in migraine frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial between amitriptyline and placebo (Aim 1) and between topiramate and placebo (Aim 2). These hypotheses were powered to detect a 20 percentage point improvement from placebo is considered a minimum clinically meaningful difference by pediatric headache experts. 1 For the comparative effectiveness study, we will determine if there is a difference in the proportion of subjects with a 50% reduction in migraine frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial between amitriptyline and topiramate (Aim 3). This hypothesis was powered to detect a 15 percentage point or greater difference, considered clinically important by pediatric headache experts for comparison of two active interventions. Based upon the findings of this 3 in 1 clinical trial, our overall goal is to determine, using a specified a priori tiered approach, which of these therapies is superior in the prevention of migraine headaches. The first tier for that decision is the primary endpoint: 50% reduction rate for migraine frequency. Migraine disability will be used for the second tier decision. Tolerability will be used for the third tier. If superiority cannot be determined through this tiered approach, then the outcome of the trial would be that both therapies are efficacious and individualized clinical decisions based on subject presentation should guide the first choice in practice. All final recommendations must separately account for the safety data generated by this novel study. Safety concerns could trump the conclusions from any of the three tiers. * Migraine frequency is defined as the number of days with migraine for a given 4 week period. The secondary objectives are: To determine if amitriptyline and/or topiramate will result in a decrease in absolute migraine disability score (measured by PedMIDAS) from the end of the 4 week baseline period to the last 4 weeks of this trial compared to placebo.

16 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean To determine if amitriptyline and/or topiramate will result in a decrease in absolute migraine frequency days measured by the change in absolute migraine frequency from the 4 week baseline period to the last 4 weeks of this trial compared to placebo. To determine if amitriptyline and topiramate are well tolerated in subjects To determine if amitriptyline or topiramate differ from placebo on the occurrence of treatment emergent serious adverse events. Study Design: This is a phase III intent to treat, 3-arm, multi-center, randomized, double-blind, placebocontrolled safety and efficacy study. Every subject who is randomized will be considered part of the treatment group for analysis of the primary and secondary endpoints. Subjects will undergo a 4 week baseline period, receive treatment for 24 weeks (8 weeks titration, 12 weeks maintenance phase, 4 weeks endpoint evaluation), and a 6 week washout/end of study drug period (2 weeks wean, 4 weeks off drug), with timelines and interventions as indicated in the flow chart below: Screen Randomize Titrate Treat Washout/Final Visit 1 V 2 V 3,4 V 5, 6, 7 V 8 Phone 1 & 2 4 weeks 0 weeks 8 weeks 12 weeks 4 weeks 6 weeks Interventions and Duration: Placebo, Amitriptyline, or Topiramate. The intervention will include an 8-week titration, 16- week constant dose maintenance phase and 6 week wash-out/end of study drug. Sample Size and Population: The sample size will include 675 randomized subjects, 8 to 17 years old, inclusive, from up to 40 selected participating sites in the United States. Subjects will be randomized in a 2:2:1 fashion to receive either amitriptyline (n=270), topiramate (n=270), or placebo (n=135). Subjects will be stratified by age (8-12, 13-17) and the baseline number of migraines per month (episodic: 4-14, chronic: 15 or more). Because this strategy provides four strata, this study will not stratify the randomization by site.

17 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 1 STUDY OBJECTIVES 1.1 Primary Objective The primary objective is to conduct a three trials in one project that will use a specific a priori decision algorithm (see paragraph below) to determine the best choice prevention strategy for pediatric migraine. We plan to test if amitriptyline and/or topiramate are superior to placebo in reducing migraine frequency in children and adolescents age 8 to 17 and to conduct a novel comparative effectiveness study between amitriptyline and topiramate. Specifically, for the placebo-controlled aims (AMI vs. Placebo: Aim 1; TPM vs. Placebo: Aim 2) we will determine if there is a difference in the proportion of subjects who meet our primary outcome measure of a 50% reduction in migraine frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial. Migraine frequency is defined as the number of days with migraine for a given 4 week period. These hypotheses were powered to detect a 20 percentage point difference from placebo, an effect that is considered clinically meaningful by pediatric headache experts. 2 For the comparative effectiveness study (Aim 3), we will determine if there is a difference in the proportion of subjects with a 50% reduction in migraine frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial between amitriptyline and topiramate. This hypothesis was powered to detect a 15 percentage point or greater difference, considered to be clinically important by pediatric headache experts for comparison of two active interventions. In order to accomplish this objective, we will use an a priori decision making process that incorporates the novel data that will result from this 3 trials in one project. We propose a three tiered approach for analysis of the results of this trial to pick a winner among the three therapies tested. The first tier is based upon our primary endpoint, 50% reduction rate for migraine frequency during one month. This endpoint is the most relevant to current practitioners and is recommended as the key variable for migraine prevention medication trials by the International Headache Society (IHS). 3 It is also, in our experience, the primary outcome that families expect when they bring their children to our headache center. In our plan, there are four possible practice recommendations: (1) topiramate first choice because it is superior to placebo and amitriptyline on primary outcome; (2) amitriptyline first choice because it is superior to placebo and topiramate on primary outcome; (3) both therapies possible first choice and tie breaker is the secondary outcome of migraine-related disability because both are superior to placebo but were not different on primary outcome; and (4) neither therapy first choice because neither are superior to placebo. If scenario (3) occurs, and a recommendation cannot be made based upon the primary endpoint, we would need to go to a tie breaker, and we will utilize tier 2, our secondary endpoint of migraine-related disability. If one medication is superior to the other on this variable, it is the winner. If not, we would go to tier 3, tolerability. If one medication was better tolerated than the other, it would be the winner. Problems with tolerability would be defined as having a drop-out rate greater than 35% or a dropout rate that is statistically worse than the other therapy. If a winner

18 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean cannot be identified based upon tier 3 criteria, then the outcome of the trial would be that both therapies are efficacious and it would be individualized clinical decisions based upon subject presentation that would guide first choice in practice. Of course, recommendations will also take into account the safety data generated by this novel study. The specific aims are to: Aim 1: To test if amitriptyline (AMI) is superior to placebo in reducing migraine frequency and migraine-related disability Primary Hypothesis #1: Amitriptyline, at a target dose of 1 mg/kg/day, will result in an increased percentage of subjects meeting the primary endpoint compared to placebo Major Secondary Hypothesis #1: Amitriptyline also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to placebo Aim 2: To test if topiramate (TPM) is superior to placebo in reducing migraine frequency and migraine-related disability Primary Hypothesis #2: Topiramate, at a target dose of 2 mg/kg/day, will result in an increased percentage of subjects meeting the primary endpoint compared to placebo Major Secondary Hypothesis #2: Topiramate also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to placebo Aim 3: To compare the efficacy of amitriptyline and topiramate in reducing migraine frequency and migraine-related disability Primary Hypothesis #3: Topiramate will result in an increased percentage of subjects meeting the primary endpoint compared to amitriptyline Major Secondary Hypothesis #3: Topiramate also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to amitriptyline Aim 4: To prospectively and systematically estimate the safety and tolerability profiles of each therapy Major Secondary Hypothesis #4: Amitriptyline and topiramate will be well tolerated Major Secondary Hypothesis #5: AMI and TPM will not differ from placebo on the occurrence of treatment-emergent serious adverse events. We also expect that AMI and TPM will have overall safety profiles that do not preclude determination of first line therapy for clinical practice according to our decision algorithm.

19 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 2 BACKGROUND 2.1 Rationale for Study General Issues Pediatric Migraine Headache General Overview Prevalence Pediatric migraine is a prevalent disorder that results in significant disability for children and families and tremendous costs to society. Pediatric migraine is one of the five most prevalent childhood disorders in the U.S. 4-6 This disease affects up to 10% of children 4 and up to 28% of adolescents A Chronic Disease Pediatric migraine is a chronic illness that represents challenges to youth due to the episodic nature of painful attacks, as well as, the inter-event worry about the next attack and the recurrent, unpredictable interruptions in day-to-day life Cost of Pediatric Migraine Health care costs are 70% higher for a family with a migraineur than a non-migraine affected family, and direct medical costs for children with migraine are reported to be similar to those for adults. 8 The majority of children with migraine continue to experience migraines into adulthood, 9 and migraine has an annual economic impact in the U.S. of approximately $36 billion (direct medical costs + lost productivity). 10 Effective early treatment that significantly reduces migraine frequency and disability would change this trajectory of morbidity and costs. 1, Underfunded Despite Prevalence Lack of investment has severely limited headache research, and therefore, the development and testing of effective treatments (especially for children). There is a clear priority for research focused on migraine (NINDS PA ), and in particular, clinical trials of treatments for pediatric migraine. 2, 11 It has been reported that based upon NIH funding in 2007, an estimated 36 cents per person with migraine in the U.S. was spent for advancing scientific understanding of this disease and its treatment (compared to: $35 for Epilepsy, $49 for Stroke, and $372 for Parkinson s Disease). 12 Research focused on treatment of pediatric migraine is even more limited, resulting in a notable gap in the knowledge needed for evidence-based practice Neurologic Basis of Pediatric Migraine Migraine is a neurological disease and current understanding of its pathophysiology guides selection of prevention drug candidates. The pathophysiology of migraine is based on genetic inheritance of hypersensitivity that is influenced by environmental factors. 13 The genetic

20 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean evidence is most strongly supportive of a childhood inheritance pattern in 14, 15 contrast to the proportion of adults that develop migraine later in life. Migraineurs are hypersensitive to multiple stimuli including visual (photophobia), auditory (phonophobia), sensory (cutaneous allodynia), and cognitive (difficulty functioning) even between the individual attacks Prophylaxis in Childhood May Prevent Adult Neurologic Progression As headaches become more frequent, this hypersensitivity becomes synergistic with the migraines and leads to increasing frequency, sensitivity, and disease impact. 19 This point in adults appears to be a frequency of migraines greater than 3 per month. Recent studies have suggested that not only can untreated or ineffectively treated migraines become progressive, but may cause long-term neurological changes that can be quantified with neuroimaging Early intervention in childhood has the potential to interrupt this progression and eliminate long-term suffering and neurological changes Treatment for Pediatric Migraine Current Treatment for Pediatric Migraine A variety of medications with different mechanisms of action have been demonstrated in adults to be effective in migraine prevention. These include amitriptyline, the historical standard and most frequently utilized migraine prevention medication in clinical practice, and topiramate, the most recent medication proven effective for migraine prevention in adults. 1, 2, 11 Amitriptyline is both a non-selective re-uptake inhibitor (resulting in down-regulation in secondary neuron s receptor and thus desensitization) and also may act directly on inhibitory receptors (NMDA) and channels responsible for neurotransmission (sodium, L-type calcium and voltage-gated potassium channels). Topiramate s mode of action appears to have multiple mechanisms that also result in desensitization. These include potentiation of GABAergic transmission, inhibition of excitatory signaling via AMPA receptors, blockage of voltage dependent sodium channels and carbonic anhydrase enzyme inhibition all of which are inhibitory and lower a subject s hypersensitivity. Although these mechanisms are overlapping, they are distinct and it may be expected that there is a differential response between the agents. Based on the observations that untreated migraines may become progressive once they reach a frequency of 1/week or greater with diffuse hypersensitivity, treatment needs to utilize diffuse mechanisms to lower the hypersensitivity of the nervous system below this level. Both amitriptyline and topiramate have the potential to achieve this Practice Variation in Treatment for Pediatric Migraine Most children and adolescents with migraine do not receive prophylactic therapy because of the lack of placebo-controlled efficacy and safety

21 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean information, and even when they do, practice variation is large. 23 In collaboration with the NINDS Clinical Research Collaboration (CRC) and as part of our 2 year planning process for this application, we sent questions to participating neurology practitioners. Of 226 responders, 184 (81%) reported seeing children with migraine in their day-to-day practice. Of medications they reported using for prevention of childhood migraine; amitriptyline and topiramate were the most likely to be prescribed. Although these two medications are commonly used in clinical practice by pediatric headache specialists, including members of the American Headache Society (AHS), they lack the empirical data to be recommended as Class I evidence as recognized by the practice parameters of the American Academy of Neurology (AAN) because placebo-controlled data 2, 11 are necessary Current Medication Treatment for Pediatric Migraine Remains Empiric There is little agreement and a great deal of practice variation on the typical and maximum dosage of prevention medications used (around a 5- fold difference) and the time it takes to determine if a prevention medication works (as little as 2 weeks to more than 16 weeks; with about 2 out of 3 reporting less than 8 weeks). Efficacy, tolerability, and safety data from a clinical trial focused on how commonly used prevention medication therapies compare to placebo and to each other will help transform this field Impact on Future Treatment of Pediatric Migraine Relevance to (and impact on) clinical practice is the critical feature of the planned trial and the reason it has been designed to examine both medication versus placebo and comparative effectiveness questions. In our NINDS CRC survey, responders indicated that reduction in migraine frequency and reduction in migraine-related disability were the top outcomes for determining the effectiveness of prevention therapy, followed by low incidence of side effects. Over 97% of responders indicated that they would change prescribing practice if a medication was shown in a clinical trial to reduce migraine frequency by 50%. A minimum of 20 percentage point difference from placebo in this reduction effect was considered clinically meaningful. It was also determined via regular and extensive consultation with members of the American Headache Society s Pediatric Adolescent Special Interest Section over the past year that: (a) the optimal project in terms of relevance to practice would combine a placebo-controlled design with a comparative effectiveness study that was powered to provide clinically impactful data for each of the aims proposed; (b) subjects should be representative of those seen in practice, and hence be diagnosed with migraine and include the range of migraine frequency that typically leads to prophylactic treatment, including frequent, episodic patients (i.e., > 3 per month), as well as, chronic patients (i.e., 15 per month but not continuous

22 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean headache); (c) an absolute difference of at least 20% is the threshold needed for results of a placebo-controlled trial to change practice; (d) a less robust absolute difference of 15% would be an influential threshold in a comparative effectiveness study; and (e) while migraine frequency is the best primary endpoint, information about reduction in disability and tolerability would be useful in determining which drug to use as first choice therapy for childhood migraine. Results from this trial will thus be directly translated into evidence-based (not consensus-based and/or idiosyncratic) clinical care decisions by all practitioners that treat children with migraines including pediatricians, family practitioners, neurologists, and specialists Description of Use of Interventions Route and Formulations All medications for pediatric migraine prevention are administered orally Encapsulation and Pill Swallowing This study will use an over-encapsulation blinding approach with the study medications, amitriptyline, topiramate, and placebo. Subjects who cannot swallow pills at the time of the screening visit will be given a training session using behavioral techniques. Upon return for baseline visit, if the subject continues to be unable to swallow pills, the subject will be excluded from the study Regimen a) This study will use a b.i.d. regimen for study drug administration. b) The initial starting dose will be low during the beginning of titration. c) The dosage will be advanced during titration and held constant during the maintenance period, and deescalated and ended during the weaning period Intervention Period a) The initial intervention period will include a titration period with an 8 week dosage escalation during which the dosage of study drug may be advanced every two weeks. b) The maintenance period will follow the titration period and will consist of 16 weeks on the maximum dosage achieved during the titration period. c) The weaning period of two weeks and the follow up period of 4 weeks will follow the maintenance period. During the weaning period subjects dose will be de-escalated and may return to routine clinical care during the follow up period Need and Relevance for Clinical Trial Need for Study a) Migraine is considered by the World Health Organization to be in the top 20 causes of disability worldwide. 10 For children and adolescents,

23 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean migraine is a condition for which most providers do not offer medication therapy to control the disease and the related disability because the provider does not have a good choice. b) Clinical trials that demonstrate efficacy and safety of a prevention medication therapy have not been conducted with patients that are 1, 2, 11 representative of those who come to a medical provider. c) Pediatric headache experts are asking for placebo-controlled trials and comparative effectiveness studies specifically designed to provide the critical evidence needed to impact practice Relevance a) This trial represents the first large scale, pediatric migraine prevention, double blind, randomized, placebo controlled trial conducted in the U.S. b) For the first time, subjects enrolled in a pediatric migraine prevention medication clinical trial will be representative of those patients seen in day-to-day practice. Subjects in this trial will be from the age range of patients that often present for care from primary care providers, neurologists, and headache specialists (age 8-17). c) Migraine frequency will range from 4 per month to daily (but not continuous). The few clinical trials of prophylactic medications have almost always excluded subjects with more than 12 migraines per month. Yet, prevalence estimates of children and adolescents with 15 migraines per month in clinical settings range from 15% to 35% d) The stratification in this trial will create a balance of subjects with episodic and chronic migraine without specifically limiting the population to a group unrepresentative of typical practice. e) As requested by pediatric headache specialists, the results of this trial will be generalizable to the population of youth that present for care. 2.2 Supporting Data-Previous Evidence Supporting Data on Prevalence Headache and back pain are the two pain conditions afflicting society today. Migraine is a primary headache that can be severe and disabling. Migraine and chronic migraine are the most frequent recurrent headache disorder brought to medical attention. 27 It is estimated that over 12% of the population is afflicted by migraine with a female predominance of 3:1. 28 The disease is often first diagnosed in childhood with the most rapid increase in prevalence occurring in adolescence into the 20 s. In adults, there is growing evidence that untreated or ineffectively treated migraine can become progressive leading to neurological alterations as evident by neuroimaging changes 29 and can result in headaches that become refractory to treatment. These changes highlight migraine as a neurological condition that has a combined genetic and environmental pathophysiology. 13 Although genetic intervention is not yet feasible, both extrinsic and intrinsic environmental changes (via neurotransmission and

24 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean hypersensitivity alterations from neuroactive pharmaceutical treatments) are possible. Early intervention has the greatest potential to interrupt this progression and prevent long-term disability Supporting Data on Gender Stratification Migraine effects up to 10% of children 4 and up to 28% of adolescents. 7 This prevalence progressively increases from early childhood into the teenage years with a shift during adolescence to a female predominance (ages 3 to 7 years, 3%; age 7 to 11, 4% to 11%; ages 11 to 15+, 8% to 23%; up to 28% between ages 15 to 19) 5-7, 30. Recent population based studies have demonstrated that the incidence rate increases most rapidly during adolescence into young adulthood Supporting Data on Impact of Pediatric Migraine The impact of a disease can be measured both by the disease specific disability and by the influence on the subject s quality of life Migraine represents challenges in this due to its episodic nature with an impact during an attack, as well as, the anxiety and worry about the next attack. 27 The impact of childhood migraine is further complicated by the child s migraine influencing the parents 8, 10, 23, 35 lives through lost work and social activities Supporting Data on Disability Furthermore, as migraine headaches have a genetic component, the parent s migraine is likely to have an effect upon the child s health that may have a bidirectional influence on disability. Migraine-related disability is measured through the disease-specific loss of function. 33 This includes lost school and work days and lost social activities as well as the ability to fully participate in these activities. Various instruments have been developed to assess disability in adult migraine. The PedMIDAS was developed to assess the impact of migraine in children and adolescents. 33 This tool has been validated and shown to be very sensitive to treatment effects Supporting Data on Quality of Life Quality of life instruments measure the overall disease non-specific effects on a subject s life. Using the PedsQL, we have demonstrated that the impact of migraine on the lives of children and adolescents is clinically significant, with migraine affecting a child s life similarly to childhood cancer, cardiac disease, and rheumatic disease. 31 This observation mirrors findings seen in adults using SF PedMIDAS and PedsQL measure the impact on an individual s life. Population studies have demonstrated this impact has significant societal implications. In 1989, it was estimated that over 130,000 school days are missed every two weeks due to headache with over 3 million bedridden days occurring in the U.S. per month, thus generating a significant educational impact Supporting Evidence on Societal Impact

25 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean The societal impact on the family can be measured through parental short-term disability and work absenteeism with 11% and 35% more of each of these in families with a child with migraine compared to non-migraine families. 8 In adults, migraine results in significant disability and tremendous cost to society. Estimates on loss of productivity due to migraine is $13 billion per year ($16.7 billion in 2009 dollars), $8 billion of which is due to work absenteeism Supporting Evidence on Genetic Factors The pathophysiology of migraine is based on genetic inheritance and environmental factors. 13 The influence of genetic factors is more significant for children in contrast to adults that develop migraine later in life. 14, 15 Population, twin, and family genetic studies suggest that the genetic influence is 60-70% with a mixed inheritance pattern that has dominant, recessive, and maternal patterns. 13 Neurophysiology studies have demonstrated that migraineurs have a hypersensitive nervous system that can be measured directly via physiological tools (MEG, visual stimulation, auditory stimulation) or indirectly through patient reports of photophobia, phonophobia and cutaneous allodynia with central sensitization. 17 In females, migraine can be further exacerbated by hormonal influences with over 50% of adolescents and adult females have menstrual-related migraine that appears to be due to triggering of migraine when estrogen levels drop Supporting Evidence from Neuroimaging Studies Neuroimaging studies have demonstrated that if untreated or ineffectively treated, migraine can lead to increased iron deposition in deep brainstem structures a sign of sustained increased metabolic activity, and destruction of cortical tissue that appears to be irreversible. 20, 29 Based on these pathophysiological observations, minimizing the neurohypersensitivity of a migraineur and thus diminishing the attack frequency has a significant potential to prevent this neuroprogression Supporting Evidence from Practice Parameters Practice parameter guidelines published in 2004 on the pharmacological treatment of pediatric migraine identified only one agent (flunarizine, not available in the 37, 38 U.S.) with adequate Grade I evidence for the prevention of pediatric migraine. Several open labeled and small studies did demonstrate the relative effectiveness of a limited number of anti-depressant medications (notably amitriptyline), 39 antiepileptic medications (including topiramate 40 ), blood pressure medications (including calcium channel blockers flunarizine, and beta-blockers), 37 and antiserotonin agents. 37 This practice parameter highlighted the lack of large-scale definitive studies and called for an increase in multi-centered, placebo-controlled trials to examine the safety, tolerability, and efficacy of preventive medications. 2

26 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Subsequent to this practice parameter, a few small, randomized studies have been added including divalproate (n=300) 41 and topiramate (n=29 50 mg, n= mg, and n= mg) with only the 100 mg dose of topiramate having a significant benefit. 40, 42 As a result, neurologists and other care providers who see pediatric headache patients in everyday practice have little evidence from which to make critical treatment decisions, particularly with prevention medications. 27 This lack of knowledge around medications represents a critical barrier to improving preventive and treatment outcomes for children and adolescents with migraine pain Supporting Evidence Summary Despite the increasing prevalence of pediatric migraine, its substantial impact on daily functioning and quality of life, and the potential for long-term neurophysiological changes, there are few clinical trials focused on the prevention of pediatric migraine. 43 Placebo-controlled trials and comparative effectiveness studies are critically needed to advance this field and to change clinical practice. 3 STUDY DESIGN 3.1 Overview of Study Design This study is an intent to treat, 3-arm, randomized, double-blind, parallel group, placebocontrolled trial to test amitriptyline and topiramate with 675 children and adolescents between age 8 and 17 with migraine recruited from up to 40 sites across the U.S. Subjects will be randomized in a 2:2:1 fashion (AMI; TPM; Placebo). Every subject who is randomized will be considered part of the treatment group for analysis of the primary and secondary endpoints. Key endpoints will be migraine frequency, migraine-related disability, tolerability, and safety. Subjects will be involved for approximately 34 weeks in the various phases of the study, with visits, time lines, and interventions as indicated in the flow chart: Screen Randomize Titrate Treat Washout/Final Visit 1 V 2 V 3,4 V 5, 6, 7 V 8 Phone 1 & 2 4 weeks 0 weeks 8 weeks 12 weeks 4 weeks 6 weeks 3.2 Overview of Study Procedures After informed consent (and assent where appropriate)) has been obtained, a 4 week baseline period will occur with diary collection. If eligibility criteria are met, the subjects will be randomized to one of 3 treatment arms and will enter into an 8-week titration period with study drug. This titration phase will be modifiable based on effectiveness and tolerability (see Section 5.3). This will be followed by a 16-week constant dose or maintenance phase. At the conclusion of maintenance, a 6 week period will ensue to wean off medication (2 weeks) and finalize study (then 4 weeks off drug). A final safety phone call will occur 4 weeks after the completion of the wean off period. Subjects will be involved with the study for approximately 34 weeks.

27 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Safety labs will be collected along with repository specimens at three intervals during the study. Physical exams will be conducted at each study visit. A PedMIDAS disability score will be collected every 3 months during the study. Neurological exams will be conducted at the screening and baseline exams, at the end of dose titration, at the end of the maintenance period and at the study endpoint. Electrocardiograms (ECG) will be collected at screening and after the completion of of dose titration. A targeted symptom questionnaire will be conducted at every visit and a brief version of the symptom questionnaire will be conducted by phone between visits. Subjects describing suicidal ideation in response to the symptom questionnaires will be directed immediately for psychiatric evaluation and management of the event. The Columbia Suicide Severity Rating Scale instruments will be used to score any subject reports of suidiality. Adverse events and the use of concomitant medications will be recorded at each study visit. Study drug compliance will be ascertained by pill count and subject report on the daily headache diary and batched biosample anlysis. Questionnaires will be completed by subjects at screening, the end of titration, and at the study endpoint. 3.3 Study Visit and Procedure Schedule Table 3.3 summarizes each study visit and the procedures which will be completed.

28 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Table 3.3 Study Visit and Procedure Schedule. Study Visits Informed Consent Screening Visit 1 day-28 to Day 0 X Baseline and Randomization Visit 2 *** Day 0 Visit wks Titration + Maintenance Endpoint $ Visit wks Visit wks Visit wks * Adverse Events will be solicited using the Symptom questionnaires followed with the C-SSRS Baseline or Since Last Visit questionnaire if needed. + Titration of study medication will be managed by the site PI following our protocol which allows for increasing dose, holding dose, or decreasing dose based upon treatment emergent side effects. Using this approach, a final tolerated dose will be obtained by week 8 or week 10. Additional Titration Adjustment Visits conducted by phone or in person are described in section $ End of trial medication management will also be done by the site PI following our protocol. ** The ECG at Visit 5 could show abnormal results, specifically a lengthening of the QT interval that would lead to stopping study medication and early termination due to safety concerns. Full details about the dosing schedule, titration plan, study blinding, and handling of study drug is in Section 5. *** There will be a phone visit after Visits 2-7 at 14 +/- 4 days to collect adverse events using the symptom questionnaire. Visit wks Baseline Medical History X Prior Medications X Urine Pregnancy Test X X X X X X X X Visit wks Adverse Events * X X X X X X X X Headache Diary X X X X X X X X PedMIDAS / HIT-6 X X X Questionnaires X X X Vital Signs & Demographics X X X X X X X X Concomitant Medications X X X X X X X X Physical Exam X X X X X X X X Neurological Exam X X X X X CBC X CHAMP Metabolic Profile X X X Drug Adherence Sample X X CHAMP Biorepository samples X X Electrocardiogram (ECG)** X X** Inter visit phone call*** X X X X X X Drug Accountability X X X X X X X Study Drug Administration X X X X X X X Weaning & Off Drug Phone Visits + 26 wks & + 30 wks Weaning-2 wks Off Drug-4 wks

29 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 4 SELECTION AND ENROLLMENT OF SUBJECTS 4.1 Inclusion Criteria Diagnosis: Migraine with or without aura (International Classification of Headache Disorders, 2 nd Edition (ICHD-II) or chronic migraine (ICHD-II revised.) Frequency: Migraine frequency based upon prospective headache diary of 28 days must be 4. Migraine frequency defined as any migraine during one day in the 28 day baseline period* PedMIDAS: PedMIDAS Disability Score > 10, indicating at least mild disruption in daily activities and < 140, indicating extreme disability that may require more comprehensive, multi-component therapy Age: Females or males 8-17 years, inclusive * Migraine frequency is defined as the period from the onset to the stop time of painful migraine symptoms not to exceed 24 hours with the clock starting at midnight. If painful symptoms last longer than 24 hours, this is considered a new and distinct migraine headache. If painful symptoms recur within 24 hours of initial onset, this is considered part of the initial migraine episode and would be counted as one migraine. 44, 45 See section for further definition. 4.2 Exclusion Criteria Continuous migraine defined as an unrelenting headache for a 28 day period Weight less than 30 kg or greater than 120 kg Unwilling to avoid taking non-specific acute medication such as NSAIDS (e.g., ibuprofen), more than 3 times per week, or migraine specific acute medications such as triptans more than 6 times per month Currently taking other prophylactic anti-migraine medication within a period equivalent to 2 weeks of that medication before entering the screening phase, or the use of Botulinum toxin (Botox ) within 3 months of entering the screening phase Subjects who have previously failed an adequate trial of AMI or TPM for prophylaxis of at least 3 months duration at doses recommended for migraine relief because of lack of efficacy or adverse events* Current use of disallowed medications/products: opioids, antipsychotics, antimanics, barbiturates, benzodiazepines, muscle relaxants, sedatives, tramadol, nutraceuticals, SSRIs, or SSNRIs Known history of allergic reaction or anaphylaxis to AMI or TPM

30 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Abnormal findings on ECG at baseline, particularly lenghtening of the QT interval greater than or equal to 450 msec Subject is pregnant or has a positive pregnancy test Subject is sexually active and not using a medically acceptable form of contraception Diagnosis of epilepsy or other neurological disesases History of kidney stones Inability to swallow pills after using behavioral techniques if indicated between screening visit and baseline visit** Present psychiatric disease as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4 th Edition (DSM IV) (e.g. psychosis, bipolar disorder, major depression, generalized anxiety disorder), alcohol or drug dependence, or documented developmental delays or impairments (e.g., autism, cerebral palsy, or mental retardation) that, in the opinion of the site investigator, would interfere with adherence to study requirements or safe participation in the trial Any and all other diagnoses or conditions which in the opinion of the site investigator, that would prevent the patient from being a suitable candidate for the study or interfere with the medical care needs of the study subject * Previously failed an adequate trial of AMI or TPM is defined as: dosage of 1mg/kg/day of AMI or 2 mg/kg/day of TPM; trial of at least 3 months duration; efficacy of having at least a 50% decrease in migraine frequency in response to drug therapy; or unable to tolerate taking the medication due to treatment-related side effects. ** Subjects who cannot swallow pills at the time of the screening visit will be given a training session using behavioral techniques. Upon return for baseline visit, if the subject continues to be unable to swallow pills, the subject will be excluded from the study. 4.3 Study Enrollment Procedures Identification of Subjects The primary methodology for identifying and recruiting subjects for this study will be through identification of potential subjects from pediatric headache medicine specialty practices, pediatric neurology practices or adult headache medicine or neurology practices that treat children and adolescents. This will include some sites that are part of the NINDS Clinical Research Consortium which have contracted to conduct the study. In order to reach our expected enrollment and based on our survey of interested sites, it is anticipated that the research sites would identify at least 4 subjects per site per month, and be able to enroll at least 1 subject every 2 months.

31 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean We anticipate that complete enrollment will be achieved at the 48 month point after the grant award is received. If we need the full 48 months, the final subjects will complete the trial in Year 5, at the 56 month point. The final months of the 5- year period will be dedicated to final site closeout tasks, data management, and data analysis. Within each research site, methods and processes for identifying patients will be individualized, but conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. To support our recruitment and retention, several marketing tools will be employed: development of print media, and web postings. Print media to support recruitment efforts will include a study introduction letter from the coinvestigators, a study flyer, and study tear off pads. The flyer and tear off pads will be made available to study research sites for use in public places, medical practices, and research centers. Web postings will be developed for use on internet sites such as clinicaltrials.gov, the NINDS web site, and other web locations. Mailings of the study introduction letter and brochure to academic and private pediatric practices may also be employed to ensure that private pediatric neurology practices are aware of the study. Individual sites may choose to conduct recruitment events to provide information to potential subjects and their parents. Recruitment events may also be conducted in tandem with professional society meetings to raise awareness of the trial among practitioners. These strategies may include the recruitment of additional research sites and investigators if the initial sites under perform in recruitment or the use of specialized medical research websites for promotion of the study Documentation of Ineligibility Screen failures will be documented on the source worksheets with the supporting data accompanying the eligibility screening form. The screen failure will be documented on the electronic case report form (ecrf). Reports detailing the reasons for screen-failure and non-participation of eligible subjects will collected from the research sites submissions to the Data Coordinating Center (DCC) using the ecrf. These reports will be reviewed by the study chair to determine if the exclusion criteria require revision in order to make the trial accessible to families and study subjects. The procedure for documentation of ineligibility or non-participation will include a completed eligibility checklist for each consented study subject. The study sites will use the eligibility checklist to record the specific item that excludes a study candidate from participation. In addition, the sites will submit a weekly screening report electronically to the CCC.

32 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Method for Obtaining Informed Consent The informed consent and the assent will be provided to the study subject and the parents for review. After allowing adequate time for review, the subject and parents will have the opportunity to ask questions and receive answers. When all questions have been answered, the consent and assent will be signed and a signed copy provided to the subject and parents. This will all be conducted before any study interventions are undertaken Procedure for Assignment of Randomization Randomization will be stratified by age (8-12 and 13-17) and number of headaches per month (episodic: 4-14, chronic: 15 or more). Because this strategy provides four strata, we have elected not to stratify the randomization at each site. The Data Coordinating Center (DCC) will generate a randomization table for each of the strata using a permuted block design with random block sizes. Briefly, after completion of all eligibility requirements and the determination of eligibility by the investigator, the ecrf will be completed by the study coordinator. The completion of this ecrf will trigger a response from the DCC to randomly assign a treatment group in keeping with the subject s age stratification. The notification of treatment assignment will then be delivered electronically to the central research pharmacy and to the site study staff. The study staff will receive a blinded notification of the bottle numbers to supply the assigned treatment to the subject s family to begin study drug titration Study Drug Supply Each site, upon initiation, will receive a startup supply of study medication that will allow enrollment of subjects into each treatment arm. This will consist of study drug, appropriately labeled to maintain blinding and corresponding to the treatment assigned from the DCC, of placebo, amitriptyline, or topiramate. Upon completion of the eligibility ecrf and at regular intervals, the central pharmacy will initiate a shipment that will re-supply the site with additional study drug. All AM doses will be prepared with identical over-encapsulation with the same color capsules. All PM doses will be prepared in the same manner with a different color capsule. For AM dosing, subjects will be instructed to take the study medication consistently with breakfast. For PM dosing, subjects will be instructed to take the study medication consistently at dinnertime. In instances when the subject or the subject s family s schedule interferes with mealtime dosage, the site PI may recommend that the time of study medication administration be adjusted to meet needs of the individual study family. For example, if a subject has numerous evening activities that interfere with dinnertime, the site PI may recommend that the evening dose of study medication be taken when the subject returns home for the evening.

33 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean The DCC, the Central Investigational Drug Service (IDS) staff, and the Central Laboratory staff will be unblinded to treatment assignment. Study staff at the site will remain blinded and only receive an instruction to deliver a specific bottle number for the subject upon randomization. The CCC staff will also remain blinded. 5 STUDY INTERVENTIONS 5.1 Interventions, Administration, and Duration The following refers to study subjects with pediatric migraine: Frequency of administration Each of the three interventions (amitriptyline, topiramate, and placebo) will be administered twice daily at home, to be taken by mouth with or without food under the supervision of the subject s parent or guardian. To maintain blinding, all subjects will receive 1 matching capsule at each dose (2 capsules/day) during the 8-week titration period. Each capsule will contain either topiramate, amitriptyline, or placebo, depending upon the group to which a subject is assigned randomly. Additionally, during titration and maintenance phase, subjects randomized to amitriptyline will receive a placebo capsule to be taken in the morning in order to maintain the blinding.

34 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Amitriptyline Brand to be Used Amitriptyline (Mylan Pharmaceuticals, Inc.) Formulations This study will use drug manufactured by Mylan Pharmaceuticals, Inc. in the following strengths: 10mg, 25 mg, 50 mg, 75 mg, 100 mg tablets which will be prepared through pill cutting and over-encapsulation with gel capsules. Table details the dosing schedule by weight for Amitriptyline during weeks 0-8. Table Amitriptyline Dosing Schedule by Weight for Weeks 0-8. Weight Group (kg) Weight Low (kg) Range High (kg) Start at Week 0 Start at Week 2 Start at Week 4 Start at Week 6 Start at Week 8 AM PM AM PM AM PM AM PM AM PM Potential Adverse Events Amitriptyline has a number of side effects. Refer to Section for a list of expected adverse events.

35 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Topiramate Brand to be Used Generic Topiramate (Teva Pharmaceuticals, Inc.) Formulations This study will use 25 mg and 50 mg tablets which will be prepared through pill cutting and over-encapsulation with gel capsules. Table details the dosing schedule by weight for Topiramate during weeks 0-8. Table Topiramate Dosing Schedule by Weight for Weeks 0-8. Weight Group (kg) Weight Low (kg) Range High (kg) Start at Week 0 Start at Week 2 Start at Week 4 Start at Week 6 Start at Week 8 AM PM AM PM AM PM AM PM AM PM Potential Adverse Events Topiramate has a number of side effects. Refer to Section for a list of expected adverse events.

36 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Placebo Placebo Capsule The placebo will be manufactured by the Central IDS and consist of 500 mg of lactose powder contained in gel capsules Formulations All placebo capsules used in this study will contain the same amount of ingredients with gel capsules. Table details the dosing schedule by weight for placebo during Weeks 0-8. Table Placebo Dosing Schedule by Weight for Weeks 0-8. Weight Group (kg) Weight Low (kg) Range High (kg) Start at Week 0 Start at Week 2 Start at Week 4 Start at Week 6 Start at Week 8 AM PM AM PM AM PM AM PM AM PM Potential Adverse Events There are no expected adverse reactions associated with taking placebo.

37 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 5.2 Double Blind Treatment Phase The double blind treatment phase for this study is 24 weeks (8 week titration, followed by a 16 week maintenance period), followed by a 6 week weaning off period (2 week wean, 4 week off drug (no medication)). 5.3 Titration Period Overview of Titration Period A subject s dosage may be held or decreased every two weeks during the titration period if the subject experiences dose limiting side effects that in the individual site investigator s opinion warrant a slower titration.the plan for dosage escalation for amitriptyline, topiramate, and placebo are outlined in Tables Site Investigator s Role in Dosage Titration The site investigator will recommend each increased, decreased, or stable dosage based upon the results of the evaluation during the study visit and the review of the targeted symptom questionnaires from phone and study visits. The revised dosage for the next study period will be communicated to and implemented by the Investigational Research Pharmacy at the site. The documentation of the dosage adjustment and communication of the adjustment to the Investigational Research Pharmacy will be retained in the source and ecrf Dosage Escalation Guidelines Medication Dispensing Medications will be dispensed in a manner to maintain the blind. The study drugs, AMI, TPM, and placebo will be encapsulated so that the AM and PM doses are color coded differently. Study drug will be dispensed from previously prepared bottles based upon treatment assignment and the subject s weight Treatment Kits Treatment kits will contain a 4 week supply of study drug, plus enough drug to cover the visits windows with a dosage increase every two weeks during titration phase Subjects Who are Unable to Advance During Titration If a subject has difficulty tolerating a given dose during the titration period, the investigator may: a) Maintain the study medication at the current dose for: an additional 2 weeks and then increase the dose, or the remainder of the titration and maintenance periods; OR b) Reduce the study medication to the previously titrated dose for:

38 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean an additional two weeks and then re-titrate the dose, or maintain dosage for the remainder of the titration periods subjects who require a dosage decrease at week 2 must be withdrawn from study drug exposure and move to early termination (Section 6.3.3) subjects who require a decrease below the baseline dosage at any interval must be withdrawn from study drug exposure and move to early termination (Section 6.3.3) subjects may only receive one dosage reduction during titration c) For subjects who have been unable to advance to their maximum dosage by week 8, they may advance one more dosage at week 10.

39 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Figure Titration Scenarios. Start Maintenance Evaluation Wean a. Expected Titration b. Titration withhold (solid) or delayed (dashed) c. Titration with reduction

40 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Figure Dosing Titration Plan by Bottle Dispensed

41 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Communication Regarding Dose Changes If the investigator recommends a change in dose, this will be communicated electronically to the DCC, which will communicate the dosage change to the Investigational Research Pharmacy. A revised bottle number will be provided to the study site staff in a manner that maintains the double blind. Such changes will be reviewed by study monitoring staff for data quality assurance and safety monitoring. 5.4 Maintenance Period Overview of Maintenance Period During the 16-week maintenance period, subjects will continue to receive 2 capsules daily (divided dose) containing either topiramate (2mg/kg/day or the maximum dose achieved during the titration period), amitriptyline (1mg/kg/day or the maximum dose achieved during the titration period plus a placebo capsule), or placebo given in a divided dose of 1 capsule twice daily. The dosage of study medication should remain constant during the maintenance period Dosage De-Escalation during Maintenance Period If a subject experiences unacceptable tolerability problems during maintenance phase, no further increase or decrease of dosage is permitted. Premature discontinuation of study therapy will be documented in the source binder and ecrf. These subjects will be removed from study drug exposure and move to early termination (Section 6.3.3) Plan for Maintenance Period Dosage The plan for maintenance period dosage by weight is outlined below in Table Some subjects may not progress to the planned maximum dosage during titration and will be maintained during the maintenance period on the highest dosage achieved during titration.

42 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Table Maintenance Period Dosage. Weight Weight Range Week Week Group Low High (kg) (kg) (kg) Placebo AM PM Amitriptyline AM PM Topiramate AM PM Weaning Period Overview of Weaning Period All subjects who complete or who discontinue study medication during the maintenance period will enter the weaning period. Subjects who do not complete the titration period and are removed from study drug exposure and progress to early termination will undergo weaning if they have progressed to one dosage increase beyond the baseline dosage for their weight group, or been on study drug for three full weeks Plan for Dosage De-Escalation during the Weaning Period Subjects will have their weekly dosage tapered at a rate of approximately 75% of the dose achieved during maintenance during the first five days, followed by approximately 50% for the next five days, and approximately 25% the final four days. To achieve this end and to maintain the double blind, all subjects will continue to receive 2 matching capsules each day.

43 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Plan for Weaning Period Dosage The plan for weaning period dosage, based upon the maximum dosage achieved, is outlined in Table For subjects who have been unable to progress to the predicted maximum dosage, the table includes the lower possible dosages available during titration and maintenance. Subjects will have their weekly dosage tapered at a rate of approximately 75% of the dosage achieved during maintenance during the first five days, followed by approximately 50% for the next five days, and approximately 25% the final four days. To achieve this while maintaining the double blind, all subjects will continue to receive 2 matching capsules each day. Subjects who have been on study drug less than three full weeks will not require a weaning period. Table Weaning Period Dosage Plan Maximum dosage achieved Week Week Week Week Week Week Week Week Day Day Day Day Day Day Placebo AM PM AM PM AM PM AM PM No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug Amitriptyline AM PM AM PM AM PM AM PM No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug Topiramate AM PM AM PM AM PM AM PM No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug

44 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 5.6 Concomitant Interventions Allowed Rescue Medications For acute headache treatment, subjects will be educated on effective use of allowable rescue medications to stop individual attacks. This will be guided by each site investigator, but will include the importance of early treatment with doses of medications demonstrated to be effective in acute headache management, while avoiding the development of medication overuse. With the exception of almotriptan (for year olds) and rizatriptan (6-17 years old), these medications have not been approved by the FDA for the acute treatment of migraine in children and will need to be guided by the individual site investigators. Therapeutic options will be available for use at the discretion of the site investigator. 5.7 Prohibited Interventions Acute Medications Treatment with narcotic medications is prohibited, including butalbital containing compounds and codeine compounds and derivatives Preventative Medications During the trial, no other preventative medication should be used including pharmaceutical, nutraceutical or any herbal treatments suspected to have headache prevention effects (i.e., stand alone supplements of Riboflavin, CoEnzyme Q10, and Magnesium.). Psychological intervention for headaches including biofeedback assisted relaxation therapy, or any other treatments intended for headache prevention proven or unproven (i.e., acupuncture, chiropractic manipulation) are also prohibited. Subjects who are using these agents at the time of consent may elect to stop usage and add an additional period of two weeks to the screening period to allow for wash out of these medications, supplements or therapies. The screening period may extend to -45 days before day 0 for subjects who require washout from preventative medications or supplements after consent. For these subjects, the 28 day period immediately prior to Visit 2 will be considered the baseline period for purposes of headache diary collection Specifically Excluded Medications Anticonvulsants, antidepressants including other non-selective and selective serotonin receptors, tranquilizers, transcutaneous stimulators, acetazolamide, calcium channel blockers, methysergide maleate, corticosteroids (except for inhaled steroids for treatment of the nasal mucosa, sinuses, bronchii, and lungs), beta-adrenergic blocking medications, monoamine oxidase inhibitors, chronic NSAIDs or COX inhibitors, lithium carbonate, flunarizine, nonstable doses of stimulant medication, antipsychotics (past or current), thiazide diuretics, injections for headaches (including nerve blocks and botulinum toxin), or cyproheptadine.

45 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 5.8 Handling of Study Interventions The distribution of study drug to each research site, and the directions for storage and drug accountability procedures are addressed in more detail in the pharmacy section of the Manual of Operations. Study drug will be purchased in bulk by the central pharmacy for the preparation of treatment bottles. Study drug will be provided to the research sites in blinded treatment bottles. The treatment group assignment will be retained at the central pharmacy. The bottles will contain a one month supply of study drug in four treatment bottles: an AM and a PM bottle for each two week period of supply, plus additional tablets to accommodate the supply needed for titration management or treatment during the +/- 7 day visit windows. Each study site will be supplied with enrollment bottles for all weight ranges of study subjects for the initial dosing period occurring at randomization on Visit 2. Additional bottles will be supplied to the sites as needed during titration and maintenance. The study drug will be provided in an over-encapsulated form, in order to maintain blinding to treatment assignment by study staff and subjects. Unused study drug will be retained at the research site until all drug accountability procedures have been completed for the treatment bottles. Unused study drug may be destroyed per the research site s Standard Operating Procedures (SOP) after drug accountability records have been monitored and all accountability resolved, or returned to the central pharmacy if there is no SOP in place at the research site. 5.9 Adherence Assessment Adherence assessments will be conducted by the pill count method and performed by the study coordinator at the time of each study visit. Drug therapy compliance will be documented by the subject or subject s parent on the daily headache diary. The daily headache diary will be returned along with the study drug for verification of compliance at every study visit after randomization until the completion of washout. The study coordinator will complete the adherence assessment and instruct the subject or subject s parent about the study drug dosage for the next treatment period. Non-compliance issues will be reported to the site investigator during the study visit prior to the administration of further study drug. Adherence issues that are detected at the study visit will be addressed with the subject and parent at the study visit. If compliance cannot be secured, the subject may be withdrawn from study drug exposure by the site investigator move to early termination (Section 6.3.3). Adherence will also be monitored by the use of batch analysis of biosamples collected at two intervals during the study and assayed for the presence of amitriptyline or topiramate Option for Future Re-contact of Subjects by Central Coordinating Center The principal investigators would like to maintain the option for future re-contact of

46 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean study subjects after completion by the subject or termination of the study. The purpose for re-contact would be to invite participation in the conduct of ancillary studies with a subpopulation of study subjects. Optional future studies may include durability of treatment effect or other future investigations with biomarker analysis, or reporting of an unanticipated results from Biorepository analysis. An optional consent for re-contact will be included in the study informed consent and assent templates. 6 CLINICAL AND LABORATORY EVALUATIONS Table 3.3 summarizes the study visit and procedure schedule. A detailed listing of study procedures follows. 6.1 Informed Consent Informed consent will be obtained prior to conducting any study procedures. The informed consent process is described in Section under Definitions of Evaluations. 6.2 Evaluations Subjects, who meet ICHD-II for migraine with or without aura or ICHD-II revised for chronic migraine and meet all other inclusion/exclusion criteria, must have the following procedures completed during the Screening Visit after signing the informed consent and prior to study entry. The screening procedures may be conducted over 2 visits within 7 days if desired by the individual site investigator Screening Visit 1 (Up to Day-45 but no less than Day-30) 1. Completion of informed consent and assent (if applicable) prior to initiation of study procedures 2. Obtain urine pregnancy test for all females of childbearing potential. 3. Review baseline medical history; headache history including acute and prophylactic use and current regimen 4. Document all concomitant medications including prescribed over the counter and nutraceutical supplements 5. Determine if subject is able to swallow pills. Subjects who cannot swallow pills at the time of the screening visit will be given a training session using behavioral techniques. 6. Administer questionnaires (BRIEF, CDI, FDI, HADS, PedsQL) 7. Obtain vital signs (height, weight, heart rate, blood pressure) 8. Obtain demographics 9. Perform physical examination 10. Perform neurological examination including visual field exam 11. Obtain clinical laboratory tests as follows: Hematology A CHAMP Comprehensive Profile of liver and renal analytes Biorepository samples (DNA, serum, and RNA) 12. Obtain ECG. The ECG will be confirmed by the site investigator and then sent to the CCC for independent interpretation. The criteria for elongation

47 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean of the QT interval will be a QT interval greater than or equal to 450 msec 46. If the central reader determines that the QT interval has been elongated and that elongation or any other serious ECG abnormality would put the subject at risk for an adverse event, then the subject would be determined to be ineligible. 13. Instruct subject and parent/guardian to discontinue all of the subject s medications being used for migraine prevention as discussed in section 5.7 for at least 2 weeks prior to start of the prospective baseline period. If the subject is not taking any migraine preventive medication they may immediately enter the Prospective Baseline Period. Subjects who are taking preventative migraine medications and who elect to discontinue the use of the medications or supplements may extend the baseline screening period to day -45 before the Visit 2 assessments. In this case, the 28 day period immediately prior to Visit 2 will be considered the baseline period for purposes of headache diary collection. 14. Instruct subject and parent/guardian with healthy habits (adequate hydration, sleep, exercise, regular meals with healthy eating) and headache diary completion Randomization - Visit 2 (30 Days + 7 days) Visit 2 will be conducted no less than 30 days after Visit 1 (Screening Visit) Eligibility Determination-Headache Diary Collect and review headache diary to determine migraine frequency eligibility (Eligible: > 4-30 migraine days a month). Subjects who report a continuous headache of 28 days of duration will be determined ineligible. If the migraine frequency is appropriate to meet eligibility criteria and there are no laboratory findings restricting eligibility (i.e., identification of significant abnormalities, that in the site investigators opinion, would restrict treatment, evidence of illicit drug use, or pregnancy), the PedMIDAS disability questionnaire will be presented and scored. If the PedMIDAS score is > 10 but < 140, the visit will proceed. If these criteria are not met, the subject will be determined to have failed screening. Subjects who failed to meet eligibility criteria based on the headache diary or PedMIDAS score may be re-evaluated for study eligibility at the discretion of the site investigator after a minimum of three months if migraine frequency and PedMIDAS disability scores have changed. Confirm that subjects who could not swallow pills at the time of the screening visit have been successful with pill swallowing training. If the subject continues to be unable to swallow pills, the subject will be excluded from the study.

48 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Confirm that the subject has an acceptable ECG result from the central review which will allow participation. Upon successful completion of screening procedures, subjects who meet all inclusion/exclusion criteria will be randomized in a double-blind fashion to one of three treatment groups (amitriptyline, topiramate, or placebo) as outlined in the randomization section. The duration of the Double Blind Phase will be 26 weeks (8 week titration, 16 week maintenance, 2 week weaning off study medication). 1. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before eligibility is determined. 2. Determine if any adverse events have occurred since subject signed informed consent 3. Administer PedMIDAS and HIT-6 4. Randomize subject 5. Obtain vital signs (height, weight, heart rate, blood pressure) 6. Update demographics 7. Perform physical examination 8. Perform neurological examination including visual field exam 9. Dispense headache diary 10. Instruct subject on the use of symptom questionnaire and phone symptom screening procedure. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Baseline instrument to score any subject reports of suicidality obtained from the symptom questionnaires. 11. Review concomitant medications 12. Dispense study medication, medication instructions, and emergency contact card 13. Schedule phone symptom screening calls for week Titration Phase The Titration Phase will extend for 8 weeks. Clinic visits will occur at Visit 3 (4 weeks after randomization) and Visit 4 (8 weeks after randomization). Extra visits may be scheduled at the discretion of the investigator as discussed in section Visit 3 (4 Weeks ± 7 days) 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire If subject reports an adverse event, follow the adverse event procedure outlined in Section 7. If depression or suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient

49 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean follow-up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Obtain vital signs (height, weight, heart rate, blood pressure) 6. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 7. Update demographics 8. Perform physical examination 9. Review concomitant medications 10. Dispense headache diary for next study interval 11. Determine if subject will advance to next level of medication titration 12. Increase study medication dosage if no safety or tolerability issues. If issues are reported, the site investigator will decide to advance, hold or decrease dosage to previously tolerated level. 13. Dispense study medication; discuss revised study medication instructions 14. Schedule phone symptom screening calls for 2 weeks from visit Visit 4 (8 Weeks ± 7 days) 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire If depression or suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality.

50 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Obtain vital signs (height, weight, heart rate, blood pressure) 6. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 7. Update demographics 8. Perform physical examination 9. Review concomitant medications 10. Dispense headache diary for next study interval 11. Determine if subject will advance to next level of medication titration 12. Increase study medication dosage if no safety or tolerability issues. If issues are reported, the site investigator will decide to advance, hold or decrease dosage to previously tolerated level. 13. Dispense study medication; discuss revised study medication instructions 14. Schedule phone symptom screening calls for 2 weeks from visit Maintenance Phase The Maintenance Phase extends for 16 weeks. Clinic visits will occur at Visit 5 (12 weeks after randomization) Visit 6 (16 weeks after randomization), and Visit 7 (20 weeks after randomization). Extra visits may be scheduled at the discretion of the investigator. Visit 5 (12 Weeks ± 7 days) 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire and discuss previous phone symptom screening If depression or suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality.

51 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Administer Questionnaires (BRIEF, CDI, FDI, HADS, PedsQL) If depression or suicidal ideation is identified from Item 9 of the CDI, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. 6. Administer PedMIDAS and HIT-6 7. Obtain vital signs (height, weight, heart rate, blood pressure) 8. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 9. Update demographics 10. Perform physical examination 11. Review concomitant medications 12. Perform neurological examination including visual field exam 13. Obtain laboratory tests as follows: A CHAMP Comprehensive Profile of liver and renal analytes Sample for adherence levels of Amitriptyline or Topiramate 14. Obtain ECG. The ECG will be confirmed by the site investigator and then sent to the CCC for independent interpretation. The criteria for elongation of the QT interval will be a QT interval greater than or equal to 460 msec. 46 If the central reader determines that the QT interval has been elongated and that elongation would put the subject at risk for an adverse event, then the subject would be moved to early termination (Section 6.3.3). Confirm that the subject has an acceptable ECG result from the central review when this result is available to allow continued participation. 15. Dispense headache diary for next study interval 16. Determine if subject will continue on maintenance dose of medication 17. Dispense study medication 18. Schedule phone symptom screening calls for 2 weeks from visit Visit 6 (16 Weeks ± 7 days)

52 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire and discuss previous phone symptom screening If depression or suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Obtain vital signs (height, weight, heart rate, blood pressure) 6. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 7. Update demographics 8. Perform physical examination 9. Review concomitant medications 10. Dispense headache diary for next study interval 11. Determine if subject will continue on maintenance dose of medication 12. Dispense study medication 13. Schedule phone symptom screening calls for 2 weeks from visit Visit 7 (20 Weeks ± 7 days) 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire and discuss previous phone symptom screening If depression or suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the

53 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self-injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Obtain vital signs (height, weight, heart rate, blood pressure) 6. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 7. Update demographics 8. Perform physical examination 9. Review concomitant medications 10. Perform neurological examination including visual field exam 11. Dispense headache diary for next study interval 12. Determine if subject will continue on maintenance dose of medication 13. Dispense study medication 14. Schedule phone symptom screening calls for 2 weeks from visit Endpoint Visit The endpoint visit will occur 24 weeks after randomizations +/- 7 days. Visit 8 (24 Weeks ± 7 days) 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire and discuss previous phone symptom screening If depression or suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required.

54 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Administer PedMIDAS and HIT-6 6. Administer questionnaires (BRIEF, CDI, FDI, HADS, PedsQL). If depression or suicidal ideation is identified from Item 9 of the CDI, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. 7. Obtain vital signs (height, weight, heart rate, blood pressure) 8. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 9. Update demographics 10. Perform physical examination 11. Review concomitant medications 12. Perform neurological examination including visual field exam 13. Obtain clinical laboratory tests as follows: A CHAMP Comprehensive Profile of liver and renal analytes Sample for adherence levels of Amitriptyline or Topiramate 14. Biorepository samples (serum and RNA) Dispense headache diary for next study interval 15. Dispense study medication 16. Discuss weaning procedure 17. Instruct subject on additional treatment options beyond the study for acute treatment and for preventative treatment if the subjects continue to have 1 or more migraine per month. The subject and investigator will not be unblinded to treatment assignment at the conclusion of the maintenance period or at the end of the subject s participation in the study. See section 8.3 regarding the study blind at Study Conclusion 18. Schedule phone symptom screening calls for 2 weeks from visit Final Evaluations The weaning off drug and off drug phase will extend for 6 weeks after visit 8. Subjects will wean off study medication between weeks 24 and 26 and be observed for any off drug problems. At 26 weeks subject will be off study medication. Weaning Off Drug Phase

55 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Visit 9 (26 weeks ± 7 days) conducted by phone 1. Conduct and review phone symptom questionnaire If depression or suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow -up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 2. Request subject return all remaining study drug and headache diary to the study site by mail. After study drug is received, a pill count will be performed and compliance assessed. 3. Document any ongoing or resolved adverse events; the information will be collected by phone. 4. Schedule phone symptom screening calls for 4 weeks from visit Off Drug Phase Visit 10 (30 weeks ± 7 days) conducted by phone 1. Conduct and review phone symptom questionnaire If depression or suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, self-injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject.

56 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 2. If not completed after Visit 9, request subject return all remaining study drug to the study site by mail, a pill count performed and compliance will be assessed. 3. Document any ongoing or resolved adverse events; the information will be collected by phone. This will conclude the subject s involvement with the study, unless the subject has allowed permission for re-contact at a later time. 6.3 Titration Adjustment, Early Termination and Unscheduled Visits Titration Adjustment Visit A study visit may be required for subjects who require a dosage titration adjustment. If, in the opinion of the site investigator, the subject requires a dosage titration adjustment to either hold or decrease study medication due to any intolerance issues, the investigator may manage the dosage change by telephone visit or request that the subject complete a dosage titration adjustment visit in person During a telephone visit, the following interventions will be performed: 1.Conduct and review the symptom questionnaire If depression or suicidal ideation is identified, determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self-injury, the site investigator will develop an action plan for the immediate care needs of the subject. 2.Complete the Dosage Modification Form to document the reason for dosage titration adjustment and to communicate the revised dosage schedule to the DCC. 3.Dispense the modified dosage of study medication and allow a treatment period for the new dosage of two weeks During an in person dosage titration adjustment visit, all of the interventions listed in the telephone visit will be conducted with the addition of the following interventions: 1.Collect and review headache diary for completion of data fields 2.Dispense headache diary for next study interval if needed. 3.Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen

57 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Counsel subject about importance of adherence 4.Obtain vital signs (height, weight, heart rate, blood pressure) 5. Obtain urine pregnancy test for all females of childbearing potential. 6.Perform physical examination 7.If, in the opinion of the investigator, other interventions are required for the safety of the subject, such as the neurological examination or study laboratory tests, these may be conducted at this visit. 8.Review concomitant medications and adverse events 9.If, in the opinion of the investigator, the subject should be discontinued from exposure to study drug, please document that decision and move to early termination (Section 6.3.3) Unscheduled Visit If, in the opinion of the site investigator, the subject requires an unscheduled visit to manage safety or tolerability issues, the visit may be conducted at the investigator s discretion. The visit will be recorded in source and ecrf using the routine forms provided by the CCC and DCC Early Termination Visit For subjects who discontinue the study prior to Visit 9, the following interventions will be performed unless informed consent has been withdrawn. 1.Distribute symptom questionnaire for completion by subject 2.Collect and review headache diary for completion of data fields 3.Conduct and review phone symptom questionnaire If depression or suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Notify the sponsor through urgent ecrf AE report if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self-injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4.Collect study drug 5.Perform final drug accountability 6.Administer PedMIDAS and HIT-6 7.Administer questionnaires (BRIEF, CDI, FDI, HADS, PedsQL) If depression or suicidal ideation is identified from Item 9 of the CDI, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Notify the sponsor

58 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean through urgent ecrf AE report if any symptom is determined to be a serious adverse event. Administer the Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. 8.Obtain vital signs (height, weight, heart rate, blood pressure) 9.Obtain ECG if early termination occurs before Visit 5 or if subject reports cardiac adverse events as a reason for early termination. The ECG will be interpreted by the site investigator and then sent to the CCC for independent interpretation. 10. Perform physical examination 11. Obtain clinical laboratory tests as follows: A CHAMP Comprehensive Profile of liver and renal analytes Sample for adherence levels of Amitriptyline or Topiramate Biorepository samples (serum and RNA) 12. Perform neurological examination including visual field exam 13. Review concomitant medications and adverse events 14. Document reason for early termination Pregnancy A urine pregnancy test will be performed at each study visit for females of child bearing potential. Subject pregnancy must be reported by the investigational staff within 1 working day of their knowledge of the event using the urgent ecrf AE report. Any subject who becomes pregnant during the study must be promptly withdrawn from study drug exposure, but will continue to be followed on the protocol at regularly scheduled visits, or with unscheduled visits or phone follow up. Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be required and reported through the adverse event reporting system for tracking purposes only. 6.4 Special Instructions and Definitions of Evaluations Informed Consent Research conducted in this project will be reviewed and approved by the appropriate Institutional Review Board (IRB) for each site. Following local IRB approval, the site principal investigator or their IRB approved designee will discuss the study with the family and obtain written informed consent (and assent if required by the local IRB) using the locally approved consent form. The informed consent process will be documented in source. All NIH, federal, and local IRB regulations and guidelines will be followed. Recruitment will occur at the clinical sites The CCC will provide template consent and assent forms to investigative sites. Any modifications to the template consent and assent will be reviewed by the CCC Regulatory Staff prior to submission to the local IRB. The CCC Regulatory Staff will ensure the required elements for

59 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean consent are contained within each form, and that all forms are HIPAA compliant Each subject s original informed consent document will be maintained in the subject s study source documents Sites will obtain written informed consent (and assent if required by the local IRB) from eligible subjects Documentation of Pediatric Migraine The diagnosis of pediatric migraine is made using a combination of clinical and diary findings. For purposes of this study, pediatric migraine is characterized by diagnosis of migraine with or without aura or chronic migraine that meets the ICHC-II criteria Migraine frequency is a key parameter in this study. It is defined in this protocol as the number of days with migraine for a given 4 week ( 28 day) period where one migraine is counted as beginning at the onset of painful migraine symptoms, not to exceed 24 hours with the clock starting at midnight. If painful symptoms last longer than 24 hours without resolution, this is considered a new and distinct migraine headache, which would result in a frequency count of two migraine days. If painful symptoms recur within 24 hours of initial onset, this is considered part of the initial migraine episode and would be counted as one migraine, or one migraine day Medical History A medical history includes chief complaint, history of migraine, past medical history A comprehensive medical history will be obtained at the screening visit and will be documented in the source documents. Subjects may provide an optional consent to allow use of their previously documented medical history to be reviewed for trial inclusion Treatment History/Prior Headache Medications At study entry, the prior history of treatment with any migraine prevention agent will be documented. Subjects who have failed adequate trials of the study medications (defined as a trial of at least 3 months duration at doses recommended for headache relief) will be excluded Physical Examination A physical examination includes central nervous system, behavioral, HEENT, cardiovascular, pulmonary, gastrointestinal, genitourinary, dermatologic, musculoskeletal assessment Physical examinations will be obtained at every clinic visit and will be documented in the source documents.

60 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Vital Signs and Demographics Vital signs include height, weight, blood pressure, heart rate, and respiration Demographic information includes subject s name, address, phone, , and parent/guardian contact information, ethnicity, gender, and race Neurological Examination with Vision Examination A neurologic examination includes assessment of the subject s mental status, cranial nerve function, motor and sensory function, deep tendon reflexes, cerebellar function and gait A Funduscopic and visual field examination will be conducted Laboratory Evaluations - CBC, Renal, Liver Function, Adherence Drug Levels of Amitriptyline and Topiramate and Biorepository A random non-fasting sample of blood obtained on the day of the clinic visit will be analyzed for complete blood count (Visit 1 only), liver panel and renal function. Blood will be drawn three times during the study: Visits 1, 5 and 8. About 4 teaspoons (20 ml) of blood will be drawn from a vein for each lab test. This yields a total volume of 60 ml by the completion of the study. The 20 ml/visit is less than 5% of the total blood volume of a child ages 8-17 (3777ml 4095 ml) which would be ml. With this low volume of blood loss (about 0.5% of the total volume), no extraordinary precautions will be needed to protect the child from adverse events from blood loss Clinical laboratory tests will be performed centrally by the CCC clinical laboratory. The results will be retained in the source documentation, with the exception of the adherence drug levels of amitriptyline and topiramate which will be retained at the DCC and not provided to study sites. The ecrf will directly record the central lab result and when a value is flagged as high or low by the central laboratory. This section of the ecrf will not be accessible to the CCC or the site study staff in order to maintain the study blind A clinically significant laboratory abnormality (in the opinion of the local site principal investigator) will be considered as an adverse event The central clinical laboratory normal values for complete blood count, liver panel, renal function, and adherence drug levels for amitriptyline and topiramate will be updated annually Table summarizes the specific analytes for evaluation in the CBC, and the CHAMP Comprehensive Profile of liver and renal analytes.

61 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Table Analytes for CBC, CHAMP Comprehensive Profile of Liver and Renal analytes and Adherence Drug Levels CBC - Hematology Panel hematocrit hemoglobin platelet count red blood cell (RBC) count white blood cell (WBC) count CHAMP Comprehensive Profile of Liver and Renal Analytes albumin alkaline phosphatase ALT AST bicarbonate blood urea nitrogen (BUN) calcium chloride creatinine glucose lactic dehydrogenase (LDH) potassium Sodium total bilirubin total protein Adherence Drug Levels Amitriptyline Topiramate A CHAMP Study Biorepository will be used to retain samples for future biomarker analysis. Blood for DNA analysis, serum for biomarker analysis, and blood samples for RNA analysis will be obtained on an optional basis from consenting subjects. The samples will be obtained during regular study sample collections occurring at Visit 1, 8 and Early Termination. A select group of sites will obtain the samples for RNA analysis ECG A twelve lead ECG will be obtained utilizing the site s ECG equipment Interpretation of ECG results will be performed by the central reader at the CCC.

62 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean A focus on the QT interval will be conducted to detect elongations in the interval greater than or equal to 450 msec at Visit 1 and greater than or equal to 460msec at Visit ECG tracings will be transmitted electronically or in print to the central reader on the day of the ECG examination. The results of the interpretation will be returned to the study site and retained in the study source The central reader will be responsible for the interpretation of results to determine eligibility or exclusion or continuation in the study after the ECG exam at visit Urine Pregnancy Test A random urine sample will be obtained and the test will be performed at the site The pregnancy test results will be reviewed the site investigator prior to randomization and prior to dispensing study drug at each visit Positive pregnancy test results will be reported on an urgent ecrf AE report and be managed as an SAE for tracking purposes only Headache Diary A headache diary will be dispensed at each visit and the subject and subject s parent(s) will be instructed on the completion of the daily headache diary The headache diary will record the daily incidence, frequency, and duration of all of the subject s headaches and migraine symptoms for a period of one month The headache diary will also record any rescue medications and daily study drug use by the subject PedMIDAS The PedMIDAS scale evaluates the impact of migraines on school, home, play, and social activities. It is comprised of six items that pertain to days missed in various activities over the past 90 days. Questions are answered by the youth in consultation with their parents. The total PedMIDAS score (sum of items 1-6) will be used in this trial The PedMIDAS examination will be dispensed ate visit 2 and the subject and subject s parent(s) will be instructed on completion of the PedMIDAS to determine eligibility based on a disability score > 10, indicating at least mild disruption in daily activities and < 140,

63 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean indicating extreme disability that may require more comprehensive, multi-component therapy The PedMIDAS will be used as a study procedure at 2 additional study timepoints after visit 2 to collect information on headache related disability that has occurred in the last 3 months For further description see the Study Questionnaire Table Secondary Measure Questionnaires The following study questionnaires will be administered to the subject and subject s parent(s) during the study visit. Table provides a summary of all study questionnaires Behavioral Rating Inventory & Executive Function (BRIEF) The BRIEF is a measure of executive function and is a questionnaire completed by the parent/guardian. It consists of two indexes, Behavioral Regulation and Metacognition, which are then used to calculate an overall composite score (Global Executive Composite; GEC). The GEC will be used in the current trial and reliability of the overall GEC score is 0.97 to Clinical Depression Inventory (CDI) The CDI is a reliable and valid 27-item scale assessing symptoms of depression. 47, 48 It yields a total score and subscale scores on negative mood, interpersonal problems, ineffectiveness, anhedonia and negative self-esteem. Separate norms are available for boys and girls ages 7-12 and 13-17, which are then converted to T-scores. The total score and a positive screen cutoff of a T-score > 65 will be used. The CDI secondary measure will be scored during the visit and the results presented to the site investigator for review during the visit, responses that require immediate action will be acted upon by the site investigator Functional Disability Inventory (FDI) The FDI assesses children s and adolescent s self-reported difficulty in physical and psychosocial functioning due to their physical health. 49 The FDI contains 15 items related to activity limitations that are rated on a 5- point scale (0-no trouble; 4-Impossible). Scores range from 0 to 60, with higher scores indicating greater disability. The total score will be used in this trial Hospital Anxiety and Depression Scale (HADS) The HADS is a 14-item self-assessment measure of depressive and anxiety symptoms (7 items each). 50 Each item is rated on a 4-pioint scale and totaled for the respective subscale (Anxiety and Depression). Cutoffs for severity of symptoms for anxiety and depression are provided. The raw score for each respective subscale will be used in this trial.

64 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Pediatric Quality of Life Inventory (PedsQL) The PedsQL 4.0 is a measure that is commonly used for comprehensive assessment of the impact of chronic illness The 23-item pediatric self-and parent-report scales are validated for ages 5-18 and include items covering the domains of Physical, Social, Emotional and School Functioning. A total score is calculated by transforming 0-4 scaled items to scale and computing an average. The total score will be used in this trial Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Baseline The Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Baseline Version 6/23/10 is a validated instrument used for the prospective assessment of suicidality. 54 It will be used in concert with the symptom questionnaire to document any suicidal ideation or behavior of subjects Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit(C-SSRS) Children s Since Last Visit Version 6/23/10 is a validated instrument used for the prospective assessment of suicidality. 54 It will be used at interim visits in concert with the symptom questionnaire to document any suicidal ideation or behavior of subjects HIT-6 version 1.1 (Headache Impact Test). The HIT-6 is a tool used to measure the impact headaches have on an adult s ability to function in a variety of settings. It will be used at the same intervals as the PedMIDAS, Visits 2, 5 and 8 as an exploratory secondary measure.

65 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Table Summary of Study Measures. Psychological Measure Description Construct(s) Informant (ages) Items Completion Time (mins) Data Source Reliability/ Validity Pediatric Migraine Disability Assessment (PedMIDAS) Six-item measure to assess migraine disability in school-age children and adolescents Migraine-related disability Patient report (6 items) Ages Score used: Total disability score Cronbach s coefficient alpha value of 0.77 to 0.78; test-retest reliability of 0.80 Headache Impact Test (HIT-6) Six item measure to assess migraine disability in adults (pain, social and role functioning, vitality, psychological distress, cognitive functioning). Migraine-related disability Patient Report (6 items) Ages 18 and over 6 3 Score Used: Total disability score (range 36 to 78; higher scores indicative of greater disability). Internal reliability of 0.87 to 0.90; test-retest reliability of 0.78 Behavioral Rating Inventory of Executive Functioning (BRIEF) Measures executive functioning across two scales, behavioral regulation and metacognition Behavioral functioning, executive functioning Parent report Ages Score used: Global Executive Composite (GEC) Reliability of the overall GEC score is 0.97 to 0.98 Children s Depression Inventory (CDI) Assess cognitive, affective and behavioral signs of depression in children and adolescents Depressive symptoms Ages Score used: Total Score, T-score based on age and gender Cronbach s coefficient alpha values 0.71 to 0.89; test-retest coefficients range from.74 to.83 Functional Disability Inventory (FDI) Global measure of functional disability with scores ranging from 0 to 60. Activity limitations Ages Score used: Total score (0-60) Cronbach s coefficient alpha value of 0.85 to Hospital Anxiety and Depression Scale (HADS) Self-assessment of emotions, namely anxiety and depression Anxiety (HADS-A) and Depression (HADS-D) Youth and above Scores used: Raw scores for anxiety and depression (0-21) Cronbach's coefficient alpha for HADS-A varied from.68 to.93 (mean.83) and for HADS-D from.67 to.90 (mean.82). Pediatric Quality of Life Inventory (PedsQL) Measures health-related quality of life Physical, Emotional, Social, School Functioning Child and Parent Age 8-12 Age Score used: Total Scale Score (0-100) Cronbach s coefficient alpha value of 0.89 for child report, 0.92 parent report Columbia-Suicide Severity Rating Scale (C- SSRS) Baseline Prospective assessment of suicidality Suicidality Ideation, Intensity, Behaviors, Attempts Youth Score used: Total Scale Score (1-5) Kendall s tau-b was 055,.61 and.62 (p values<0.01) Columbia-Suicide Severity Rating Scale (C- SSRS) Since Last Visit Prospective assessment of suicidality Suicidality Ideation, Intensity, Behaviors, Attempts Youth Score used: Total Scale Score (1-5) Kendall s tau-b was 055,.61 and.62 (p values<0.01)

66 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Study Drug Administration Study drug will be dispensed to eligible subjects along with medication instructions during study visits Study drug will be collected at each visit and drug accountability will be performed by pill count Compliance with medication instructions will be addressed during the study visit. Subjects will be counseled about medication compliance at every dosing visit Concomitant Treatment Any concomitant treatments will be recorded Adverse Events Adverse events will be solicited by the use of a standard open-ended question and the use of a targeted symptom questionnaire at each visit Adverse events will be obtained by the use of a phone symptom questionnaire administered at the 2 week interval between visits This site investigator will review the results of the symptom questionnaires and the phone symptom questionnaire to determine if an immediate action plan is required to maintain subject safety For further detail of handling adverse events see Section 7. 7 MANAGEMENT OF ADVERSE EXPERIENCES 7.1 Adverse Event The investigator or site staff will be responsible for detecting, documenting, and reporting events that meet the definition of an Adverse Event (AE) or Serious Adverse Event (SAE). Adverse events will be collected at any time following signing of the informed consent and until the final phone contact. An adverse event is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse, or misuse Events meeting the definition of an AE include: a) Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition.

67 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean b) New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study. c) Signs, symptoms, or the clinical sequelae of a suspected interaction. d) Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concomitant medication (overdose per se will not be reported as an AE/SAE). Lack of efficacy or failure of expected pharmacological action per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfill the definition of an AE or SAE Events that do not meet the definition of an AE include: a) Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE. b) Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital). c) Anticipated day to day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen. d) If subjects report symptoms of migraine, the disorder being studied, migraine symptoms (i.e., head pain, nausea, vomiting, phonophobia, and photophobia) are not considered an AE unless the symptoms are more severe than expected compared to baseline symptoms or worsen. e)inpatient treatment of status migrainosus, which may routinely be treated on an outpatient in many centers, will not be considered as a serious adverse event, although the presence of status migrainosus should be reported as an adverse event if it represents a worsening of symptoms Expected Adverse Reactions Adverse Events Expected with Amitriptyline Table Common Adverse Events with Amitriptyline by Body System Body System Adverse Event Central Nervous System Dizziness Headache Somnolence Asthenia Tiredness Endocrine / Metabolic Weight Gain Gastrointestinal Abdominal Pain Constipation Xerostomia Ophthalmic Blurred Vision

68 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Table Less Common Adverse Events with Amitriptyline by Body System Body System Adverse Event Cardiovascular Blood cell or blood vessel changes Dysrhythmia Elongation of QT interval Heart rate changes Increased or decreased blood pressure Myocardial infarction Syncope Central Nervous System Seizure Dermatologic Jaundice Gastrointestinal Altered taste Bloating Hepatobiliary Decreased liver function Laboratory Abnormalities Abnormal liver enzymes Decreased red blood cell count Decreased white blood cell count Psychological Suicidal thoughts Suicide Suicidal Thoughts with Amitriptyline Usage The onset of suicidal thoughts with amitriptyline usage will be carefully monitored for during the study by the use of the symptom questionnaire at frequent intervals by making the subjects and families aware of selfmonitoring for the onset of this possible side effect.

69 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Adverse Events Expected with Topiramate Table Common Adverse Events with Topiramate by Body System Body System Adverse Event Central Nervous System Anxiety Coordination problems Decreased concentration Difficulty with attention Dizziness Feeling nervous Hypoesthesia Insomnia Memory problems Somnolence Tingling Tiredness Endocrine/Metabolic Weight loss Gastrointestinal Abdominal pain Altered taste Diarrhea Dry Mouth Dyspepsia Loss of appetite Nausea Musculoskeletal Arthralgia Ophthalmic Blurred vision Double vision Psychological Depression Mood problems Respiratory Pharyngitis Sinusitis Body as a whole general Back pain Injury Table Less Common Adverse Events with Topiramate by Body System Body System Adverse Event Central Nervous System Confusion Headache Ophthalmic Nearsightedness Twitchy eyes Respiratory Sinusitis Upper respiratory tract infection Urinary Kidney Stones

70 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Table Rare Adverse Events with Topiramate by Body System Body System Adverse Event Hepatobiliary Liver failure Idiosyncratic Reactions 7. Psychological Erythema multiforme Decreased sweating Elevated body temperature Excessive acidity of the blood Hyperammonemia with or without encephalopathy Stevens-Johnson Syndrome Toxic epidermal necrolysis Suicidal thoughts Suicide Decreased Sweating with Topiramate Usage Decreased sweating with topiramate usage may be prevented by closely monitoring children for evidence of increased body temperature, especially during hot weather, and assuring that adequate steps are taken to maintain hydration Suicidal Thoughts with Topiramate Usage The onset of suicidal thoughts with topiramate usage will be carefully monitored for during the study by the use of the symptom questionnaire at frequent intervals by making the subjects and families aware of selfmonitoring for the onset of this possible side effect Adverse Events Related to Weight Change Decreases and increases in weight will be monitored closely during study visits. Change in weight that exceed two isobars on the normal CDC growth chart published May 30, 2000 for children ages 2-20 will be considered an adverse event and reported as a grade 2 event. A detailed report of the reason for weight change will be documented. The site investigator may determine if the subject may continue on the study drug or move to early termination (Section 6.3.3) Adverse Events Expected with Placebo There are no expected adverse reactions associated with taking placebo. 7.3 Dose Modification Guidelines and Procedures Dose Modifications for Growth It is not anticipated that subjects will advance to the next weight group during their 34 weeks of involvement in the study; therefore there is no planned dose modification for growth.

71 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Subjects with Abnormal Laboratory Parameters For subjects with abnormal laboratory parameters, the site investigator will make a determination to repeat the abnormal laboratory parameter, and hold or decrease the dosage of study drug For subjects with liver enzymes elevated 2.5 times the upper limit of normal (ULN), the site investigator will repeat the liver enzyme panel after one month and hold or decrease the study drug. The site investigator may also, after consultation with the sponsor, order additional liver studies, such as a hepatitis profile or other tests as needed. Study drug will be discontinued for subjects with liver enzymes elevated > 5 times x upper limit of normal and for subjects with total bilirubin 2 x upper limit of normal. After two consecutive findings of either elevated liver enzymes > 5 times x upper limit of normal or bilirubin 2 x upper limit of normal, the subject will move to early termination (Section 6.3.3) For subjects with serum bicarbonate levels of < 17mEq/L, the bicarbonate level will be repeated. In addition the site investigator may initiate more frequent testing to detect the development of metabolic acidosis For subjects in whom the repeat evaluation remains abnormal, the laboratory parameters will be considered dose limiting. The dose level will be decreased to the dose level immediately below the one in which the toxicity was observed Subjects in whom the repeat laboratory evaluations have returned to acceptable criteria may continue with the previous dose Subjects who are found to have a positive pregnancy test will have that result reported as an urgently reported serious adverse event for tracking purposes only and will be removed from study drug exposure but continue to be followed during the regularly scheduled intervals or as unscheduled visits until the outcome of pregnancy and any congenital anomaly/birth defect for the baby have been reported Laboratory results for Amitriptyline and Topiramate will be collected for adherence analysis only. These samples are biosamples and as such, the. resulting blood levels will not be revealed to investigators or subjects, but will be used for analysis to answer scientific questions at the end of the study. The samples will be retained for batch analysis Subjects with Rash Subjects who develop a rash considered by the site investigator to be related to the study drug will be carefully observed. If necessary,

72 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean unscheduled visits may be scheduled to determine if withdrawal from study drug exposure is required. Subjects who develop a potentially life threatening rash (Stevens Johnson Syndrome, Toxic Epidermal Necrolysis) will be withdrawn from study drug exposure and move to early termination (Section 6.3.3). These subject s parents/guardians and the site investigator will be unblinded to treatment assignment Subjects with Intolerable Side Effects This situation is a Dose Limiting Toxicity in the titration phase; the study drug will be decreased to the dose level immediately below the one in which the toxicity was observed. a) If the subject s migraine frequency increases on a lower dosage then the subject will be determined to be a treatment failure and removed from study drug exposure and move to early termination (Section 6.3.3). b) If the subject s adverse events continue on this lower dosage, then the subject is removed from study drug exposure and.moved to early termination (Section 6.3.3). 7.4 Serious Adverse Events A serious adverse event is an important medical event which may not result in death, may not be life-threatening, nor require hospitalization, but may be considered serious when, based upon appropriate medical judgment; the adverse event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition Definition of Serious Adverse Event A Serious Adverse Event or Serious Suspected Adverse Reaction is considered serious if, in the view of either the investigator or the sponsor, it results in any of the following outcomes: death a life threatening adverse event requires inpatient hospitalization or prolongation of existing hospitalization a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect important medical events that may not result in death, be lifethreatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. other conditions as specified in this protocol For purposes of this protocol, any report of the expression of suicidal ideation will also be considered a Serious Suspected Adverse Reaction. Such reports will be

73 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean obtained through the routine use of the phone symptom screening questionnaire and the targeted symptom questionnaire administered at every visit, and through subject reports. Suicidal ideation and suicidal intent may also be reported on the CDI questionnaire as noted by a yes response to I think about killing myself but I would not do it and I want to kill myself on item #9. NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency department for observation and/or treatment that would not have been appropriate in the physician s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether hospitalization occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. 7.5 Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs Any abnormal laboratory test results (hematology, clinical chemistry, or positive pregnancy test) or other safety assessments (i.e., ECGs, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant by the investigator are to be recorded as AEs or SAEs. However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject s condition are not to be reported as AEs or SAEs. Therefore, the occurrence of migraine headache will not be considered an adverse event, unless the subject is admitted to the hospital for longer than overnight treatment, because it is an expected baseline condition of every subject. 8 CRITERIA FOR INTERVENTION OR DISCONTINUATION 8.1 Subject Termination Reasons for Subject Termination Subject participation may be terminated for any of the following reasons: Subjects, or their parent or guardian, choose to discontinue the study Significant protocol violation, such as non-compliance with study procedures or attendance at study visits Tolerability Lengthening of the QTc interval on ECG Lost to Follow-Up Other (to be specified by site investigator)

74 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean When a subject withdraws prior to completing the trial, the reason for withdrawal is to be clearly indicated on the appropriate ecrf and source document. Such subjects should have all the tests and examinations scheduled for the last study visit performed at the time of their withdrawal. Discontinued subjects will not be replaced. Study drug assigned to a withdrawn subject may not be assigned to another subject An early termination visit will be conducted if at all possible with the elements described in Section Unblinding to treatment assignment: if unblinding to treatment assignment becomes necessary due to subject safety issues or for clinical management of a serious adverse event, the site investigator, medical monitor or DSMB may request to become unblinded to a subject s treatment assignment. Site investigators who wish to pursue unblinding must make the request in writing to the study chair. After approval of unblinding for the site investigator, the subject will be discontinued from study participation. Notification will be provided by the DCC. 8.2 Site Termination An investigational site may be terminated by the CCC or DCC at any time. Investigational sites will be closed upon study completion. An investigational site is considered closed when all required documents and study supplies have been collected, the site IRB has been notified, and a site closure visit has been performed The individual site investigator may initiate site closure at any time, provided there is reasonable cause and sufficient notice is given in advance of the intended termination Reasons for the early closure of an investigational site by the CCC or DCC or by the investigator, or termination of a study by the sponsor, may include, but are not limited to: Failure of the site to meet enrollment goals after assistance efforts have been provided by the CCC Failure of the investigator to comply with the protocol, the CCC s or DCC s procedures, or good clinical practice guidelines Safety concerns Sufficient data suggesting lack of efficacy after the interim analysis inadequate recruitment of subjects by the investigator 8.3 Study Termination The study may be terminated by the study chair for any or all of the following reasons:

75 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Failure of the study to meet enrollment goals and achieve sufficient power to answer the scientific questions of the study Loss of funding Safety concerns Sufficient data suggesting lack of efficacy after interim analysis Conclusion of all planned study activities At the conclusion of the study, after all actively enrolled subjects have completed the final visit and monitoring, data analysis, and reporting activities have been concluded the investigators will provide the study results and treatment assignments to the site investigators who will provide the information to the study subjects. 9 STATISTICAL CONSIDERATIONS 9.1 Specific Aims and Hypothesis The specific aims are to: Aim 1: To test if amitriptyline (AMI) is superior to placebo in reducing migraine frequency and migraine-related disability Primary Hypothesis #1: Amitriptyline, at a target dose of 1 mg/kg/day, will result in an increased percentage of subjects meeting the primary endpoint compared to placebo Major Secondary Hypothesis #1: Amitriptyline also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to placebo Aim 2: To test if topiramate (TPM) is superior to placebo in reducing migraine frequency and migraine-related disability Primary Hypothesis #2: Topiramate, at a target dose of 2 mg/kg/day, will result in an increased percentage of subjects meeting the primary endpoint compared to placebo Major Secondary Hypothesis #2: Topiramate also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to placebo Aim 3: To compare the efficacy of amitriptyline and topiramate in reducing migraine frequency and migraine-related disability Primary Hypothesis #3: Topiramate will result in an increased percentage of subjects meeting the primary endpoint compared to amitriptyline.

76 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Major Secondary Hypothesis #3: Topiramate also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to amitriptyline Aim 4: To prospectively and systematically estimate the safety and tolerability profiles of each therapy Major Secondary Hypothesis #4: Amitriptyline and topiramate will be well tolerated Major Secondary Hypothesis #5: AMI and TPM will not differ from placebo on the occurrence of treatment - emergent serious adverse events. We also expect that AMI and TPM will have overall safety profiles that do not preclude determination of first line therapy for clinical practice according to our decision algorithm. 9.2 Outcomes Primary Outcome The primary objective is to determine the best choice prevention strategy for pediatric migraine headache. We plan to test if amitriptyline and/or topiramate are superior to placebo in reducing headache frequency in children and adolescents age 8 to 17 with migraines. Specifically, we will conduct a three trials in one study to determine if there is a difference in the proportion of subjects who meet our primary outcome measure of a 50% reduction in headache frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial. Headache frequency is defined as the number of days with headache for a given 4 week period. A 20 percentage point difference from placebo in this reduction effect is considered clinically meaningful by pediatric headache experts Secondary Outcome The secondary outcome measures in the study include: Reduction in migraine disability score on PedMIDAS (Time Frame: end of the week baseline period to the last 4 weeks of the 24-week trial) Tolerability of amitriptyline and topiramate (Time Frame: visit 2 until the last 4 weeks of the 24-week trial) Occurrence of treatment-emergent serious adverse events (Time Frame: visit 2 to the last 4 weeks of the 24-week trial) Reduction in absolute migraine frequency (Time Frame: 4 week baseline period to the last 4 weeks of the 24-week trial) 9.3 Data Monitoring This study is a multi-site Phase III clinical trial. Therefore, there is a need for a careful data and safety monitoring plan to ensure the well-being of the youth in this study and the scientific integrity of the project. On-site monitoring begins with the site initiation visits and occurs throughout the duration of the study. The goal of the site initiation visit is to ensure that the site has been completely trained in protocol procedures and Good Clinical Practices (GCP)and that

77 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean facilities and personnel are adequate. Onsite monitoring visits will be conducted by the DCC monitoring staff. Scheduled monitoring will occur once per year during the conduct of the trial, with the option of making a second visit to selected centers each year, if needed, to address overenrollment, under-enrollment, or protocol deviation issues. The Monitoring Plan details the frequency and level of intensity of on-site monitoring visits. In general, sites will be monitored for all subjects at a level of 100% of study data gathered for inclusion and exclusion criteria, informed consent procedures, and adverse events. Depending on the goals of the study, a certain percentage of the study data are monitored against the study s database. The DCC will collaborate with the CCC, who may conduct remedial site training to ensure compliance with GCP and all regulations. During scheduled interim monitoring visits, the monitors will verify that the protocol is being followed and that data are being collected according to protocol requirements. The monitors will review the Study Regulatory File to determine that all required documentation is being collected and that the IRB approval for the site is current. They will then verify that each subject has signed the correct version of the informed consent document, and that this document is filed in the subject s notebook. At each visit, the monitor performs an audit of the case report forms in the subject s notebook by checking them against the database and source documents. Adverse event documentation is checked for completeness and accuracy. Drug and supplies accountability will also be monitored. At the study closeout, the monitors confirm that all data have been reviewed, all source documents have been verified, and all required documents are present in the Study Regulatory File. Table 9.3 below describes the variables to be reviewed during monitoring visits. Table 9.3. Variables to be Reviewed During Monitoring Visits. Variable % of Records Reviewed Informed consents 100% Eligibility criteria for all screened subjects 100% Adverse events 100% Drug accountability 100% of active subjects Protocol adherence 20% of active subjects Verification of ecrfs with source documents 20% of active subjects Verification of ecrfs with headache diaries 100% Central study files-inclusion of all applicable documents 100% Protocol deviations/violations 100% Medical Safety Monitor Dr. David Dodick will serve as the independent medical monitor for this trial. Dr. Dodick is a Professor of Neurology at the Mayo Clinic in Arizona, President of the American Headache Society, and Editor of the journal of the International Headache Society, Cephalalgia. He will work in collaboration with the DCC to

78 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean review all reported serious adverse events in near real time and evaluate them to identify the need for timely intervention. Dr. Dodick will work closely with the DCC and use the AE reporting system of the DCC. For any AE s which are characterized as serious events, an automatic will be sent to Dr. Dodick to prompt a review of the event for determination of whether the event is unanticipated and related to study drug and thus requires expedited reporting to the FDA. If deemed expedited, a MedWatch form is created electronically and submitted to the FDA. With the assistance of the coordinators at the DCC, Dr. Dodick has the option of requesting additional information about any SAE. He will complete a form for each review and this information will be entered into the data entry system. He may become unblinded upon request to the DCC based upon the results of any of his activities He will receive (A, B, C) blinded monthly tabulation reports of adverse events and serious adverse events by the type of event for the purpose of determining if any safety trends exist that may require a more frequent review by the DSMB than the planned biannual review. In the case of an immediate subject safety issue, the medical monitor will be charged with contacting the site investigator to support the safety needs of the subject. He will also actively interact with the Data Safety Monitoring Board (DSMB) and inform the DSMB of any particular concerns that may require the urgent attention of the group. This will be coordinated by the DCC and balanced by review of the DSMB Data Safety Monitoring Board (DSMB) An NIH-appointed DSMB is charged with the task of providing regular oversight of the data and safety monitoring issues as detailed in the document: NINDS Guidelines for Data and Safety Monitoring in Clinical Trials These experts will periodically review and evaluate the accumulated data for subject safety, adverse events, study conduct, and study progress. The DSMB will make recommendations to NINDS concerning continuation, modification, or termination of the study. Once a DSMB has been formed, the initial meeting will specify the frequency of future meetings and specific guidelines to be used for monitoring the study. We recommend that the DSMB conduct two face to-face meetings per year to review the ongoing study data. Given the sample size, we believe that subject accrual over six month intervals will be an adequate time period to provide sufficient information for performance and safety review. In addition, provisions will be made for emergency meetings should any SAEs require urgent review between regularly scheduled meetings. The DCC will prepare regular reports for the DSMB to review at each meeting. These reports will include overall summaries, AE and SAE summaries by treatment group in a blinded fashion, or summaries by treatment group in an

79 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean unblinded fashion depending on the preferences expressed by the members of the DSMB. These reports will include a summary of the following topics: Performance Monitoring Performance monitoring will examine subject recruitment, comparison with targeted recruitment, retention, protocol adherence, and quality of data collection procedures Treatment Monitoring Treatment monitoring will examine data on treatment integrity and adherence Safety Monitoring Safety monitoring will examine data related to the safety of the subjects, including confidentiality, all adverse events or side effects related to the treatment Interim Safety Assessment All clinically significant SAEs and AEs of special interest will be reported to the medical monitor and to the DSMB. The interim safety assessment will supplement the ongoing regular safety review conducted by the medical monitor and consist of review of the tabulated monthly safety report with a trend analysis generated by the DCC for review by the medical monitor. Due to the increased concern associated with the risk of suicidal ideation, we will use data collection methods that map to the Columbia Classification Algorithm for Suicide Assessment (C-CASA) to assess suicidality, specifically the symptom questionnaire, phone symptom questionnaire and CDI questionnaire. A positive answer to selected questions on these screening forms will result in an immediate referral to address the urgent care need of the subject and the use of the C-SSRS Baseline or C-SSRS Since Last Visit questionnaire. If a statistically significant difference (at the 0.05 level) is found in the incidence of suicidal ideation between either active treatment and placebo, the DSMB will be consulted to consider whether the trial should discontinue the affected arm Efficacy Monitoring Two interim efficacy assessments will occur. The first when 225 subjects have completed their 24-week visit, the second when 450 subjects have completed their 24-week visit. For the interim analyses, the Lan-DeMets alpha spending function approach with O Brien-Fleming stopping boundaries will be used. However, the Lan-DeMets method allows for analyses at unequal intervals and does not require pre-specifying the time of any interim analyses. Therefore, the proposed method has the flexibility to adapt should the DSMB request an interim analysis at an alternative time point or if the DSMB is unavailable at the time of a scheduled interim analysis. Importantly, the placebo arm will be dropped

80 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean only if both active treatments cross the stopping boundary at one of the pre-specified interim assessments. If only one crosses the boundary at the first look, both will be assessed again at the second look and the placebo arm dropped only if both cross the bound at that look Futility Monitoring Futility monitoring will be performed at each interim analysis. We will report the conditional power based on the pre-specified effect of interest. If both conditional power values fall below 20%, we will stop the trial early for futility. 9.4 Data Management and Statistical Analysis Plan Summary of Study Design This study will utilize an intent-to-treat, three-arm, randomized, double-blind, parallel design, placebo controlled study in order to simultaneously assess the impact of two medication therapies (amitriptyline and topiramate) for migraine prevention in children and adolescents. A total of 675 children and adolescents between age 8 and 17 with migraine will be enrolled into the trial at up to 40 sites across the U.S. Subjects will be randomized in a 2:2:1 fashion to receive either amitriptyline (n=270), topiramate (n=270), or placebo (n=135). Each subject will be followed for 34 weeks. All subjects will complete a headache diary during an initial 4 week baseline period, an 8 week titration period, and a 16 week constant dose period. This will be followed by a 2-week period for weaning subjects off medication, and 4 weeks off drug. Subjects will be recruited over a three year period, with an average of 17 subjects per site Randomization Randomization will be stratified by age (8-12, 13-17) and the baseline number of migraines per month (episodic: 4-14, chronic: 15 or more). Because this strategy provides four strata, we have elected not to stratify the randomization by site. The DCC will generate a randomization table for each strata using a permuted block design with random block sizes Statistical Analysis Plan Primary Hypotheses Primary Hypotheses #1 and #2: Amitriptyline and topiramate will result in an increased percentage of subjects meeting the primary endpoint compared to placebo. Primary Hypothesis #3: Topiramate will result in an increased percentage of subjects meeting the primary endpoint compared to amitriptyline. Each of these primary hypotheses will involve a comparison of migraine frequency (percentage of days with any migraine) between the last 4 weeks of treatment (weeks 20-24) and the 4-week baseline period. A

81 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean migraine episode will be defined as the period from the onset to the cessation of painful migraine symptoms, not to exceed 24 hours. If painful symptoms last > 24 hours, it will be considered a new and distinct migraine episode. If painful symptoms recur within 24 hours, it will be considered part of the initial migraine episode. Study subjects will be allowed to take acute pain medications, including OTC and triptans. A prior clinical trial of prevention medication in pediatric migraine found that the beneficial effects of topiramate over placebo increased throughout the duration of the trial, and reached the optimal outcome during the final 4 weeks. 45 Therefore, the choice was made to evaluate the final 4 weeks versus baseline as the primary analysis for the proposed trial. For each subject, the primary outcome will involve a determination of whether a 50% or greater reduction in migraine frequency was observed during the last 4 weeks of active treatment as compared with the migraine frequency during the 4-week baseline period. 3 The only exception will be that any subjects who must be removed from therapy prior to the completion of the 24-week treatment period will be considered failures with respect to the primary endpoint. The primary hypothesis will be assessed using a logistic regression model, adjusted for the two stratification variables. For example, the following model will be fit to these data: where Yi represents the binary variable indicating whether or not the i th subject met the primary outcome requirement of a 50% or greater reduction in migraine frequency, X1i is an indicator variable for the baseline age group for the i th subject (=0 if age 8-12, =1 if age 13-17), X2i is an indicator variable for the baseline number of migraines per month for the i th subject (=0 if 4-14, =1 if 15 or more), X3i is an indicator variable for whether the i th subject was randomized to the AMI group, and X4i is an indicator variable for whether the i th subject was randomized to the TPM group. Correspondingly, the three hypotheses of interest can be assessed by performing a hypothesis test of the three pair-wise treatment comparisons of interest: Amitriptyline vs. Placebo: vs.. Topiramate vs. Placebo: vs.. Amitriptyline vs. Topiramate: vs.. Each of the primary hypotheses will be tested using a chi-square test at a significance level of (= 0.05/3). Due to randomization, it is unlikely that important covariates (such as gender) will be imbalanced in this study. However, should important imbalances occur, we will control for these additional covariates in the logistic regression model.,

82 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Major Secondary Hypotheses 1-3 Major Secondary Hypotheses #1 and #2: Amitriptyline and topiramate will also result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to placebo. Major Secondary Hypothesis #3: Topiramate will also result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to amitriptyline. Three of the major secondary hypotheses (see Section ) will involve a comparison of the change in absolute migraine disability score, as measured by the PedMIDAS. Each subject will have a PedMIDAS score measured at baseline (covering the three months prior to enrollment) and the 24 weeks visit (the end of the maintenance period covering three months of enrollment). The outcome measure for this comparison will be the differences in these two PedMIDAS scores. The mean change from baseline over time for the two groups will be assessed using a linear regression model, adjusted for the baseline PedMIDAS score Major Secondary Hypothesis 4 Major Secondary Hypothesis #4: Amitriptyline and topiramate will be well tolerated. Major secondary hypothesis 4 (see Section 1.1.4) will assess tolerability for the two active treatment groups. Concerns regarding tolerability will be defined as either having a percentage of subjects who complete the entire 24-week treatment period for the two active treatments arms that is significantly lower than the percentage for placebo subjects or significantly less than 65%. %. To assess tolerability, the percentage of subjects who complete the entire treatment period will be compared across the three groups and the percentage in the active treatments will be examined to see if they are significantly greater than 35%. Both analyses will be conducted using standard chi-square tests Major Secondary Hypothesis 5 Major Secondary Hypothesis #5: Amitriptyline and topiramate will not differ from placebo on the occurrence of treatment-emergent serious adverse effects. Major secondary hypothesis 5 (see Section 1.1.4) will involve a comparison of treatment-related SAE s across the three treatment groups. This will be assessed in two ways. First, the percentage of subjects who experience any treatment-related SAE in each of the three groups will be compared using a chi-square test. Then, the rates of treatment-related SAE s across the three groups will be compared using a Poisson regression model.

83 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Decision Algorithm for Final Recommendation The main objective of this project is to empirically determine the best choice prevention medication for current practice. In order to accomplish this goal, we need an a priori decision making process that incorporates the novel data that will result from this 3 trials in one project. We propose a tiered approach to how the results of this trial will be used to pick a winner among the therapies tested. This algorithm is briefly described below. The first tier is based upon our primary endpoint, 50% reduction rate for migraine frequency. If both drugs are superior to placebo, but no clear winner can be identified based on the primary endpoint, we will consider the tier 2 endpoint of migraine-related disability. If one medication is superior to the other with respect to disability in tier 2, it will be declared the winner. If not, we would consider tolerability as the third tier. If no winner can be identified based upon all three criteria, then the outcome of the trial would be that both therapies are efficacious and individualized clinical decisions based on patient presentation should guide the first choice in practice. Of course, all recommendations must separately account for the safety data generated by this novel study and any safety concerns could trump the conclusions from any of the three tiers. Figure summarizes this decision making plan.

84 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Figure Decision Algorithm.

85 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean Impact of Missing Data Both primary analyses will follow the intent-to-treat paradigm. As such, it will be critically important to minimize the occurrence of missing data. Obviously, the optimal strategy for dealing with missing data is to make every effort to obtain complete data during the conduct of the study. Our team will use a variety of methods in order to minimize the percentage of missing data in this trial. Nevertheless, there is likely to be a small percentage of missing data. These subjects will be treated differently depending on the underlying reason for their data being missing. Subjects who have missing data due to tolerability issues (see Table below) will be considered treatment failures for the purposes of the primary analysis. For all other subjects who do not provide a final 24-week outcome, we will use a multiple imputation method to impute their outcome. This multiple imputation will be implemented using a model based on migraine frequency at baseline and each intermediate time-point for all subjects with observed data. We will use five separate implementations of this approach, and will average the parameters across all five imputations for the final analysis. Table Summary of Reasons for Early Termination Due to Tolerabilty / Safety Concerns End of study data collection Protocol reference, page # Reason reason Withdrawn-early termination Section , page 36 Dosage decrease at week 2 Withdrawn-early termination Section , page 36 Dosage decrease below baseline Withdrawn-early termination Section 6.2.4, item 14, page 49 QTc interval > 460 at visit 5 Withdrawn-early termination Section , page 70 Rash related to study drug or SJS rash Withdrawn-early termination Section , page 69 Repeated abnormal increased liver enzymes or bilirubin Withdrawn-early termination Section 7.3.4, page 70 Increased migraine frequency on lower dose after toxicity Withdrawn-early termination Section 7.3.4, page 70 Adverse events continue on lower dosage The approach described above will be used for reporting all primary study results. However, in order to test the robustness of our findings, we will employ a number of additional analyses using different approaches for handling the missing data: 1) Use a Kaplan-Meier curve to obtain the estimated percentage of subjects in each group with a 50% reduction in migraine frequency at 24 weeks. This approach adequately accounts for all censored subjects (assuming censoring is non-informative) and is valid under the assumption that once a child achieves a 50% reduction in migraine frequency, the reduction will be maintained throughout the remainder of the study.

86 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean 2) Assume that all subjects with missing data would not achieve a 50% reduction in migraine frequency at 24 weeks. This is a conservative approach that should dilute any true differences between the groups if dropout is purely random. We do not anticipate issues associated with missing days for subjects with completed diaries. The daily headache diary asks a subject to respond in a yes/no manner as to whether a headache occurred on each day and to check off typical migraine symptoms when present. For days that no value is marked, staff at the CCC will contact the subject to determine whether a headache occurred on that day and if the headache had migraine features. If no determination can be made, those days will be assumed to be migraine free. The CCC has established that there was >97% adherence to headache diary completion in their current single-site NIH trial of Drug and Non-Drug Treatment of Pediatric Chronic Headache. The same procedures will be used in this trial to minimize occurrences of missing data Secondary Analysis A number of additional secondary analyses are planned. A comparison of the mean rate of migraines in each group will be conducted using a Poisson regression model. The percentage of subjects with a 50% or greater reduction in migraine frequency and migraine disability across each 4-week block of time will be examined using a generalized linear model. Improvement in the PedMIDAS Grade Score 32 will also be assessed. The PedMIDAS will be classified using a grading scale, with values ranging from I (best) to IV (worst). For the purposes of analysis, improvement will be defined as an improvement of 2 units or more from baseline or a reported score of I at the end of treatment. The percentage of subjects with improvement in each of the treatment groups will be compared using a chi-square test. The patient satisfaction scores among subjects within each treatment group will be compared using a rank-based nonparametric test. A chi-square test will also be used to compare the improvement in migraineassociated symptoms (nausea, vomiting, photophobia, phonophobia) across the three groups. For this comparison, the percentage of migraines within each treatment group will be compared with the associated symptom. A generalized estimating equations model will also be utilized to assess the frequency of these symptoms over time across the groups Sample Size Justification The sample for this study is 675 subjects (135 placebo, 270 amitriptyline, and 270 topiramate.) Details regarding the planning and power analysis used to determine the sample size are recorded later in this section. In order to properly determine the required sample size for the trial, the CCC investigators completed a review of the limited literature pertaining to pediatric headache research. This review revealed four applicable studies. Three of these

87 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean studies evaluated topiramate versus placebo. 40,45,56 One study examined amitriptyline in a clinical database. 39 Based on this review, estimates of the proportion of subjects in each study group that will meet the primary endpoint of a 50% reduction in migraine frequency can be made. Table 9.4.3a demonstrates the percentage of subjects in existing pediatric headache prevention medication trials who achieve the primary endpoint of 50% reduction in migraine frequency. Table a Percentage of patients in existing pediatric headache prevention medication trials who achieve the primary endpoint of 50% reduction in migraine frequency. Reference PBO Response Rate TPM Response Rate Winner, % 54% Lakshmi, % 95% Lewis, % 83% The table shows an average response rate between 45% and 52% for the placebo group. There is generally more variability regarding the percentage of subjects on topiramate who achieve the primary endpoint. The average percentage of subjects achieving the primary endpoint is 77% in the topiramate group, but the effect ranges from 54% to 95% across the studies. Finally, a database from a prior study conducted at the CCC suggests that 70% of subjects taking amitriptyline will achieve a 50% or greater reduction in migraine frequency. 39 Of note, the Lakshmi sample and CCC database include representation from children with <15 and 15 migraines per month. For sample size estimation in this trial, it is critically important to keep in mind that this study essentially provides three trials in one. Hence, the chosen sample size must allow adequate power for testing all three primary hypotheses of interest. For the two comparisons with placebo, the results of our NINDS Clinical Research Collaboration survey demonstrated that the majority of responders felt that a minimum absolute increase of 20% in the percentage of subjects achieving a 50% reduction in migraine frequency was clinically meaningful and the threshold needed for the results of a placebo-controlled trial to change practice. The sample size has been chosen to ensure adequate power assuming that 50% of those on placebo versus 70% of those in each of the treatment groups will achieve a 50% or greater reduction in migraine frequency during the final 4 week endpoint evaluation of the 24-week treatment period. Clearly, smaller differences are important for the head-to-head comparison and it becomes much more difficult to define a minimum clinically meaningful effect (since one could argue that, assuming equal cost and safety profiles, any difference between two active treatments is clinically meaningful). As shown in Table 9.5.4, there is some preliminary evidence that suggests more than 85% of patients in the topiramate group may achieve the primary endpoint of 50% reduction in migraine

88 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean frequency. Thus, the study is powered to detect an absolute difference of 15% or greater in the percentage of subjects achieving a 50% reduction in migraine frequency for the head-to-head comparison. As stated above, since there are three primary hypotheses, a Bonferroni correction will be applied with a plan to test each hypothesis at the level. To allow for the drop-out rate for a multi-site trial, we assume a 15% drop-out rate. This selection was based on drop-out rate observed in the Lakshmi study 40.Under these assumptions, enrolling a total of 675 subjects (135 placebo, 270 amitriptyline, and 270 topiramate) provides: At least 85% power to detect all treatment/placebo comparisons 90% power to detect a head-to-head difference of 70% of those on amitriptyline vs. 85% of those on topiramate will achieve a greater than 50% reduction in migraine frequency This demonstrates that the study has adequate power to assess each primary hypothesis of interest. However, since the main objective of the study is to provide a recommendation to clinical investigators regarding the best treatment for children with migraine, the actual power of the study may be thought of as making a correct and generalizable decision using the following algorithm employing three tiers of decision making: The first tier is based upon our primary endpoint, 50% reduction rate for migraine frequency. If both drugs beat placebo, but no clear winner can be identified based on the primary endpoint, we will consider the tier 2 endpoint of migraine-related disability. If one medication is superior to the other with respect to disability in tier 2, it will be declared the winner. If not, we would consider tolerability as the third tier. If no winner can be identified based upon all three criteria, then the outcome of the trial would be that both therapies are efficacious and individualized clinical decisions based on patient presentation should guide the first choice in practice. Of course, all recommendations must separately account for the safety data generated by this novel study and any safety concerns could trump the conclusions from any of the three tiers. To assess the ability of the trial to meet this goal, a series of simulation studies were conducted. Each simulation consisted of 10,000 replications for each of 64 conditions defined by all possible combinations of plausible values for the true response rates in the three treatment groups: placebo {40%, 45%, 50%, 55%}, amitriptyline {50%, 60%, 70%, 80%}, and topiramate {50%, 70%, 85%, 95%}. For each simulated condition, one of four possible decisions was reached: (1) amitriptyline recommended first-line therapy, (2) topiramate recommended firstline therapy, (3) both amitriptyline and topiramate are recommended as first-line therapy use secondary endpoints to decide between the two, and (4) neither can be recommended as first-line therapy. The first row in Table b demonstrates that the approach maintains the type I error level at or below the desired level of The last two rows demonstrate the advantages of the overall three-in-one approach for selecting a winner. The last row, corresponding to the specific conditions used to justify the same size for

89 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _ clean the primary hypotheses, demonstrates that the overall approach provides benefits above and beyond what can be achieved with the separate hypotheses. As the table demonstrates, if this set of conditions holds true, our study would have nearly 100% power to correctly select topiramate as the appropriate first-line treatment for children with migraine. The second row demonstrates that the combined approach provides a greater likelihood of correctly selecting the winner when the absolute difference between the favorable response rates for amitriptyline and topiramate is only 10%. Under these conditions, our study would have 91% power to correctly select topiramate as first-line treatment - a substantial improvement over the 44% power for the individual head-to-head comparison Table b Probability of picking any winner and of picking the correct winner as a function of treatment response rate. Assumes type I error rate of 0.017, sample size of 135 in placebo group and 270 in amitriptyline and topiramate groups. PBO Rate AMI Rate TPM Rate Decision Prob. of Picking Winner Prob. of Picking Correct Winner* AMI Better TPM Better Both None 50% 50% 50% 1% 1% 0% 98% 3% 97% 50% 60% 70% 0% 71% 20% 9% 91% 91% 50% 70% 85% 0% 94% 6% 0% 100% 100% *If a single drug is best, the correct winner is thought to be selected if the final decision is for either that drug or both drugs. The conclusions obtained from the simulations are only strengthened by the fact that this only examines the first tier of the decision algorithm. Assuming that disability and tolerability trends will parallel those of the primary endpoint, this should only increase the overall probability of selecting the correct winner at the end of the trial Interim Monitoring Plan Overview The interim monitoring plan for this study must take into account the complex nature of the proposed project, i.e., the fact that this is really three separate trials in one. As a result, the proposed interim monitoring plan is based on the following premises: 1) The placebo arm will only be dropped if both active treatments are proven superior to placebo during the course of the study.

90 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean 2) The head-to-head comparison will be stopped early only if both active treatments have been proven superior to placebo during the course of the study Interim Monitoring Plan Specifics The following sections describe the proposed interim monitoring plan. This plan will be discussed at an initial DSMB meeting and revised accordingly Interim Analysis Focus Two interim efficacy assessments will occur when 225 and 450 subjects have completed their 24-week visit. We will use the Lan-DeMets alpha spending function approach with O Brien-Fleming stopping boundaries. Table below illustrates the proposed stopping boundaries under the assumption of three equally spaced analyses (two interim analyses and the planned final analysis). However, the Lan-DeMets method allows for analyses at unequal intervals and does not require pre-specifying the time of any interim analyses. Therefore, this method has the flexibility to adapt should the DSMB request an interim analysis at an alternative time point or if the DSMB is unavailable at the time of a scheduled interim analysis. Importantly, the placebo arm will be dropped only if both active treatments cross the stopping boundary at one of the pre-specified interim assessments. Importantly, if only one crosses the boundary at the first look, both will be assessed again at the second look and the placebo arm dropped only if both cross the bound at the second review. Table O Brien-Fleming Stopping Boundaries Assuming Three Equally Spaced Analyses. Efficacy Number of Subjects Completing Nominal P-Value Analysis 24-Week Follow-Up to Conclude Efficacy < Futility Assessment Futility will be assessed at the time of each interim analysis. We will report the conditional power based on the pre-specified t of interest (Lan, Simon, & Halperin, 1982). If both conditional power values fall below 20%, we would recommend stopping the trial early for futility. Due to the complex nature of the study, and the fact that definitive evidence would be required if neither of the active treatments proved superior to placebo, we propose that the trial should only be stopped for futility if both treatments were simultaneously futile (which has an exceptionally low probability) Safety Assessment-Periodic Assessment Safety will be assessed in a periodic manner throughout the study. The medical monitor will receive tabulations of all AE s/sae s on a monthly basis. Safety will be assessed in two ways both the percentage of subjects who experience

91 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean any AE and the rate of AE s across the three groups will be compared, by body system, using standard chi-square tests. The additional questions related to whether the AE/SAE is related to treatment, is unanticipated, or is severe will be used to subset these into a series of additional tables. This monthly review will identify any disconcerting discrepancy in the frequency of an AE/SAE between the treatment groups, with particular emphasis placed on the four AE s of most concern to practicing clinicians due to the known side effect profiles of these two treatments: (1) depression, (2) suicidal ideation, (3) fatigue, and (4) slow thinking or problems with attention. Should any such discrepancy arise, or if the medical monitor feels that an SAE should be shared on an emergency basis with the participating clinical sites, he will contact the DSMB to request a special review Safety Assessment-Data from Questionnaires Data obtained using psychometrically-sound measures of depression, attention, and cognitive functioning from the current NINDS Common Data Elements will also be available for each subject in this trial at baseline, end of drug titration (week 8), and end of maintenance (week 24). To further understand the impact of the study medications on these important outcomes beyond our prospective AE monitoring approach, each monthly report will also include a comparison of the following across the three treatment groups: (1) total score from the Child Depression Inventory (CDI), (2) frequency of subjects that answer yes to intent and ideation on question #9 from the CDI, (3) Behavior Rating Inventory of Executive Function (BRIEF) global executive composite score. This information will help supplement the AE information the medical monitor reviews on a regular basis Safety Assessment-Reports to the DSMB A DSMB closed session report will include all available safety information to allow the DSMB to monitor for trends. These unblinded reports will also include a memo from the Safety Monitor to allow the communication of any concerns or findings that may be of interest to the DSMB in their study deliberations. In general, interim safety monitoring will rely on these interim reviews to identify any potential trends of interest. However, due to the increased concern associated with the risk of suicidal ideation, we will use a more stringent guideline to trigger a concern for this variable. If the difference in the incidence of suicidal ideation between either active treatment and placebo becomes statistically significant at the 0.05 level at any of the interim reviews, the DSMB will determine whether the trial should discontinue the affected treatment arm. 10 DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORTING 10.1 Records to be Kept Source documentation will be retained at each site in support of the Electronic Case Report Forms. Source documentation will include the report of all study examinations, procedures, laboratory results, headache diaries, PedMIDAS forms, HIT-6 forms, questionnaires, drug

92 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean accountability records, concomitant medication records, ECG tracings, reports of adverse events, and essential documents Document Retention In compliance with the ICH/GCP guidelines, the investigator and study staff will maintain accurate and timely entry of source data into the ecrfs as directed in the manual of operations. All source documents that support the ecrf data collected from each subject will be retained in a secure setting with limited access by non-study staff. All remaining trial documents as specified in Essential Documents for the Conduct of a Clinical Trial and as specified by the manual of operations will be retained in a secured setting also. The investigator and study staff will take measures to prevent accidental or premature destruction of these documents. Essential documents must be retained until the sponsor has notified the investigator that they may be destroyed. These documents will be retained for a longer period if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator as to when these documents no longer need to be retained. If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping the study records, custody must be transferred to an investigator who will accept the responsibility. In addition, in compliance with the NINDS request for a central data access point for future analyses, the study data will be retained indefinitely in a data storage repository that will allow investigators a constant source of material with all personal information removed to be used for medical scientific, educational or research purposes. Data from this long term storage site will be available to other researchers for future study of migraine as well as other diseases after the study investigators have completed their analyses and publications have been completed and accepted. The processes for other investigators to gain access to the study data are in development by the CHAMP principal investigators and the NINDS. More specifics will be included in a future protocol revision Electronic Case Report Form (ecrf) The ecrfs will be available for data entry for each subject. Data must be entered onto ecrfs in the required timeline as specified in the manual of operations. Source data must be available to support every entry into the ecrf. Source data must be recorded in English. All source forms must be completed in black ballpoint pen and must be accurate, legible contemporaneous, objective and attributable. All source documents that support the ecrf data collected from each subject will be retained in a secure setting with limited access by non-study staff. A locked filing cabinet inside a locked room in the study center is preferable for retention of study records. Every attempt will be made to maintain the confidentiality of study subjects including use of coded numeric identities instead of subjects names Missing Data Overview Both primary analyses will follow the intent-to-treat paradigm. As such, it will be critically important to minimize the occurrence of missing data. Obviously, the optimal strategy for dealing with missing data is to make every effort to obtain complete data during the conduct of the study. The DCC and CCC Staff will use a variety of methods

93 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean in order to minimize the percentage of missing data in this trial. Nevertheless, there is likely to be a small percentage of missing data Missing Data from Withdrawn Subjects For subjects who withdraw completely from study participation before their 24-week outcome can be obtained, we will use a multiple imputation method to impute their outcome. This multiple imputation will be implemented using a model based on migraine frequency at baseline and each intermediate time-point for all subjects with observed data. We will use five separate implementations of this approach, and will average the parameters across all five imputations for the final analysis. The approach described above will be used for reporting all primary study results. However, in order to test the robustness of our findings, we will employ a number of additional analyses using different approaches for handling the missing data: 3) Use a Kaplan-Meier curve to obtain the estimated percentage of subjects in each group with a 50% reduction in migraine frequency at 24 weeks. This approach adequately accounts for all censored subjects (assuming censoring is noninformative) and is valid under the assumption that once a child achieves a 50% reduction in migraine frequency, the reduction will be maintained throughout the remainder of the study. 4) Assume that all subjects with missing data would not achieve a 50% reduction in migraine frequency at 24 weeks. This is a conservative approach that should dilute any true differences between the groups if dropout is purely random Missing Data from Headache Diary The daily headache diary asks a subject to respond in a yes/no manner as to whether a headache occurred on each day and to check off typical migraine symptoms when present. For days that no value is marked, staff at the study site will contact the subject to determine whether a headache occurred on that day and if the headache had migraine features. If no determination can be made, those days will be assumed to be migrainefree Role of Data Management Overview Successful study data management involves a partnership between study staff at each clinical site and the DCC Clinical Site Responsibilities in Data Collection and Management Every investigator and the study staff at each site are responsible for the collection of the study data as original source. Further, they are responsible for data entry from the source records onto the ecrfs. The ecrfs will be continuously available for data entry for each subject. Data must be entered onto ecrfs in the required timeline as specified in the manual of operations. For most study data points the timeline for entry onto the ecrf is within 5 business days following the completion of a study visit.

94 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean Source data must be available to support every entry into the ecrf. Source data must be recorded in English. All source forms must be completed in black ballpoint pen and must be accurate, legible contemporaneous, objective and attributable Electronic Case Report Forms (ecrfs) The ecrfs are to be completed within 5 business days of the subject s visit, with the exception of results of tests performed outside the investigator s office, so that the online record will always reflects the latest observations on the subjects enrolled and active in the trial. The ecrfs will be completed according to the sponsor s instructions, and reviewed by the DCC staff to determine ecrf acceptability. If necessary, queries will be generated and transmitted to the study site for resolution Data Management by the Data Coordinating Center (DCC) Approach to Data Management The DCC is a component of the Clinical Trials Statistical and Data Management Center (CTSDMC) at the University of Iowa. The CTSDMC has developed extensive standard operating procedures that guide the development and maintenance of our web and database systems. The CTSDMC has developed a set of core functions that have been carefully validated and can be employed in multiple applications. The development of these core functions has greatly reduced the time and effort that it takes to implement an electronic data capture and data management system Online Data Entry The CTSDMC online data entry systems have been designed and implemented using Microsoft technologies and development tools. The development environment used for creating the online data entry systems employs Microsoft Visual Studio.Net to create Active Server Pages (ASP/ASP.Net). ASP is a server-side scripting technology from Microsoft that allows web developers to generate dynamic, data-driven web applications. ASP scripts are able to connect directly to the SQL Server database by using ActiveX Data Objects (ADO). By using Microsoft products (Internet Information Server 7 and MS SQL Server 2008), the Center is able to achieve a high level of integration between our web and database systems Data Security In order to maintain strict security for data entered over the Internet, all data are encrypted using the Secure Sockets Layer (SSL) protocol. This protocol allows an encrypted link to be established between the DCC web server and the computer at each clinical site. CTSDMC data entry systems have secure firewalls to protect from viral attacks or hacking via the Internet. In addition, all systems are protected by Norton Antivirus software and are swept daily. The web servers are monitored for any suspicious activity that would indicate an attempt to break into the system. Access to data entry screens is ID and password protected. The system requires strong passwords (a minimum of eight characters, at least two of which must be symbolic or numeric). Passwords must be changed at regular intervals, or minimum of every 6 months. Previously used passwords may not be reused. All passwords stored at the CTSDMC are encrypted to prevent unauthorized usage.

95 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean Secured Data Location All CTSDMC Servers are located in a secured area, with access restricted to CTSDMC Personnel only. The Servers have internal IP Security Policies that limit exposure from unauthorized sources. The Systems Coordinator carefully monitors the accounts of CTSDMC Staff with database update rights. Other CTSDMC Staff database accounts are "read-only" to prevent unauthorized modification of data. The CTSDMC database server, file server, and access server are key-locked to prevent unauthorized use Redundancy Plan for Data Security The CTSDMC strives to provide 24-hour/7-day per week coverage by maintaining replication on mission-critical web and database servers. The replication process allows data saved to the primary server to be simultaneously written to a secondary server. If a failure or service interruption occurs on the primary server, a rapid failover to the secondary server allows for application recovery. The CTSDMC maintains the primary and secondary servers in separate locations to protect against extended power outages or natural disasters Data Recovery Plan All servers are backed-up regularly utilizing Veritas Backup Exec Software on a PowerVault 124T tape unit, providing eight tapes in rotation. This package allows the CTSDMC to perform complete back-ups of all Internet, database, and file servers. A full back-up of all data is performed weekly, and incremental backups are performed the other five days. This procedure allows the CTSDMC to recover data from a number of different time points if necessary. The weekly back-up tapes are stored in a secured, offsite location to provide protection from natural disasters. In addition, a safety-deposit box is retained to store tapes of frozen datasets and electronic copies of interim, safety, and final reports Data System Compliance with 21 CRF Part 11 All data entry systems at the CTSDMC are developed to be in compliance with FDA regulations outlined in 21 CFR Part 11, and in accordance with Good Clinical Practices. The DCC will train and certify all data entry personnel in the data entry process before they are granted permission to enter data into the production database. The Center maintains an Internet-based training system in which personnel perform data entry tasks and then complete a quiz. Based on successful performance, a user is certified and assigned a role that grants them authorization to enter data into designated areas Plan for Development of Database This trial uses a web-based data entry system. Data entry screens for ecrfs are modeled on paper case report forms that were developed as design prototypes. In order to prevent invalid values from being entered into the database, radio buttons and dropdown lists are used whenever possible. When it is necessary to enter a numeric value, such as a subject s weight, the system includes checks that question values that are outside a defined range or allow data entry personnel to override confirmed out-ofrange values. Checks are also performed for valid values, missing values, and logical consistency between items on the same form (intra-form checks) or between items from different forms (inter-form checks). Any discrepancy generates an edit screen that

96 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean prompts the user to resolve the discrepancy by correcting the data or indicating that the discrepant data are valid and acceptable. Software development is automated and applications are written to build a data dictionary for each database application. The data dictionary tool contains information on all data items collected by the study, including variable names, variable types, valid values, skip-out rules, mandatory field checks, range checks, overridable fields, and value labels. Database tables and initial web screens are developed directly from the data dictionary using programming logic designed to manage the data entry tables, skipout rules, and initial variable validation checks. All application development is based on user requirement documents that are developed through a collaboration of the DCC data management team, the DCC IT team, and approved by the DCC and CCC teams After a program is written, it undergoes multiphase testing to ensure that it is working properly to test the accuracy of the code in a development environment. Next, an independent team of DCC data managers evaluates the program in a test environment using a predefined and approved testing plan. This plan includes a variety of tests, including validation of the data dictionary, evaluations of system security, faults, error messages, roles, serviceability, and system performance under a heavy volume of data (i.e., simultaneous data entry by multiple users) Validation of Database During validation testing, an application (i.e., Fogbugz) is used to document/resolve errors and to identify design issues. Following validation in the Test environment, the software is moved into a staging environment. This environment allows for a final look in a clean, stable environment that mirrors production. The software is once again validated in the staging environment. When any errors are documented and resolved, the software is ready to be moved into Production Case Report Forms Data entry screens are prepared to resemble case report forms prepared as part of the ecrf design process Training for Study Data Entry All data entry personnel are trained and certified in the data entry process prior to allowing them permission to perform data entry into the production database. The Center maintains an internet-based training system in which personnel perform data entry tasks and then complete a quiz. Based on successful performance, a user is certified and assigned a role that grants them authorization to enter data into designated areas. A significant advantage of an internet-based data system is that it automatically provides realtime reminders of incomplete data forms and discrepant values (i.e., missing, out of range). While a data entry session can be saved at any time, the system defines required fields that must be included before a form is submitted. Each time the study web page is accessed, a list of all incomplete forms appears on the screen. After an incomplete form has been accessed, the user is directed to complete all required fields before the form may be submitted. This process greatly facilitates the timely collection and entry of study data, and greatly reduces problems associated with missing data.

97 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean 10.9 Quality Assurance The accuracy and reliability of data are paramount to the success of this study. Actions will be taken to assure that reliable and accurate data are obtained. This will begin with the selection of qualified investigators and appropriate study centers. The second most important action to data and study quality assurance will be study staff training. Training the study staff in all of the protocol procedures prior to the beginning of study enrollment at a center, and providing ongoing training during the study as procedures are updated or the protocol is revised will be a priority. The third action for data quality assurance will be periodic monitoring visits conducted by the DCC monitoring staff to verify source data and correct entry onto the ecrf. The timing of these periodic visits and the extent of reviews will be documented in the monitoring plan contained in the study manual of operations. Regular review of ecrf data by monitoring staff will take place between the periodic visits to identify any trends or systematic errors that may occur. Case Report Forms, including questionnaires will be reviewed for accuracy and completeness by DCC monitoring staff and any discrepancies will be resolved with the investigator or study staff, as appropriate. Appropriate computer edit programs will be run to assure the accuracy of the database Access to Study Source The study quality assurance program will require access to all study records, including source documents, for inspection and comparison with the ecrfs. Subject privacy must, however, be respected. Sufficient prior notice will be provided to allow the investigator to prepare properly for a monitoring visit. Findings from routine monitoring visits will be discussed with the investigator Notification of Sponsor of External Regulatory Review Auditing procedures may also be conducted by agents of any regulatory body reviewing the results of this study. The investigators should immediately notify the sponsor if they have been contacted by any regulatory agency concerning an upcoming inspection Adverse Experience Reporting The safety of study subjects is of the utmost concern to the sponsor and investigators in this study. Reporting of complete and accurate safety information according to acceptable timelines is key to the protection of subjects, and is required by the regulatory agencies with oversight of this study. Standard Operating Procedures for adverse event reporting have been developed by the sponsor to ensure compliance with regulatory requirements, including grading of adverse events according to the NCI Common Toxicity Criteria III, and a reporting timeline of 14 days for adverse events and one business day for SAEs. Adverse events regarding changes in subject weight during the study will be determined using the CDC growth curve for children ages A change from baseline of two isobars during the study will be determined to be a grade 2 adverse event. This study will be conducted in compliance with those procedures Adverse Event Classification Definitions Adverse Event (AE) An adverse event is defined as any untoward medical occurrence in a subject administered an investigational pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding),

98 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. This includes any occurrence that is new in onset or increased in severity, grade or frequency from the baseline condition, or abnormal results of diagnostic procedures including laboratory test abnormalities which are considered AEs if they: result in discontinuation from the study, require treatment or any other therapeutic intervention, require further diagnostic evaluation (excluding a repetition of the same procedure to confirm the abnormality), are associated with clinical signs or symptoms judged by the investigator to have a significant clinical impact Serious Adverse Event Any untoward medical occurrence that at any dose: results in death, is life-threatening The subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an expression of suicidal ideation or action. Note: Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the outcomes listed in the definition above. For purposes of this study, subject pregnancy will be considered an important medical event and will be reported for tracking purposes only as an SAE Expectedness of Adverse Experiences Expected Adverse Event An expected AE is one which is listed in the package insert/summary of product characteristics for amitriptyline or topiramate. The most common expected adverse events associated with both of these drugs are included in the protocol. For this study, headache and migraine headache are expected and will not be reported as adverse events. Expected Adverse Events for amitriptyline and topiramate are listed in Section 7.2.

99 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean Unexpected Adverse Event An unexpected AE is one for which the nature or severity is not consistent with the applicable product information (e.g., Investigator s Brochure) or package insert/summary of product characteristics for an approved product. Expectedness of serious adverse experiences will be reviewed by the Medical Monitor and final interpretations made by the sponsor or his study staff Relatedness or Attribution of Association of an Adverse Event (AE) With Use of the Study Drug An AE is considered associated with the use of the drug if the attribution is possible, probable, or definite. Table describes the attributes of each of these categories. Attribution Unrelated Unlikely Table Attribution of Adverse Events. Definition An AE which is not related to the use of the drug An AE for which an alternative explanation is more likely (e.g., concomitant drug(s), concomitant disease(s), and/or the relationship in time suggests that a causal relationship is unlikely Possible An AE which might be due to the use of the drug. An alternative explanation e.g., concomitant drug(s), concomitant disease(s) is inconclusive. The relationship in time is reasonable; therefore the causal relationship cannot be excluded Probable Definite An AE which might be due to the use of the drug. The relationship in time is suggestive. An alternative explanation is less likely e.g., concomitant drug(s), concomitant disease(s) An AE, which is listed as a possible adverse reaction and cannot be reasonably explained by an alternative explanation e.g., concomitant drug(s), concomitant disease(s). The relationship in time is very suggestive Adverse Event Procedures All Adverse Events All AEs will be reported after the first dose of study medication has been administered and through the last dose of study medication administration. SAE s occurring within a period of 30 days following the last intake of study medication will also be handled according to this procedure. Those meeting the definition of SAE must be reported using the AE Form submitted urgently. Medical events that occur between the signing of the Informed Consent and the first intake of study drug will be documented in the medical history source, but not included on the ecrf. Each subject or their parent or guardian, should voluntarily report any AEs or in response to general, non-directed questioning (e.g., How has your health been since the last visit? ). In addition a symptom questionnaire will be used at each visit and each phone visit to elicit a targeted symptom list. For each AE volunteered by the subject or their parent or guardian, the investigator should obtain all the information required to complete the AE page of the CRF, in accordance with the guidelines that accompany it in the manual of operations.

100 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must be recorded using medical terminology in the source document and on the CRF. Whenever possible, diagnoses should be given when signs and symptoms are due to a common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as upper respiratory infection ). Investigators must record on the CRF their opinion concerning the relationship of the AE to study therapy. All measures required for AE management must be recorded in the source document and reported according to sponsor instructions and timelines. Adverse events must be reported on the ecrf within 14 business days of report by the subject or observation by the study staff. The sponsor assumes responsibility for appropriate reporting of AE s to the regulatory authorities. The sponsor will also report to the investigator all serious AE s that are unexpected and associated with the use of the drug. The investigator must report these events to the appropriate IRB in accordance with local regulations Serious Adverse Events All SAEs occurring during the clinical trials must be reported within one working day of the site becoming aware of the event to the sponsor or the sponsor s study staff. The initial report of an SAE will be made via the online adverse event reporting system in the ecrf. The investigator must initially provide as much information as is available but will be required to submit the minimal information: i.e., subject ID, the date of the event, and the adverse event term within one working day. Follow-up reports may be required as additional information is learned by the site. For any adverse event meeting the definition of serious, the Independent Medical Monitor will be notified via to review the event for relatedness and expectedness. If the Independent Medical Monitor determines that the event is indeed serious, related, unexpected and life-threatening, or death, then an expedited report will be submitted to the FDA with a MedWatch form. All Adverse Events will be reported to the members of the DSMB, NINDS, and IRBs as required. All Adverse Events will be coded using MedDRA. Adverse Events will be reviewed periodically by the Independent Medical Monitor in aggregate for trends. All initial reports of an SAE must be confirmed within three business days by an updated written, more detailed report submitted in the ecrf. Instructions for completion of the SAE report are detailed in the manual of operations. All SAEs that have not resolved by the end of the study, or that have not resolved upon discontinuation of the subject s involvement with the study, must be followed until either: the event resolves, or stabilizes, or

101 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean the event returns to baseline, if a baseline value is available, or the event can be attributed to other than the study drug, or to other than study conduct Reporting Pregnancy as a Serious Adverse Event Any pregnancy that occurs during this study must be reported to the DCC utilizing the Adverse Event report form submitted urgently. This report is for tracking purposes only. All pregnancies that are identified during the study must be followed to conclusion and the outcome of each must be reported. The investigator should report all pregnancies within 24 hours (as described in section ) using the AE report form including all known information about the pregnancy, such as any completed lab tests and their results, the health status of the subject and the fetus and the plan for follow up and monitoring during the pregnancy. The initial report should include the date of permanent discontinuation of study drug. The investigator should counsel the subject and her parents about the potential risks to the fetus of study drug exposure, but should not attempt to persuade the subject regarding continuation or discontinuation of the pregnancy. A subject who becomes pregnant while on the study will be counseled to discuss her choices with her own physician. Monitoring of the subject should continue until the conclusion of the pregnancy, and a follow-up AE report form detailing the outcome of the pregnancy should be submitted within fifteen calendar days of the first knowledge of the delivery and should specifically state whether or not a congenital anomaly or birth defect has been reported in the baby. 11 HUMAN SUBJECTS 11.1 Ongoing Review of Potential Risks The risks associated with participation in this study are associated with potential side effects of study medication (amitriptyline or topiramate). Potential risks associated with side effects or adverse events will be closely monitored in this trial. In particular, some expected side effects of these medications are of particular interest to pediatric headache specialists, including increased fatigue, depressive symptoms, suicidal ideation, and cognitive and attention problems (including impact on school performance). A structured symptom checklist, in addition to an open-ended questionnaire about possible adverse health experiences, has been designed for this trial to systematically and prospectively assess potential risks to youth who are taking amitriptyline or topiramate. It is also important to assess for these specific side effects in youth taking a placebo in a blinded-study of migraine therapies. Amitriptyline has been associated with relatively minor side effects in headache studies. Our Headache Center s extensive experience in treating pediatric headache and the low level of adverse events in our current trial where every subject receives amitriptyline suggests that doses of amitriptyline at 1 mg/kg/day are generally well-tolerated by children and adolescents. Topiramate has been associated with relatively minor side effects in headache studies. Our Headache Center s extensive experience in treating pediatric headache and the few trials that have been reported using this medication in youth suggests that doses of topiramate at mg/day are generally well-tolerated by children and adolescents. Risks to confidentiality are minimal because all data will be coded by subject number Adequacy of Protection Against Risks

102 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean Recruitment and Informed Consent Potential subjects will be identified during an evaluation in the participating clinical trial site. The neurologist/physician/nurse practitioner who examines the child or adolescent will explicitly state that they will continue to receive the same high quality of care from them should they choose not to participate. If the family is interested in participating, informed consent and assent will be obtained. The neurologist / physician / nurse practitioner, research nurse/coordinator, and/or the site PI will provide a full description of the study and answer any questions that the family may have. Approved procedures and forms of the IRB for each site will be utilized (or if needed for a site, Cincinnati Children s IRB procedures and forms will be used). The purposes and the risks of the investigation and the procedures of the study will be explained. The families will be explicitly told that their medical care will not be affected if they choose not to participate. No screening or assessment procedure will occur until after written consent is obtained Protection against Risk Baseline evaluations and tests (ECG, pregnancy screening, blood testing) will be conducted and exclusion criteria applied to ensure that subjects who are enrolled are not at known risk (e.g., use of amitriptyline during pregnancy or if ECG abnormal). During the trial, these evaluations and tests will be repeated (e.g., ECG at visit 5, pregnancy screening at every visit, blood testing at visits 5 and 8) to ensure that known risks do not appear (drug toxicity, pregnancy, ECG abnormality appearing upon exposure to amitriptyline). Side effects related to the medication intervention (amitriptyline or topiramate) will be closely monitored by the study physicians/nurse practitioners and research coordinators through regularly scheduled safety visits and using the NCI Common Toxicity Criteria Version III. Study site staff will closely monitor co-morbid conditions (such as asthma, irritable bowel syndrome, depressed feelings, etc.) for the duration of the study. Adverse Events will be reported from the time of randomization until 30 days following the last day of drug exposure. Adverse events will be classified as serious based on FDA regulations (21 CFR ). Toxicity reporting will be separated into organ systems and definitions for severity will be determined according to those contained in the Common Toxicity Criteria, Version III from the National Cancer Institute (NCI). The FDA has recommended the use of the NCI Common Toxicity Criteria, Version III for other clinical trials in children conducted at Cincinnati Children s after they had determined that the definitions were appropriate for pediatric trial use. The Common Toxicity Criteria provide standardized definitions of severity for a very large list of toxicities seen in clinical trials, including both symptoms and laboratory abnormalities. If a specific event is not included in the listings of the NCI Common Toxicity Criteria, then the clinical site investigator will rate the severity according to the general definitions provided for the categories of Mild, Moderate, Severe, Life-threatening in the Common Toxicity Criteria. The use of these standard definitions will ensure that there is uniformity in assessing severity of adverse events by the medical providers involved in this trial. The investigators in this trial will complete an Adverse Event form at each visit for every symptom or laboratory adverse event detected using the Online Adverse Event Reporting System developed by the DCC. For any adverse event meeting the definition of serious, the Independent Medical Monitor will be notified

103 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean via to review the event for relatedness and expectedness. If the Independent Medical Monitor determines that the event is indeed serious, related, unexpected and life-threatening or death, then an expedited report will be submitted to the FDA with a MedWatch form. All Adverse Events will be reported to the DSMB, NINDS, and IRB as required. All Adverse Events will be coded using MedDRA. Adverse Events will be reviewed periodically by the Independent Medical Monitor in aggregate for trends Protection against the Risk of Suicidality and Possible Clinical Depression The structured symptom review that will occur at each study visit specifically asks about suicidal ideation and increased sadness. A positive response to either question regarding wanting to hurt yourself or have been hurting yourself would require the site coordinator to immediately contact the site PI and a clinical evaluation will occur during the study visit, including an assessment of present lethality using either the C- SSRS Baseline or C-SSRS Since Last Visit Questionnaire. Based upon assessment of possible risk to self or others, the site PI will initiate locally appropriate emergency care for the subject and/or appropriate outpatient follow-up. Also, the Child Depression Inventory, a secondary measure in this trial to be administered at the screening visit, visit 5, and visit 8, has one item that asks about suicidality (Item 9 answers of concern: I want to kill myself. or I think about killing myself but I would not do it ) and yields a total score for which a cut-off of a T score of 65 is a positive screen for further clinical evaluation of a diagnosis of clinical depression. When the CDI is given, the site coordinator will score it during the visit and review the specific response to Item 9 about suicidality. If a subject reports suicidal ideation, either as part of the safety/adverse event assessment at each study visit (using open-ended questioning or the structured checklist that specifically asks about suicidality), or as part of the secondary measures assessment at the screening visit, visit 5, or visit 8 in which the CDI questionnaire that includes a specific suicidality question is administered, the site coordinator will immediately contact the site PI and a clinical evaluation will occur during the study visit, including an assessment of present lethality using either the C- SSRS Baseline or C-SSRS Since Last Visit Questionnaire. Based upon assessment of possible risk to self or others, the site PI will initiate locally appropriate emergency care for the subject and/or appropriate outpatient follow-up. If suicidality is considered to be related to the study medication, the site PI will make appropriate decisions about continuation, lowering dose, or stopping the study medication. Also, within 24 hours, the CCC PIs (Drs. Powers, a psychologist, and Hershey, a neurologist) will be notified of the incident and the action plan. This situation will also be documented per the study adverse event process and the medical monitor will be notified per the SAE plan detailed above. If a subject reports increased sadness as part of the adverse event monitoring procedure that is of clinical concern to the coordinator and site PI, or on the CDI has a total T score greater than 65, the site coordinator will immediately contact the site PI and a clinical evaluation will occur during the study visit. Based upon assessment of depression, the site PI will initiate locally appropriate care for the subject and/or appropriate outpatient follow-up. If clinically significant depression is considered to be related to the study medication, the site PI will make appropriate decisions about continuation, lowering dose, or stopping the study medication. Also, within 24 hours, the CCC PIs (Drs. Powers, a psychologist, and Hershey, a neurologist) will be notified of the positive screening for depression and the action plan developed. This situation will also be documented per the study adverse event process.

104 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean Plan for Protection against School Performance Decline If a subject reports marked decline in school performance (e.g., typical A-B student now failing tests/classes) as part of the adverse event monitoring procedure (open ended question followed by structured symptom questionnaire), the site PI will conduct a clinical evaluation and initiate appropriate local referrals. If clinically significant decline in school performance is considered to be related to the study medication, the site PI will make appropriate decisions about continuation, lowering dose, or stopping the study medication. Also, within 24 hours, the CCC PIs (Drs. Powers, a psychologist, and Hershey, a neurologist) will be notified of the incident and the action plan. This situation will also be documented per the study adverse event process Institutional Review Board (IRB) Review and Informed Consent This protocol and the informed consent document and any subsequent modifications will be reviewed and approved by the IRB or ethics committee responsible for oversight of the study. A signed consent form will be obtained from the subject. For subjects who cannot consent for themselves, such as those below the legal age, a parent, legal guardian, or person with power of attorney, must sign the consent form; additionally, the subject's assent must also be obtained if he or she is able to understand the nature, significance, and risks associated with the study. The consent form will describe the purpose of the study, the procedures to be followed, and the risks and benefits of participation. A copy of the signed consent form will be given to the subject, parent, or legal guardian, and this fact will be documented in the subject s record Subject Confidentiality All laboratory specimens, evaluation forms, reports, video recordings, and other records that leave the site will be identified only by the Study Identification Number (SID) to maintain subject confidentiality. All records will be kept in a locked file cabinet. All computer entry and networking programs will be done using SIDs only. Clinical information will not be released without written permission of the subject, except as necessary for monitoring by IRB, the FDA, the NINDS, the OHRP, the sponsor, or the sponsor s designee. A description of this clinical trial will be available on as required by U.S. law. This web site will not include information that can identify an individual subject. At most, the web site will include a summary of the results. The web site can be searched at any time Subject Compensation To help cover the costs of participating in this study, the subject s family will receive a payment per visit for the costs/inconvenience/time (for example: travel, parking, and meals) associated with participation in the research study. If the subject does not finish the whole study, reimbursement will be provided for each study visit that is completed. The study medication, the study visits, and medical testing needed for the study will be provided at no charge to the subject. The compensation guidelines will be customized for each site to ensure that the study (1) adheres to all IRB guidelines at the site and (2) accurately estimates travel costs based on the average distance subjects will travel to the site.

105 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean 11.6 Study Modification/Discontinuation The study may be modified or discontinued at any time by the IRB, the NINDS, the sponsor, the OHRP, the FDA, or other government agencies as part of their duties to ensure that research subjects are protected. All protocol amendments must be issued by the sponsor, signed and dated by the investigator, and should not be implemented without prior IRB approval, except where necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in of telephone number(s)). In situations requiring a departure from the protocol, the investigator or other study staff will contact the project manager or other appropriate sponsor representative by fax or telephone. If possible, this contact will be made before implementing any departure from protocol. In all cases, contact with the sponsor must be made, as soon as possible, in order to discuss the situation and agree on an appropriate course of action. The CRF and source document will describe any departure from the protocol and the circumstances requiring it. 12 PUBLICATION OF RESEARCH FINDINGS Publication of the results of this trial will be governed by the policies and procedures developed by the Executive Committee. Any presentation, abstract, or manuscript will be made available for review by the sponsor and the NINDS prior to submission. An investigator who wishes to publish the results of this study must contact the publication committee in order to obtain permission for the required data analyses and queries of the trial database. 13 REFERENCES 1. Hershey AD, Powers SW, Winner P, and Kabbouche M. Pediatric Headaches in Clinical Practice. West Sussex, UK John WIley & Sons, Ltd., Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, and Silberstein S. Practice parameter: pharmacological treatment of migraine headache in children and adolescents: report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology 63: , Tfelt-Hansen P, Block G, Dahlof C, Diener HC, Ferrari MD, Goadsby PJ, Guidetti V, Jones B, Lipton RB, Massiou H, Meinert C, Sandrini G, Steiner T, and Winter PB. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 20: , Abu-Arefeh I, and Russell G. Prevalence of headache and migraine in schoolchildren. BMJ 309: , PMCID: Stewart WF, Linet MS, Celentano DD, Van Natta M, and Ziegler D. Age- and sex-specific incidence rates of migraine with and without visual aura. Am J Epidemiol 134: , 1991.

106 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean 6. Stewart WF, Lipton RB, Celentano DD, and Reed ML. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA 267: 64-69, Split W, and Neuman W. Epidemiology of migraine among students from randomly selected secondary schools in Lodz. Headache 39: , Stang PE, Crown WH, Bizier R, Chatterton ML, and White R. The family impact and costs of migraine. Am J Manag Care 10: , Bille B. A 40-year follow-up of school children with migraine. Cephalalgia 17: ; discussion 487, Stewart WF, Ricci JA, Chee E, Morganstein D, and Lipton R. Lost productive time and cost due to common pain conditions in the US workforce. JAMA 290: , Victor S, and Ryan SW. Drugs for preventing migraine headaches in children. Cochrane Database Syst Rev CD002761, Schwedt TJ, and Shapiro RE. Funding of research on headache disorders by the National Institutes of Health. Headache 49: , PMCID:PMC Journal-In Process. 13. Svensson DA, Larsson B, Bille B, and Lichtenstein P. Genetic and environmental influences on recurrent headaches in eight to nine-year-old twins. Cephalalgia 19: , Russell MB, Iselius L, and Olesen J. Migraine without aura and migraine with aura are inherited disorders. Cephalalgia 16: , Russell MB, and Olesen J. Migrainous disorder and its relation to migraine without aura and migraine with aura. A genetic epidemiological study. Cephalalgia 16: , Ashkenazi A, Silberstein S, Jakubowski M, and Burstein R. Improved identification of allodynic migraine patients using a questionnaire. Cephalalgia 27: , PMCID: Burstein R, Cutrer MF, and Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 123 ( Pt 8): , Kropp P, Siniatchkin M, and Gerber WD. On the pathophysiology of migraine--links for "empirically based treatment" with neurofeedback. Appl Psychophysiol Biofeedback 27: , Bigal M. Migraine chronification--concept and risk factors. Discov Med 8: , PMCID:PMCID:PMC Journal-In Process. 20. Cohen AS, and Goadsby PJ. Functional neuroimaging of primary headache disorders. Expert Rev Neurother 6: , Goadsby PJ. Neuroimaging in headache. Microsc Res Tech 53: , Goadsby PJ. Migraine pathophysiology. Headache 45 Suppl 1: S14-24, Bigal ME, Lipton RB, Winner P, Reed ML, Diamond S, and Stewart WF. Migraine in adolescents: association with socioeconomic status and family history. Neurology 69: 16-25, Galli F, Patron L, Russo PM, Bruni O, Ferini-Strambi L, and Guidetti V. Chronic daily headache in childhood and adolescence: clinical aspects and a 4-year follow-up. Cephalalgia 24: , Guidetti V, Galli F, Fabrizi P, Giannantoni AS, Napoli L, Bruni O, and Trillo S. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. Cephalalgia 18: , Koenig MA, Gladstein J, McCarter RJ, Hershey AD, and Wasiewski W. Chronic daily headache in children and adolescents presenting to tertiary headache clinics. Headache 42: , 2002.

107 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean 27. Hershey AD, Powers SW, Nelson TD, Kabbouche MA, Winner P, Yonker M, Linder SL, Bicknese A, Sowel MK, and McClintock W. Obesity in the pediatric headache population: a multicenter study. Headache 49: , PMCID:PMC Journal-In Process. 28. Lipton RB, Stewart WF, Diamond S, Diamond ML, and Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41: , Welch KM, Nagesh V, Aurora SK, and Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 41: , Lewis DW, Ashwal S, Dahl G, Dorbad D, Hirtz D, Prensky A, and Jarjour I. Practice parameter: evaluation of children and adolescents with recurrent headaches: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 59: , Powers SW, Patton SR, Hommel KA, and Hershey AD. Quality of life in childhood migraines: clinical impact and comparison to other chronic illnesses. Pediatrics 112: e1-5, Hershey AD, Powers SW, Vockell AL, LeCates SL, Segers A, and Kabbouche MA. Development of a patient-based grading scale for PedMIDAS. Cephalalgia 24: , Hershey AD, Powers SW, Vockell AL, LeCates S, Kabbouche MA, and Maynard MK. PedMIDAS: development of a questionnaire to assess disability of migraines in children. Neurology 57: , Powers SW, Patton SR, Hommel KA, and Hershey AD. Quality of life in paediatric migraine: characterization of age-related effects using PedsQL 4.0. Cephalalgia 24: , Stang PE, and Osterhaus JT. Impact of migraine in the United States: data from the National Health Interview Survey. Headache 33: 29-35, Crawford MJ, Lehman L, Slater S, Kabbouche MA, LeCates SL, Segers A, Manning P, Powers SW, and Hershey AD. Menstrual migraine in adolescents. Headache 49: , PMCID:PMCID:PMC Journal-In Process. 37. Lewis DW, Diamond S, Scott D, and Jones V. Prophylactic treatment of pediatric migraine. Headache 44: , Gherpelli JL. New migraine prophylactic drug options. Rev Hosp Clin Fac Med Sao Paulo 57: , Hershey AD, Powers SW, Bentti AL, and Degrauw TJ. Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache 40: , Lakshmi CV, Singhi P, Malhi P, and Ray M. Topiramate in the prophylaxis of pediatric migraine: a double-blind placebo-controlled trial. J Child Neurol 22: , Apostol G, Cady RK, Laforet GA, Robieson WZ, Olson E, Abi-Saab WM, and Saltarelli M. Divalproex extended-release in adolescent migraine prophylaxis: results of a randomized, double-blind, placebo-controlled study. Headache 48: , PMCID:PMC Journal- In Process. 42. Jones MW. Topiramate--safety and tolerability. Can J Neurol Sci 25: S13-15, Hershey AD. Current approaches to the diagnosis and management of paediatric migraine. Lancet Neurol 9: , PMCID:PMC Journal-In Process. 44. Dodick DW, Freitag F, Banks J, Saper J, Xiang J, Rupnow M, Biondi D, Greenberg SJ, and Hulihan J. Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs. Clin Ther 31: , PMCID:PMC Journal-In Process. 45. Lewis D, Winner P, Saper J, Ness S, Polverejan E, Wang S, Kurland CL, Nye J, Yuen E, Eerdekens M, and Ford L. Randomized, double-blind, placebo-controlled study to evaluate the

108 The CHAMP Study CHAMP Study Protocol CHAMP DSMB Approved Version 1_ _clean efficacy and safety of topiramate for migraine prevention in pediatric subjects 12 to 17 years of age. Pediatrics 123: , PMCID:PMC Journal-In Process. 46. Pearl W. Effects of gender, age, and heart rate on QT intervals in children. Pediatr Cardiol 17: , Kovacs M. Rating scales to assess depression in school-aged children. Acta Paedopsychiatr 46: , Kovacs M. Children's Depression Inventory. North Tonawanda, NY: Multi-Health Systems Inc., Walker LS, and Greene JW. The functional disability inventory: measuring a neglected dimension of child health status. J Pediatr Psychol 16: 39-58, Zigmond AS, and Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 67: , Varni JW, Burwinkle TM, Seid M, and Skarr D. The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambul Pediatr 3: , Varni JW, Seid M, and Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 39: , Varni JW, Seid M, and Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. Med Care 37: , Mundt JC, Greist JH, Gelenberg AJ, Katzelnick DJ, Jefferson JW, and Modell JG. Feasibility and validation of a computer-automated Columbia-Suicide Severity Rating Scale using interactive voice response technology. J Psychiatr Res 44: , Winner P, Pearlman EM, Linder SL, Jordan DM, Fisher AC, and Hulihan J (2005). Topiramate for migraine prevention in children: arandomized, double-blind, placebo-controlled trial. Headache. 45(10):

109 Summary of Protocol Changes The Childhood and Adolescent Migraine Prevention (CHAMP) Study Protocol Version 1.0 was DSMB approved on 3/23/2012 Protocol Version 2.0 Version 2.0 was approved on 4/11/2013. This revision included clarifying the screening procedures may be conducted over 2 visits (Section 6.2) and timing designated as days between Visit 1 and Visit 2 (Section 6.2.2). This revision also addressed the timing and review process of item 9 (suicidal ideation) on the Child Depression Index CDI (Section 6.2.1) and adding making the appropriate clinical decision to ensure subject safety in place of the term depression (Section 6.2.3). Edits were made to provide clarity on the conduct of the inter-visit phone calls and use of the phone symptom questionnaire to record adverse event (Section 6.4). Protocol Version 3.0 Version 3.0 was approved on 4/12/2014. This version reflected the deletion of language referring to early termination of study subject participation and replacing that language with withdrawal from study drug exposure. For subjects withdrawing from study drug exposure, Visit 8 became the final study visit. Data collection from study subjects who have been removed from study drug exposure continued to follow study data collection procedures and study visits for all remaining visits conducted prior to Visit 8 (Table 3.3, Sections 5.3, 5.4, 5.5, 5.9, and 6.3) Protocol Version 3.1 Version 3.1 was approved on 9/1/2014. This version included to the addition of named manufacturers for both study drugs to insure that an adequate supply of study drug could be maintained. Specifically stated, Sandoz, Inc., or Qualitest, USA were listed manufacturers for Amitriptyline and Camber Pharmaceuticals, or Sun Pharma were listed as the manufacturers for Topiramate (Section 5.1). Protocol Version 3.2 Version 3.2 was approved on 9/6/16. This version was created to address minor administrative changes to better clarify all of the objectives for publication purposes. The rationale for these changes was to insure all of the objectives are clearly stated with more consistent ordering across other study documents. Specifically, the objectives in the PRÉCIS were revised to collapse all detail regarding the primary objective into one paragraph and number the four secondary objectives. A summary statement was added for clarity in the PRÉCIS, Section 1.1, and Section 9.2.

110 CHAMP Study Protocol Version 3.2Version The Childhood and Adolescent Migraine Prevention Study Study Chairs: Andrew D. Hershey, MD, PhD, FAHS Associate Director of Research, Division of Neurology Professor of Pediatrics and Neurology University of Cincinnati College of Medicine Co-Director, Headache Center Cincinnati Children s Hospital Medical Center Cincinnati, Ohio Scott W. Powers, PhD, ABPP, FAHS Director of Clinical and Translational Research Cincinnati Children s Research Foundation Professor of Pediatrics and Psychology University of Cincinnati College of Medicine Co-Director, Headache Center Director, Center for Child Behavior and Nutrition Research Cincinnati Children s Hospital Medical Center Cincinnati, Ohio Supported by: The National Institute of Neurological Disorders and Stroke (NINDS) Grant # 1U01NS Amitriptyline and Topiramate in the Prevention of Childhood Migraine Investigational Drug Application (IND) Holder: Andrew D. Hershey, MD, PhD, FAHS IND # 112,220 Any modification to the protocol should be annotated on the change control memo. The annotation should note the exact words that are changed, the location in the protocol, the date the modification was approved by the Study Chairs and the date it became effective. CHAMP DSMB Approved Version 3.2 September 02, 2016

111 CHAMP Study Protocol Version TABLE OF CONTENTS PAGE CLINICAL SITES PARTIPATING IN THE STUDY 6 PRIMARY STUDY TEAM MEMBERS 10 PRÉCIS STUDY OBJECTIVES Primary Objective BACKGROUND Rationale for Study General Issues Supporting Data - Previous Evidence STUDY DESIGN Overview of Study Design Overview of Study Procedures Study Visit and Procedure Schedule SELECTION AND ENROLLMENT OF SUBJECTS Inclusion Criteria Exclusion Criteria Study Enrollment Procedures STUDY INTERVENTIONS Interventions, Administration, and Duration Double Blind Treatment Phase 34

112 CHAMP Study Protocol Version Titration Period Maintenance Period Weaning Period Concomitant Interventions Prohibited Interventions Handling of Study Intervention Adherence Assessment Option for Future Re-contact of Subjects CLINICAL AND LABORATORY EVALUATIONS Informed Consent Evaluations Titration Adjustment Visit, Unscheduled Visits and Discontinuation Evaluations Special Instructions and Definitions of Evaluations MANAGEMENT OF ADVERSE EXPERIENCES Adverse Event Expected Adverse Reactions Dose Modification Guidelines and Procedures Serious Adverse Events (SAE) Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs CRITERIA FOR INTERVENTION OR DISCONTINUATION Subject Termination 71

113 CHAMP Study Protocol Version Site Termination Study Termination STATISTICAL CONSIDERATIONS Specific Aims and Hypothesis Outcomes Data Monitoring Data Management and Statistical Analysis Plan DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORTING Records to be Kept Document Retention Electronic Case Report Form (ecrf) Missing Data Role of Data Management Data Management by the Data Coordinating Center (DCC) Case Report Forms Training for Study Data Entry Quality Assurance Adverse Experience Reporting HUMAN SUBJECTS Ongoing Review of Potential Risks Adequacy of Protection Against Risks Institutional Review Board (IRB) Review and Informed Consent 102

114 CHAMP Study Protocol Version Subject Confidentiality Subject Compensation Study Modification/Discontinuation PUBLICATION OF RESEARCH FINDINGS REFERENCES 103

115 CHAMP Study Protocol Version CLINICAL SITES PARTICIPATING IN THE STUDY Site: Akron, OH Site: Amherst, NY Maria Christina Victorio, MD Laszlo Mechtler Akron Children s Hospital Dent Neurological Institute One Perkins Square 3980 Sheridan Drive, Suite 200 Akron, OH Amherst, NY Phone: Phone: Fax: Fax: mvictorio@chmca.org lmechtler@dentinstitute.com Site: Atlanta, GA Site: Aurora, CO Frank Berenson Sita Kedia Atlanta Headache Specialists Children s Hospital Colorado 5887 Glenridge Drive, Suite East 16 th Avenue, Box 155 Atlanta, GA Aurora, CO Phone: Phone: Fax: Fax: fberenson@atlantaheadachespecialists.com Kedia.sita@tchden.org Site: Baltimore, MD * Site: Cincinnati, OH Howard Jacobs Marielle Kabbouche Univ. of Maryland School of Medicine Cincinnati Children s Hosp Med Center 737 West Lombard St, Room 195-A 3333 Burnet Avenue, MLC: 2015 Baltimore, MD Cincinnati, OH Phone: Phone: Fax: Fax: *Site Closed to Enrollment marielle.kabbouche@cchmc.org Site: Cleveland, OH* Site: Columbus, OH A. David Rothner Anne Pakalnis Children s Hospital, The Cleveland Clinic Nationwide Children s Hospital 9500 Euclid Avenue 700 Children s Drive Cleveland, OH Columbus, OH Phone: Phone: Fax: Fax: *Site Closed to Enrollment Ann.Pakalnis@nationwidechildrens.org Site: Colorado Springs, CO Randall Bjork Colorado Springs Neurological Associates 175 S. Union Blvd, Suite Forest Lane, Suite B116 Colorado Springs, CO Dallas, TX Phone: Phone: Site: Dallas, TX Steve Linder Dallas Pediatric Neurology Associates Fax: Fax: christenkutz@yahoo.com dmmack05@aol.com

116 CHAMP Study Protocol Version Site: Dallas, TX Chaouki Khoury Baylor University Medical Center 3600 Gaston Ave East Stop 11 Road, Suite 26 Dallas, TX Indianapolis, IN Phone: Phone: Site: Indianapolis, IN Keith Ridel Josephson Wallack Munshower Neurology Fax: Fax: chaouki.khoury@baylorhealth.edu ridelkands@gmail.com Site: Kansas City, KS Site: Louisville, KY Jennifer Bickel Michael K. Sowell Children s Mercy Hospital Univ. of Louisville Health Sciences Center 2401 Gillham Road Department of Neurology, Room 113A, HSC Kansas City, KS Louisville, KY Phone: Phone: Fax: Fax: jlbickel@cmh.edu Michael.sowell@louisville.edu Site: Marshfield, WI Hema Murali Marshfield Clinic 1000 North Oak Avenue 51 No. Dunlap Suite 335 Marshfield, WI Memphis, TN Phone: Phone: Site: Memphis, TN Diana LeBron LeBonheur Children's Hospital Fax: Fax: murali.hema@marshfieldclinic.org dlebron@uthsc.edu Site: Mineola, NY Vijaya Atluru Winthrop University Hospital 259 First Street 425 West 59 th Street, Suite 4A Mineola, New York New York, NY Phone: Phone: Site: New York, NY Josh Cohen The Headache Inst.- St. Luke Roosevelt Fax: Fax: vatluru@winthrop.org joscohen@chpnet.org Site: Norfolk, VA Site: Oklahoma City, OK L. Matthew Frank Deepti Chrusciel Eastern Virginia Medical School University of Oklahoma Health Sciences 850 Southampton Ave., 3rd Floor 920 Stanton L Young Blvd, Suite 2040 Norfolk, VA Oklahoma City, OK Phone: Phone: Fax: Fax: matthew.frank@chkd.org Deepti-Chrusciel@ouhsc.edu

117 CHAMP Study Protocol Version Site: Philadelphia, PA Christina Szperka Children s Hospital of Philadelphia CTRB 10019, 3501 Civic Center Blvd Philadelphia, PA Phoenix, AZ Phone: Phone: Site: Phoenix, AZ Marcy Yonker Phoenix Children s Medical Group 1919 East Thomas Road, Bldg. B 3 rd Floor Fax: Fax: szperka@ .chop.edu myonker@phoenixchildrens.com Site: Pittsburgh, PA Site: Reno, NV Nathan Bennett J. Ivan Lopez Preferred Clinical Research Renown Neuroscience Institute 140 Curry Hollow Rd, Suite 3 85 Kirman Ave, Suite 301 Pittsburg, PA Reno, NV Phone: Phone: Fax: Fax: nbennett@ppcp.org Jlopez@renown.org Site: Rochester, MN Kenneth Mack Mayo Clinic Pediatric Center 200 First Street SW 295 Chipeta Way Rochester, MN Salt Lake City, Utah Phone: Phone: Site: Salt Lake City, UT Lynn Kerr Primary Children's Medical Center Fax: Fax: mack.kenneth@mayo.edu lynn.kerr@hsc.utah.edu Site: San Francisco, CA Peter J. Goadsby University of California-San Francisco 1701 Divisadero Street, Suite Union Street San Francisco, CA Schenectady, NY Phone: Phone: Site: Schenectady, NY Richard J. Simmons Schenectady Neurological Consultants, PC Fax: Fax: GoadsbyP@neurology.ucsf.edu Neuroresearch1401@yahoo.com Site: Seattle, WA Heidi Blume Seattle Children s Hospital 4800 Sandpoint Way, MS:B South 31 st Street Seattle, WA Temple, TX Phone: Phone: Site: Temple, TX Jose Aceves Scott and White HealthCare Fax: Fax: Heidi.blume@seattlechildrens.org jaceves@swmail.sw.org

118 CHAMP Study Protocol Version Site: St. Louis, MO Site: Stanford, CA Deepa Arun Sheena Aurora Saint Louis University Stanford University 1438 South Grand Boulevard, Rm Pasteur Dr. St. Louis, MO Stanford, CA MC 5235 Phone: Phone: Fax: Fax: darun@slu.edu saurora@stanford.edu Site: Waltham, MA Alyssa LeBel Children s Hospital of Boston 9 Hope Ave; Ped. Headache Mailbox#4 111 Michigan Ave, NW Waltham, MA Washington, DC Phone: Phone: Site: Washington, DC Marc DiSabella National Children's Medical Center Fax: Fax: alyssa.lebel@childrens.harvard.edu mdisabel@cnmc.org Site: West Palm Beach, FL Marc DiSabella National Children's Medical Center 111 Michigan Ave, NW 85 Prescott Street, Suite 101 Washington, DC Worcester, MA Phone: Phone: Site: Worcester, MA Herbert G. Markley New England Regional Headache Center Fax: Fax: mdisabel@cnmc.org markleyh@nerhc.org

119 CHAMP Study Protocol Version STUDY TEAM MEMBERS* * Roster of additional study team members and their contact information is included in the Manual of Operations Clinical Coordinating Center Scott Powers, PhD, ABPP, FAHS Principal Investigator Cincinnati Children s Hospital Medical Center 3333 Burnet Ave, MLC Burnet Ave, MLC 2015 Cincinnati, OH Cincinnati, OH Phone: Phone: Andrew Hershey, MD, PhD, FAHS Principal Investigator Cincinnati Children s Hospital Medical Center Fax: Fax: Scott.Powers@cchmc.org Andrew.Hershey@cchmc.org Leigh Ann Chamberlin, RD, MEd Project Manager Cincinnati Children s Hospital Medical Center 3333 Burnet Ave, MLC Burnet Ave, MLC 2015 Cincinnati, OH Cincinnati, OH Phone: Phone: Susan LeCates, MSN, FNP Lead Coordinator Cincinnati Children s Hospital Medical Center Fax: Fax: LeighAnn.Chamberlin@cchmc.org Susan.LeCates@cchmc.org Leslie Korbee, BS, SI(ASCP) Regulatory Manager 3333 Burnet Ave, MLC 3015 Cincinnati, OH Phone: Fax: Leslie.Korbee@cchmc.org Data Coordinating Center Christopher Coffey, PhD Principal Investigator Clinical Trials Statistical and Data Management Center Department of Biostatistics University of Iowa 2400 University Capitol Centre 2400 University Capitol Centre Iowa City, IA Iowa City, IA Phone: Phone: Dixie Ecklund, RN, MSN, MBA Associate Director, DCC, Co-Investigator Clinical Trials Statistical and Data Management Center Department of Biostatistics University of Iowa Fax: Fax: christopher-coffey@uiowa.edu dixie-ecklund@uiowa.edu

120 CHAMP Study Protocol Version Research Pharmacy Denise LaGory, RPh Lead Investigational Pharmacist Cincinnati Children s Hospital Medical Center 3333 Burnet Ave, MLC 1011 Cincinnati, OH Phone: Fax: Denise.LaGory@cchmc.org Independent Medical Monitor David Dodick, MD Professor of Neurology, Mayo Clinic E. Shea Boulevard Scottsdale, AZ Phone: Fax: dodick.david@mayo.edu

121 CHAMP Study Protocol Version PRÉCIS Study Title: The Childhood and Adolescent Migraine Prevention (CHAMP) Study Objectives: The global objective is: To determine the optimal medication for the prevention of migraines in children and adolescents. The primary objective is: To test if amitriptyline (AMI) and topiramate (TPM) are superior to placebo in reducing migraine frequency* in children and adolescents, ages 8 to 17 years old, inclusive, and to conduct a comparative effectiveness study of the two therapies. Specifically, we will determine if there is a difference in the proportion of subjects with a 50% reduction in migraine frequency from the 4 week baseline period to the last 4 weeks of this 24 week trial between amitriptyline and placebo (Aim 1) and between topiramate and placebo (Aim 2). These hypotheses were powered to detect a 20 percentage point improvement from placebo is considered a minimum clinically meaningful difference by pediatric headache experts. 1 For the comparative effectiveness study, we will determine if there is a difference in the proportion of subjects with a 50% reduction in migraine frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial between amitriptyline and topiramate (Aim 3). This hypothesis was powered to detect a 15 percentage point or greater difference, considered clinically important by pediatric headache experts for comparison of two active interventions. Based upon the findings of this 3 in 1 clinical trial, our overall goal is to determine, using a specified a priori tiered approach, which of these therapies is superior in the prevention of migraine headaches. The first tier for that decision is the primary endpoint: 50% reduction rate for migraine frequency. Migraine disability will be used for the second tier decision. Tolerability will be used for the third tier. If superiority cannot be determined through this tiered approach, then the outcome of the trial would be that both therapies are efficacious and individualized clinical decisions based on subject presentation should guide the first choice in practice. All final recommendations must separately account for the safety data generated by this novel study. Safety concerns could trump the conclusions from any of the three tiers. * Migraine frequency is defined as the number of days with migraine for a given 4 week period. The secondary objectives are: 1. To determine if amitriptyline and/or topiramate will result in a decrease in absolute migraine disability score (measured by PedMIDAS) from the end of the 4 week baseline period to the last 4 weeks of this trial compared to placebo. 2. To determine if amitriptyline and/or topiramate will result in a decrease in absolute migraine frequency days measured by the change in absolute migraine frequency from the 4 week baseline period to the last 4 weeks of this trial compared to placebo. 3. To determine if amitriptyline and topiramate are well toleratedsubject

122 CHAMP Study Protocol Version To determine if amitriptyline or topiramate differ from placebo on the occurrence of treatment emergent serious adverse events. Thus, the CHAMP Study includes a primary endpoint (50% or greater reduction in headache days) and four secondary endpoints (migraine-related disability, absolute change in headache days, tolerability, and treatment-emergent serious adverse events). Comparisons will be made between amitriptyline and placebo, topiramate and placebo, and amitriptyline and topiramate. Study Design: This is a phase III intent to treat, 3-arm, multi-center, randomized, double-blind, placebocontrolled safety and efficacy study. Every subject who is randomized will be considered part of the treatment group for analysis of the primary and secondary endpoints. Subjects will undergo a 4 week baseline period, receive treatment for 24 weeks (8 weeks titration, 12 weeks maintenance phase, 4 weeks endpoint evaluation), and a 6 week washout/end of study drug period (2 weeks wean, 4 weeks off drug), with timelines and interventions as indicated in the flow chart below: Screen Randomize Titrate Treat Washout/Final Visit 1 V 2 V 3,4 V 5, 6, 7 V 8 Phone 1 & 2 4 weeks 0 weeks 8 weeks 12 weeks 4 weeks 6 weeks Interventions and Duration: Placebo, Amitriptyline, or Topiramate. The intervention will include an 8-week titration, 16- week constant dose maintenance phase and 6 week wash-out/end of study drug. Sample Size and Population: The sample size will include 675 randomized subjects, 8 to 17 years old, inclusive, from up to 40 selected participating sites in the United States. Subjects will be randomized in a 2:2:1 fashion to receive either amitriptyline (n=270), topiramate (n=270), or placebo (n=135). Subjects will be stratified by age (8-12, 13-17) and the baseline number of migraines per month (episodic: 4-14, chronic: 15 or more). Because this strategy provides four strata, this study will not stratify the randomization by site.

123 CHAMP Study Protocol Version STUDY OBJECTIVES 1.1 Primary Objective The primary objective is to conduct a three trials in one project that will use a specific a priori decision algorithm (see paragraph below) to determine the best choice prevention strategy for pediatric migraine. We plan to test if amitriptyline and/or topiramate are superior to placebo in reducing migraine frequency in children and adolescents age 8 to 17 and to conduct a novel comparative effectiveness study between amitriptyline and topiramate. Specifically, for the placebo-controlled aims (AMI vs. Placebo: Aim 1; TPM vs. Placebo: Aim 2) we will determine if there is a difference in the proportion of subjects who meet our primary outcome measure of a 50% reduction in migraine frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial. Migraine frequency is defined as the number of days with migraine for a given 4 week period. These hypotheses were powered to detect a 20 percentage point difference from placebo, an effect that is considered clinically meaningful by pediatric headache experts. 2 For the comparative effectiveness study (Aim 3), we will determine if there is a difference in the proportion of subjects with a 50% reduction in migraine frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial between amitriptyline and topiramate. This hypothesis was powered to detect a 15 percentage point or greater difference, considered to be clinically important by pediatric headache experts for comparison of two active interventions. In order to accomplish this objective, we will use an a priori decision making process that incorporates the novel data that will result from this 3 trials in one project. We propose a three tiered approach for analysis of the results of this trial to pick a winner among the three therapies tested. The first tier is based upon our primary endpoint, 50% reduction rate for migraine frequency during one month. This endpoint is the most relevant to current practitioners and is recommended as the key variable for migraine prevention medication trials by the International Headache Society (IHS). 3 It is also, in our experience, the primary outcome that families expect when they bring their children to our headache center. In our plan, there are four possible practice recommendations: (1) topiramate first choice because it is superior to placebo and amitriptyline on primary outcome; (2) amitriptyline first choice because it is superior to placebo and topiramate on primary outcome; (3) both therapies possible first choice and tie breaker is the secondary outcome of migraine-related disability because both are superior to placebo but were not different on primary outcome; and (4) neither therapy first choice because neither are superior to placebo. If scenario (3) occurs, and a recommendation cannot be made based upon the primary endpoint, we would need to go to a tie breaker, and we will utilize tier 2, our secondary endpoint of migraine-related disability. If one medication is superior to the other on this variable, it is the winner. If not, we would go to tier 3, tolerability. If one medication was better tolerated than the other, it would be the winner. Problems with tolerability would be defined as having a drop-out rate greater than 35% or a dropout rate that is statistically worse than the other therapy. If a winner cannot be identified based upon tier 3 criteria, then the outcome of the trial would be that both therapies are efficacious and it would be individualized clinical decisions

124 CHAMP Study Protocol Version based upon subject presentation that would guide first choice in practice. Of course, recommendations will also take into account the safety data generated by this novel study. The specific aims are to: Aim 1: To test if amitriptyline (AMI) is superior to placebo in reducing migraine frequency and migraine-related disability Primary Hypothesis #1: Amitriptyline, at a target dose of 1 mg/kg/day, will result in an increased percentage of subjects meeting the primary endpoint compared to placebo Major Secondary Hypothesis #1: Amitriptyline also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to placebo Aim 2: To test if topiramate (TPM) is superior to placebo in reducing migraine frequency and migraine-related disability Primary Hypothesis #2: Topiramate, at a target dose of 2 mg/kg/day, will result in an increased percentage of subjects meeting the primary endpoint compared to placebo Major Secondary Hypothesis #2: Topiramate also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to placebo Aim 3: To compare the efficacy of amitriptyline and topiramate in reducing migraine frequency and migraine-related disability Primary Hypothesis #3: Topiramate will result in an increased percentage of subjects meeting the primary endpoint compared to amitriptyline Major Secondary Hypothesis #3: Topiramate also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to amitriptyline Aim 4: To prospectively and systematically estimate the safety and tolerability profiles of each therapy Major Secondary Hypothesis #4: Amitriptyline and topiramate will be well tolerated Major Secondary Hypothesis #5: AMI and TPM will not differ from placebo on the occurrence of treatment-emergent serious adverse events. We also expect that AMI and TPM will have overall safety profiles that do not preclude determination of first line therapy for clinical practice according to our decision algorithm. Consistent with the overview of the trial in the precis and derived from these study aims, the CHAMP Study involves a primary endpoint and four secondary outcomes. Specifically, listed

125 CHAMP Study Protocol Version by endpoint, this trial will examine: a primary endpoint (50% or greater reduction in headache days) and four secondary endpoints (migraine-related disability, absolute change in headache days, tolerability, and treatment-emergent serious adverse events). Comparisons will be made between amitriptyline and placebo, topiramate and placebo, and amitriptyline and topiramate. 2 BACKGROUND 2.1 Rationale for Study General Issues Pediatric Migraine Headache General Overview Prevalence Pediatric migraine is a prevalent disorder that results in significant disability for children and families and tremendous costs to society. Pediatric migraine is one of the five most prevalent childhood disorders in the U.S. 4-6 This disease affects up to 10% of children 4 and up to 28% of adolescents A Chronic Disease Pediatric migraine is a chronic illness that represents challenges to youth due to the episodic nature of painful attacks, as well as, the inter-event worry about the next attack and the recurrent, unpredictable interruptions in day-to-day life Cost of Pediatric Migraine Health care costs are 70% higher for a family with a migraineur than a non-migraine affected family, and direct medical costs for children with migraine are reported to be similar to those for adults. 8 The majority of children with migraine continue to experience migraines into adulthood, 9 and migraine has an annual economic impact in the U.S. of approximately $36 billion (direct medical costs + lost productivity). 10 Effective early treatment that significantly reduces migraine frequency and disability would change this trajectory of morbidity and costs. 1, Underfunded Despite Prevalence Lack of investment has severely limited headache research, and therefore, the development and testing of effective treatments (especially for children). There is a clear priority for research focused on migraine (NINDS PA ), and in particular, clinical trials of treatments for pediatric migraine. 2, 11 It has been reported that based upon NIH funding in 2007, an estimated 36 cents per person with migraine in the U.S. was spent for advancing scientific understanding of this disease and its treatment (compared to: $35 for Epilepsy, $49 for Stroke, and $372 for Parkinson s Disease). 12 Research focused on treatment of pediatric migraine is even more limited, resulting in a notable gap in the knowledge needed for evidence-based practice Neurologic Basis of Pediatric Migraine Migraine is a neurological disease and current understanding of its pathophysiology guides selection of prevention drug candidates. The

126 CHAMP Study Protocol Version pathophysiology of migraine is based on genetic inheritance of hypersensitivity that is influenced by environmental factors. 13 The genetic evidence is most strongly supportive of a childhood inheritance pattern in 14, 15 contrast to the proportion of adults that develop migraine later in life. Migraineurs are hypersensitive to multiple stimuli including visual (photophobia), auditory (phonophobia), sensory (cutaneous allodynia), and cognitive (difficulty functioning) even between the individual attacks Prophylaxis in Childhood May Prevent Adult Neurologic Progression As headaches become more frequent, this hypersensitivity becomes synergistic with the migraines and leads to increasing frequency, sensitivity, and disease impact. 19 This point in adults appears to be a frequency of migraines greater than 3 per month. Recent studies have suggested that not only can untreated or ineffectively treated migraines become progressive, but may cause long-term neurological changes that can be quantified with neuroimaging Early intervention in childhood has the potential to interrupt this progression and eliminate long-term suffering and neurological changes Treatment for Pediatric Migraine Current Treatment for Pediatric Migraine A variety of medications with different mechanisms of action have been demonstrated in adults to be effective in migraine prevention. These include amitriptyline, the historical standard and most frequently utilized migraine prevention medication in clinical practice, and topiramate, the most recent medication proven effective for migraine prevention in adults. 1, 2, 11 Amitriptyline is both a non-selective re-uptake inhibitor (resulting in down-regulation in secondary neuron s receptor and thus desensitization) and also may act directly on inhibitory receptors (NMDA) and channels responsible for neurotransmission (sodium, L-type calcium and voltage-gated potassium channels). Topiramate s mode of action appears to have multiple mechanisms that also result in desensitization. These include potentiation of GABAergic transmission, inhibition of excitatory signaling via AMPA receptors, blockage of voltage dependent sodium channels and carbonic anhydrase enzyme inhibition all of which are inhibitory and lower a subject s hypersensitivity. Although these mechanisms are overlapping, they are distinct and it may be expected that there is a differential response between the agents. Based on the observations that untreated migraines may become progressive once they reach a frequency of 1/week or greater with diffuse hypersensitivity, treatment needs to utilize diffuse mechanisms to lower the hypersensitivity of the nervous system below this level. Both amitriptyline and topiramate have the potential to achieve this Practice Variation in Treatment for Pediatric Migraine

127 CHAMP Study Protocol Version Most children and adolescents with migraine do not receive prophylactic therapy because of the lack of placebo-controlled efficacy and safety information, and even when they do, practice variation is large. 23 In collaboration with the NINDS Clinical Research Collaboration (CRC) and as part of our 2 year planning process for this application, we sent questions to participating neurology practitioners. Of 226 responders, 184 (81%) reported seeing children with migraine in their day-to-day practice. Of medications they reported using for prevention of childhood migraine; amitriptyline and topiramate were the most likely to be prescribed. Although these two medications are commonly used in clinical practice by pediatric headache specialists, including members of the American Headache Society (AHS), they lack the empirical data to be recommended as Class I evidence as recognized by the practice parameters of the American Academy of Neurology (AAN) because placebo-controlled data 2, 11 are necessary Current Medication Treatment for Pediatric Migraine Remains Empiric There is little agreement and a great deal of practice variation on the typical and maximum dosage of prevention medications used (around a 5- fold difference) and the time it takes to determine if a prevention medication works (as little as 2 weeks to more than 16 weeks; with about 2 out of 3 reporting less than 8 weeks). Efficacy, tolerability, and safety data from a clinical trial focused on how commonly used prevention medication therapies compare to placebo and to each other will help transform this field Impact on Future Treatment of Pediatric Migraine Relevance to (and impact on) clinical practice is the critical feature of the planned trial and the reason it has been designed to examine both medication versus placebo and comparative effectiveness questions. In our NINDS CRC survey, responders indicated that reduction in migraine frequency and reduction in migraine-related disability were the top outcomes for determining the effectiveness of prevention therapy, followed by low incidence of side effects. Over 97% of responders indicated that they would change prescribing practice if a medication was shown in a clinical trial to reduce migraine frequency by 50%. A minimum of 20 percentage point difference from placebo in this reduction effect was considered clinically meaningful. It was also determined via regular and extensive consultation with members of the American Headache Society s Pediatric Adolescent Special Interest Section over the past year that: (a) the optimal project in terms of relevance to practice would combine a placebo-controlled design with a comparative effectiveness study that was powered to provide clinically impactful data for each of the aims proposed; (b) subjects should be representative of those seen in practice, and hence be diagnosed with migraine and include the range of migraine frequency that typically leads to prophylactic

128 CHAMP Study Protocol Version treatment, including frequent, episodic patients (i.e., > 3 per month), as well as, chronic patients (i.e., 15 per month but not continuous headache); (c) an absolute difference of at least 20% is the threshold needed for results of a placebo-controlled trial to change practice; (d) a less robust absolute difference of 15% would be an influential threshold in a comparative effectiveness study; and (e) while migraine frequency is the best primary endpoint, information about reduction in disability and tolerability would be useful in determining which drug to use as first choice therapy for childhood migraine. Results from this trial will thus be directly translated into evidence-based (not consensus-based and/or idiosyncratic) clinical care decisions by all practitioners that treat children with migraines including pediatricians, family practitioners, neurologists, and specialists Description of Use of Interventions Route and Formulations All medications for pediatric migraine prevention are administered orally Encapsulation and Pill Swallowing This study will use an over-encapsulation blinding approach with the study medications, amitriptyline, topiramate, and placebo. Subjects who cannot swallow pills at the time of the screening visit will be given a training session using behavioral techniques. Upon return for baseline visit, if the subject continues to be unable to swallow pills, the subject will be excluded from the study Regimen a) This study will use a b.i.d. regimen for study drug administration. b) The initial starting dose will be low during the beginning of titration. c) The dosage will be advanced during titration and held constant during the maintenance period, and deescalated and ended during the weaning period Intervention Period a) The initial intervention period will include a titration period with an 8 week dosage escalation during which the dosage of study drug may be advanced every two weeks. b) The maintenance period will follow the titration period and will consist of 16 weeks on the maximum dosage achieved during the titration period. c) The weaning period of two weeks and the follow up period of 4 weeks will follow the maintenance period. During the weaning period subjects dose will be de-escalated and may return to routine clinical care during the follow up period Need and Relevance for Clinical Trial Need for Study a) Migraine is considered by the World Health Organization to be in the top 20 causes of disability worldwide. 10 For children and adolescents, migraine is a condition for which most providers do not offer

129 CHAMP Study Protocol Version medication therapy to control the disease and the related disability because the provider does not have a good choice. b) Clinical trials that demonstrate efficacy and safety of a prevention medication therapy have not been conducted with patients that are 1, 2, 11 representative of those who come to a medical provider. c) Pediatric headache experts are asking for placebo-controlled trials and comparative effectiveness studies specifically designed to provide the critical evidence needed to impact practice Relevance a) This trial represents the first large scale, pediatric migraine prevention, double blind, randomized, placebo controlled trial conducted in the U.S. b) For the first time, subjects enrolled in a pediatric migraine prevention medication clinical trial will be representative of those patients seen in day-to-day practice. Subjects in this trial will be from the age range of patients that often present for care from primary care providers, neurologists, and headache specialists (age 8-17). c) Migraine frequency will range from 4 per month to daily (but not continuous). The few clinical trials of prophylactic medications have almost always excluded subjects with more than 12 migraines per month. Yet, prevalence estimates of children and adolescents with 15 migraines per month in clinical settings range from 15% to 35% d) The stratification in this trial will create a balance of subjects with episodic and chronic migraine without specifically limiting the population to a group unrepresentative of typical practice. e) As requested by pediatric headache specialists, the results of this trial will be generalizable to the population of youth that present for care. 2.2 Supporting Data-Previous Evidence Supporting Data on Prevalence Headache and back pain are the two pain conditions afflicting society today. Migraine is a primary headache that can be severe and disabling. Migraine and chronic migraine are the most frequent recurrent headache disorder brought to medical attention. 27 It is estimated that over 12% of the population is afflicted by migraine with a female predominance of 3:1. 28 The disease is often first diagnosed in childhood with the most rapid increase in prevalence occurring in adolescence into the 20 s. In adults, there is growing evidence that untreated or ineffectively treated migraine can become progressive leading to neurological alterations as evident by neuroimaging changes 29 and can result in headaches that become refractory to treatment. These changes highlight migraine as a neurological condition that has a combined genetic and environmental pathophysiology. 13 Although genetic intervention is not yet feasible, both extrinsic and intrinsic environmental changes (via neurotransmission and

130 CHAMP Study Protocol Version hypersensitivity alterations from neuroactive pharmaceutical treatments) are possible. Early intervention has the greatest potential to interrupt this progression and prevent long-term disability Supporting Data on Gender Stratification Migraine effects up to 10% of children 4 and up to 28% of adolescents. 7 This prevalence progressively increases from early childhood into the teenage years with a shift during adolescence to a female predominance (ages 3 to 7 years, 3%; age 7 to 11, 4% to 11%; ages 11 to 15+, 8% to 23%; up to 28% between ages 15 to 19) 5-7, 30. Recent population based studies have demonstrated that the incidence rate increases most rapidly during adolescence into young adulthood Supporting Data on Impact of Pediatric Migraine The impact of a disease can be measured both by the disease specific disability and by the influence on the subject s quality of life Migraine represents challenges in this due to its episodic nature with an impact during an attack, as well as, the anxiety and worry about the next attack. 27 The impact of childhood migraine is further complicated by the child s migraine influencing the parents 8, 10, 23, 35 lives through lost work and social activities Supporting Data on Disability Furthermore, as migraine headaches have a genetic component, the parent s migraine is likely to have an effect upon the child s health that may have a bidirectional influence on disability. Migraine-related disability is measured through the disease-specific loss of function. 33 This includes lost school and work days and lost social activities as well as the ability to fully participate in these activities. Various instruments have been developed to assess disability in adult migraine. The PedMIDAS was developed to assess the impact of migraine in children and adolescents. 33 This tool has been validated and shown to be very sensitive to treatment effects Supporting Data on Quality of Life Quality of life instruments measure the overall disease non-specific effects on a subject s life. Using the PedsQL, we have demonstrated that the impact of migraine on the lives of children and adolescents is clinically significant, with migraine affecting a child s life similarly to childhood cancer, cardiac disease, and rheumatic disease. 31 This observation mirrors findings seen in adults using SF PedMIDAS and PedsQL measure the impact on an individual s life. Population studies have demonstrated this impact has significant societal implications. In 1989, it was estimated that over 130,000 school days are missed every two weeks due to headache with over 3 million bedridden days occurring in the U.S. per month, thus generating a significant educational impact Supporting Evidence on Societal Impact

131 CHAMP Study Protocol Version The societal impact on the family can be measured through parental short-term disability and work absenteeism with 11% and 35% more of each of these in families with a child with migraine compared to non-migraine families. 8 In adults, migraine results in significant disability and tremendous cost to society. Estimates on loss of productivity due to migraine is $13 billion per year ($16.7 billion in 2009 dollars), $8 billion of which is due to work absenteeism Supporting Evidence on Genetic Factors The pathophysiology of migraine is based on genetic inheritance and environmental factors. 13 The influence of genetic factors is more significant for children in contrast to adults that develop migraine later in life. 14, 15 Population, twin, and family genetic studies suggest that the genetic influence is 60-70% with a mixed inheritance pattern that has dominant, recessive, and maternal patterns. 13 Neurophysiology studies have demonstrated that migraineurs have a hypersensitive nervous system that can be measured directly via physiological tools (MEG, visual stimulation, auditory stimulation) or indirectly through patient reports of photophobia, phonophobia and cutaneous allodynia with central sensitization. 17 In females, migraine can be further exacerbated by hormonal influences with over 50% of adolescents and adult females have menstrual-related migraine that appears to be due to triggering of migraine when estrogen levels drop Supporting Evidence from Neuroimaging Studies Neuroimaging studies have demonstrated that if untreated or ineffectively treated, migraine can lead to increased iron deposition in deep brainstem structures a sign of sustained increased metabolic activity, and destruction of cortical tissue that appears to be irreversible. 20, 29 Based on these pathophysiological observations, minimizing the neurohypersensitivity of a migraineur and thus diminishing the attack frequency has a significant potential to prevent this neuroprogression Supporting Evidence from Practice Parameters Practice parameter guidelines published in 2004 on the pharmacological treatment of pediatric migraine identified only one agent (flunarizine, not available in the 37, 38 U.S.) with adequate Grade I evidence for the prevention of pediatric migraine. Several open labeled and small studies did demonstrate the relative effectiveness of a limited number of anti-depressant medications (notably amitriptyline), 39 antiepileptic medications (including topiramate 40 ), blood pressure medications (including calcium channel blockers flunarizine, and beta-blockers), 37 and antiserotonin agents. 37 This practice parameter highlighted the lack of large-scale definitive studies and called for an increase in multi-centered, placebo-controlled trials to examine the safety, tolerability, and efficacy of preventive medications. 2

132 CHAMP Study Protocol Version Subsequent to this practice parameter, a few small, randomized studies have been added including divalproate (n=300) 41 and topiramate (n=29 50 mg, n= mg, and n= mg) with only the 100 mg dose of topiramate having a significant benefit. 40, 42 As a result, neurologists and other care providers who see pediatric headache patients in everyday practice have little evidence from which to make critical treatment decisions, particularly with prevention medications. 27 This lack of knowledge around medications represents a critical barrier to improving preventive and treatment outcomes for children and adolescents with migraine pain Supporting Evidence Summary Despite the increasing prevalence of pediatric migraine, its substantial impact on daily functioning and quality of life, and the potential for long-term neurophysiological changes, there are few clinical trials focused on the prevention of pediatric migraine. 43 Placebo-controlled trials and comparative effectiveness studies are critically needed to advance this field and to change clinical practice. 3 STUDY DESIGN 3.1 Overview of Study Design This study is an intent to treat, 3-arm, randomized, double-blind, parallel group, placebocontrolled trial to test amitriptyline and topiramate with 675 children and adolescents between age 8 and 17 with migraine recruited from up to 40 sites across the U.S. Subjects will be randomized in a 2:2:1 fashion (AMI; TPM; Placebo). Every subject who is randomized will be considered part of the treatment group for analysis of the primary and secondary endpoints. Key endpoints will be migraine frequency, migraine-related disability, tolerability, and safety. Subjects will be involved for approximately 34 weeks in the various phases of the study, with visits, time lines, and interventions as indicated in the flow chart: Screen Randomize Titrate Treat Washout/Final Visit 1 V 2 V 3,4 V 5, 6, 7 V 8 Phone 1 & 2 4 weeks 0 weeks 8 weeks 12 weeks 4 weeks 6 weeks 3.2 Overview of Study Procedures After informed consent (and assent where appropriate)) has been obtained, a 4 week baseline period will occur with diary collection. If eligibility criteria are met, the subjects will be randomized to one of 3 treatment arms and will enter into an 8-week titration period with study drug. This titration phase will be modifiable based on effectiveness and tolerability (see Section 5.3). This will be followed by a 16-week constant dose or maintenance phase. At the conclusion of maintenance, a 6 week period will ensue to wean off medication (2 weeks) and finalize study (then 4 weeks off drug). A final safety phone call will occur 4 weeks after the completion of the wean off period. Subjects will be involved with the study for approximately 34 weeks.

133 CHAMP Study Protocol Version Safety labs will be collected along with repository specimens at three intervals during the study. Physical exams will be conducted at each study visit. A PedMIDAS disability score will be collected every 3 months during the study. Neurological exams will be conducted at the screening and baseline exams, at the end of dose titration, at the end of the maintenance period and at the study endpoint. Electrocardiograms (ECG) will be collected at screening and after the completion of of dose titration. A targeted symptom questionnaire will be conducted at every visit and a brief version of the symptom questionnaire will be conducted by phone between visits. Subjects describing suicidal ideation in response to the symptom questionnaires will be directed immediately for psychiatric evaluation and management of the event. The Columbia Suicide Severity Rating Scale instruments will be used to score any subject reports of suidiality. Adverse events and the use of concomitant medications will be recorded at each study visit. Study drug compliance will be ascertained by pill count and subject report on the daily headache diary and batched biosample anlysis. Questionnaires will be completed by subjects at screening, the end of titration, and at the study endpoint. 3.3 Study Visit and Procedure Schedule Table 3.3 summarizes each study visit and the procedures which will be completed.

134 CHAMP Study Protocol Version Table 3.3 Study Visit and Procedure Schedule. Study Visits Screening Visit 1 day-28 to Day 0 Baseline and Randomization Visit 2 *** Day 0 Visit wks Titration + Maintenance Endpoint $ Visit wks Visit wks Visit wks Visit wks Visit wks Weaning & Off Drug**** Phone Visits + 26 wks & + 30 wks Informed Consent X Baseline Medical History X Prior Medications X Urine Pregnancy Test X X X X X X X X Adverse Events * X X X X X X X X Headache Diary X X X X X X X X PedMIDAS / HIT-6 X X X Questionnaires X X X Vital Signs & Demographics X X X X X X X X Concomitant Medications X X X X X X X X Physical Exam X X X X X X X X Neurological Exam X X X X X CBC X CHAMP Metabolic Profile X X X Drug Adherence Sample X X CHAMP Biorepository samples X X Electrocardiogram (ECG)** X X** Inter visit phone call*** X X X X X X Drug Accountability X X X X X X X Study Drug Administration X X X X X X X Weaning-2 wks Off Drug-4 wks * Adverse Events will be solicited using the Symptom questionnaires followed with the C-SSRS Baseline or Since Last Visit questionnaire if needed. + Titration of study medication will be managed by the site PI following our protocol which allows for increasing dose, holding dose, or decreasing dose based upon treatment emergent side effects. Using this approach, a final tolerated dose will be obtained by week 8 or week 10. Additional Titration Adjustment Visits conducted by phone or in person are described in section $ End of trial medication management will also be done by the site PI following our protocol. ** The ECG at Visit 5 could show abnormal results, specifically a lengthening of the QT interval that would lead to stopping study medication and study drug withdrawal due to safety concerns. Full details about the dosing schedule, titration plan, study blinding, and handling of study drug is in Section 5. *** There will be a phone visit after Visits 27 **** Subjects who have been withdrawn from study drug exposure prior to visit 8 will not attend visits 9 OR 10 OR have intervisit phone calls

135 CHAMP Study Protocol Version SELECTION AND ENROLLMENT OF SUBJECTS 4.1 Inclusion Criteria Diagnosis: Migraine with or without aura (International Classification of Headache Disorders, 2 nd Edition (ICHD-II) or chronic migraine (ICHD-II revised.) Frequency: Migraine frequency based upon prospective headache diary of 28 days must be 4. Migraine frequency defined as any migraine during one day in the 28 day baseline period* PedMIDAS: PedMIDAS Disability Score > 10, indicating at least mild disruption in daily activities and < 140, indicating extreme disability that may require more comprehensive, multi-component therapy Age: Females or males 8-17 years, inclusive * Migraine frequency is defined as the period from the onset to the stop time of painful migraine symptoms not to exceed 24 hours with the clock starting at midnight. If painful symptoms last longer than 24 hours, this is considered a new and distinct migraine headache. If painful symptoms recur within 24 hours of initial onset, this is considered part of the initial migraine episode and would be counted as one migraine. 44, 45 See section for further definition. 4.2 Exclusion Criteria Continuous migraine defined as an unrelenting headache for a 28 day period Weight less than 30 kg or greater than 120 kg Unwilling to avoid taking non-specific acute medication such as NSAIDS (e.g., ibuprofen), more than 3 times per week, or migraine specific acute medications such as triptans more than 6 times per month Currently taking other prophylactic anti-migraine medication within a period equivalent to 2 weeks of that medication before entering the screening phase, or the use of Botulinum toxin (Botox ) within 3 months of entering the screening phase Subjects who have previously failed an adequate trial of AMI or TPM for prophylaxis of at least 3 months duration at doses recommended for migraine relief because of lack of efficacy or adverse events* Current use of disallowed medications/products: opioids, antipsychotics, antimanics, barbiturates, benzodiazepines, muscle relaxants, sedatives, tramadol, nutraceuticals, SSRIs, or SSNRIs

136 CHAMP Study Protocol Version Known history of allergic reaction or anaphylaxis to AMI or TPM Abnormal findings on ECG at baseline, particularly lenghtening of the QT interval greater than or equal to 450 msec Subject is pregnant or has a positive pregnancy test Subject is sexually active and not using a medically acceptable form of contraception Diagnosis of epilepsy or other neurological disesases History of kidney stones Inability to swallow pills after using behavioral techniques if indicated between screening visit and baseline visit** Present psychiatric disease as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4 th Edition (DSM IV) (e.g. psychosis, bipolar disorder, major depression, generalized anxiety disorder), alcohol or drug dependence, or documented developmental delays or impairments (e.g., autism, cerebral palsy, or mental retardation) that, in the opinion of the site investigator, would interfere with adherence to study requirements or safe participation in the trial Any and all other diagnoses or conditions which in the opinion of the site investigator, that would prevent the patient from being a suitable candidate for the study or interfere with the medical care needs of the study subject. * Previously failed an adequate trial of AMI or TPM is defined as: dosage of 1mg/kg/day of AMI or 2 mg/kg/day of TPM; trial of at least 3 months duration; efficacy of having at least a 50% decrease in migraine frequency in response to drug therapy; or unable to tolerate taking the medication due to treatment-related side effects. ** Subjects who cannot swallow pills at the time of the screening visit will be given a training session using behavioral techniques. Upon return for baseline visit, if the subject continues to be unable to swallow pills, the subject will be excluded from the study. 4.3 Study Enrollment Procedures Identification and Retention of Subjects The primary methodology for identifying and recruiting subjects for this study will be through identification of potential subjects from pediatric headache medicine specialty practices, pediatric neurology practices or adult headache medicine or neurology practices that treat children and adolescents. This will include some sites that are part of the NINDS Clinical Research Consortium which have contracted to conduct the study. In order to reach our expected enrollment and based on our survey of interested sites, it is anticipated that the research sites would identify at least 4 subjects per site per month, and be able to enroll at least 1 subject every 2 months.

137 CHAMP Study Protocol Version We anticipate that complete enrollment will be achieved at the 48 month point after the grant award is received. If we need the full 48 months, the final subjects will complete the trial in Year 5, at the 56 month point. The final months of the 5- year period will be dedicated to final site closeout tasks, data management, and data analysis. Within each research site, methods and processes for identifying patients will be individualized, but conducted in accordance with the Declaration of Helsinki and Good Clinical Practice Guidelines. To support our recruitment and retention, several marketing tools will be employed: development of print media, and web postings. Print media to support recruitment efforts will include a study introduction letter from the coinvestigators, a study flyer, and study tear off pads. The flyer and tear off pads will be made available to study research sites for use in public places, medical practices, and research centers. Web postings will be developed for use on internet sites such as clinicaltrials.gov, the NINDS web site, and other web locations. Mailings of the study introduction letter and brochure to academic and private pediatric practices may also be employed to ensure that private pediatric neurology practices are aware of the study. Individual sites may choose to conduct recruitment events to provide information to potential subjects and their parents. Recruitment events may also be conducted in tandem with professional society meetings to raise awareness of the trial among practitioners. These strategies may include the recruitment of additional research sites and investigators if the initial sites under perform in recruitment or the use of specialized medical research websites for promotion of the study. To promote retention, birthday cards or special event cards may be sent to subjects at the discretion of the research sites Documentation of Ineligibility Screen failures will be documented on the source worksheets with the supporting data accompanying the eligibility screening form. The screen failure will be documented on the electronic case report form (ecrf). Reports detailing the reasons for screen-failure and non-participation of eligible subjects will collected from the research sites submissions to the Data Coordinating Center (DCC) using the ecrf. These reports will be reviewed by the study chair to determine if the exclusion criteria require revision in order to make the trial accessible to families and study subjects. The procedure for documentation of ineligibility or non-participation will include a completed eligibility checklist for each consented study subject. The study sites

138 CHAMP Study Protocol Version will use the eligibility checklist to record the specific item that excludes a study candidate from participation. In addition, the sites will submit a weekly screening report electronically to the CCC Method for Obtaining Informed Consent The informed consent and the assent will be provided to the study subject and the parents for review. After allowing adequate time for review, the subject and parents will have the opportunity to ask questions and receive answers. When all questions have been answered, the consent and assent will be signed and a signed copy provided to the subject and parents. This will all be conducted before any study interventions are undertaken Procedure for Assignment of Randomization Randomization will be stratified by age (8-12 and 13-17) and number of headaches per month (episodic: 4-14, chronic: 15 or more). Because this strategy provides four strata, we have elected not to stratify the randomization at each site. The Data Coordinating Center (DCC) will generate a randomization table for each of the strata using a permuted block design with random block sizes. Briefly, after completion of all eligibility requirements and the determination of eligibility by the investigator, the eligbility ecrf will be completed by the study coordinator. The completion of this ecrf will trigger a response from the DCC to randomly assign a treatment group in keeping with the subject s age stratification. The notification of treatment assignment will then be delivered electronically to the central research pharmacy and to the site study staff. The study staff will receive a blinded notification of the bottle numbers to supply the assigned treatment to the subject s family to begin study drug titration Study Drug Supply Each site, upon initiation, will receive a startup supply of study medication that will allow enrollment of subjects into each treatment arm. This will consist of study drug, appropriately labeled to maintain blinding and corresponding to the treatment assigned from the DCC, of placebo, amitriptyline, or topiramate. Upon completion of the eligibility ecrf and at regular intervals, the central pharmacy will initiate a shipment that will re-supply the site with additional study drug. All AM doses will be prepared with identical over-encapsulation with the same color capsules. All PM doses will be prepared in the same manner with a different color capsule. For AM dosing, subjects will be instructed to take the study medication consistently with breakfast. For PM dosing, subjects will be instructed to take the study medication consistently at dinnertime. In instances when the subject or the subject s family s schedule interferes with mealtime dosage, the site PI may recommend that the time of study medication administration be adjusted to meet needs of the individual study family. For example, if a subject has numerous evening activities that interfere with dinnertime, the site PI may recommend that the evening dose of study medication be taken when the subject

139 CHAMP Study Protocol Version returns home for the evening. The DCC, the Central Investigational Drug Service (IDS) staff, and the Central Laboratory staff will be unblinded to treatment assignment. Study staff at the site will remain blinded and only receive an instruction to deliver a specific bottle number for the subject upon randomization. The CCC staff will also remain blinded. 5 STUDY INTERVENTIONS 5.1 Interventions, Administration, and Duration The following refers to study subjects with pediatric migraine: Frequency of administration Each of the three interventions (amitriptyline, topiramate, and placebo) will be administered twice daily at home, to be taken by mouth with or without food under the supervision of the subject s parent or guardian. To maintain blinding, all subjects will receive 1 matching capsule at each dose (2 capsules/day) during the 8-week titration period. Each capsule will contain either topiramate, amitriptyline, or placebo, depending upon the group to which a subject is assigned randomly. Additionally, during titration and maintenance phase, subjects randomized to amitriptyline will receive a placebo capsule to be taken in the morning in order to maintain the blinding.

140 CHAMP Study Protocol Version Amitriptyline Brand to be Used Amitriptyline (Mylan Pharmaceuticals, Inc., Sandoz, Inc, or Qualitest, USA.) Formulations This study will use drug manufactured by Mylan Pharmaceuticals, Inc., Sandoz, Inc, or Qualitest, USA, in the following strengths: 10mg, 25 mg, 50 mg, 75 mg, 100 mg tablets which will be prepared through pill cutting and over-encapsulation with gel capsules. Table details the dosing schedule by weight for Amitriptyline during weeks 0-8. Table Amitriptyline Dosing Schedule by Weight for Weeks 0-8. Weight Group (kg) Weight Low (kg) Range High (kg) Start at Week 0 Start at Week 2 Start at Week 4 Start at Week 6 Start at Week 8 AM PM AM PM AM PM AM PM AM PM Potential Adverse Events Amitriptyline has a number of side effects. Refer to Section for a list of expected adverse events.

141 CHAMP Study Protocol Version Topiramate Brand to be Used Generic Topiramate (Teva Pharmaceuticals, Inc., Camber Pharmaceuticals, or Sun Pharma) Formulations This study will use 25 mg and 50 mg tablets which will be prepared through pill cutting and over-encapsulation with gel capsules. Table details the dosing schedule by weight for Topiramate during weeks 0-8. Table Topiramate Dosing Schedule by Weight for Weeks 0-8. Weight Group (kg) Weight Low (kg) Range High (kg) Start at Week 0 Start at Week 2 Start at Week 4 Start at Week 6 Start at Week 8 AM PM AM PM AM PM AM PM AM PM Potential Adverse Events Topiramate has a number of side effects. Refer to Section for a list of expected adverse events.

142 CHAMP Study Protocol Version Placebo Placebo Capsule The placebo will be manufactured by the Central IDS and consist of 500 mg of lactose powder contained in gel capsules Formulations All placebo capsules used in this study will contain the same amount of ingredients with gel capsules. Table details the dosing schedule by weight for placebo during Weeks 0-8. Table Placebo Dosing Schedule by Weight for Weeks 0-8. Weight Group (kg) Weight Low (kg) Range High (kg) Start at Week 0 Start at Week 2 Start at Week 4 Start at Week 6 Start at Week 8 AM PM AM PM AM PM AM PM AM PM Potential Adverse Events There are no expected adverse reactions associated with taking placebo.

143 CHAMP Study Protocol Version Double Blind Treatment Phase The double blind treatment phase for this study is 24 weeks (8 week titration, followed by a 16 week maintenance period), followed by a 6 week weaning off period (2 week wean, 4 week off drug (no medication)). 5.3 Titration Period Overview of Titration Period A subject s dosage may be held or decreased every two weeks during the titration period if the subject experiences dose limiting side effects that in the individual site investigator s opinion warrant a slower titration. The plan for dosage escalation for amitriptyline, topiramate, and placebo are outlined in Tables Site Investigator s Role in Dosage Titration The site investigator will recommend each increased, decreased, or stable dosage based upon the results of the evaluation during the study visit and the review of the targeted symptom questionnaires from phone and study visits. The revised dosage for the next study period will be communicated to and implemented by the Investigational Research Pharmacy at the site. The documentation of the dosage adjustment and communication of the adjustment to the Investigational Research Pharmacy will be retained in the source and ecrf Dosage Escalation Guidelines Medication Dispensing Medications will be dispensed in a manner to maintain the blind. The study drugs, AMI, TPM, and placebo will be encapsulated so that the AM and PM doses are color coded differently. Study drug will be dispensed from previously prepared bottles based upon treatment assignment and the subject s weight Treatment Bottle Sets Treatment Bottle Setswill contain a 4 week supply of study drug, plus enough drug to cover the visit windows with a dosage increase every two weeks during titration phase. The bottle sets will be labeled Bottle Set 1 for the first two weeks in a titration period, and Bottle Set 2 for the second two weeks in a titration period. At maintenance, subjects will only receive Bottle Set 1, which will contain enough study drug for a 4 week supply of study drug, plus enough drug to cover the visit windows Subjects Who are Unable to Advance During Titration If a subject has difficulty tolerating a given dose during the titration period, the investigator may: a) Maintain the study medication at the current dose for: an additional 2 weeks and then increase the dose, or

144 CHAMP Study Protocol Version the remainder of the titration and maintenance periods; OR b) Reduce the study medication to the previously titrated dose for: an additional two weeks and then re-titrate the dose, or maintain dosage for the remainder of the titration periods subjects who require a dosage decrease at week 2 must be withdrawn from study drug exposure (Section 6.3.3) subjects who require a decrease below the baseline dosage at any interval must be withdrawn from study drug exposure (Section 6.3.3) subjects may only receive one dosage reduction during titration c) For subjects who have been unable to advance to their maximum dosage by week 8, they may advance one more dosage at week 10.

145 CHAMP Study Protocol Version Figure Titration Scenarios. Start Maintenance Evaluation Wean a. Expected Titration b. Titration withhold (solid) or delayed (dashed) c. Titration with reduction

146 CHAMP Study Protocol Version Figure Dosing Titration Plan by Bottle Dispensed

147 CHAMP Study Protocol Version Communication Regarding Dose Changes If the investigator recommends a change in dose, this will be communicated electronically to the DCC, which will communicate the dosage change to the Investigational Research Pharmacy. A revised bottle number will be provided to the study site staff in a manner that maintains the double blind. Such changes will be reviewed by study monitoring staff for data quality assurance and safety monitoring. 5.4 Maintenance Period Overview of Maintenance Period During the 16-week maintenance period, subjects will continue to receive 2 capsules daily (divided dose) containing either topiramate (2mg/kg/day or the maximum dose achieved during the titration period), amitriptyline (1mg/kg/day or the maximum dose achieved during the titration period plus a placebo capsule), or placebo given in a divided dose of 1 capsule twice daily. The dosage of study medication should remain constant during the maintenance period Dosage De-Escalation during Maintenance Period If a. Premature discontinuation of study therapy will be documented in the source binder and ecrf. These subjects will be removed from study drug exposure (Section 6.3.3) Plan for Maintenance Period Dosage The plan for maintenance period dosage by weight is outlined below in Table Some subjects may not progress to the planned maximum dosage during titration and will be maintained during the maintenance period on the highest dosage achieved during titration.

148 CHAMP Study Protocol Version Table Maintenance Period Dosage. Weight Weight Range Week Week Group Low High (kg) (kg) (kg) Placebo AM PM Amitriptyline AM PM Topiramate AM PM Weaning Period Overview of Weaning Period All subjects who complete or who discontinue study medication during the maintenance period will enter the weaning period. Subjects who do not complete the titration period and are removed from study drug exposure will undergo weaning if they have progressed to one dosage increase beyond the baseline dosage for their weight group, or been on study drug for three full weeks. The study site investigators may modify the weaning instructions for subjects who have not achieved the maintenance dosage or who have been non-compliant Plan for Dosage De-Escalation during the Weaning Period Subjects will have their weekly dosage tapered at a rate of approximately 75% of the dose achieved during maintenance during the first five days, followed by approximately 50% for the next five days, and approximately 25% the final four days. To achieve this end and to maintain the double blind, all subjects will continue to receive 2 matching capsules each day Plan for Weaning Period Dosage

149 CHAMP Study Protocol Version The plan for weaning period dosage, based upon the maximum dosage achieved, is outlined in Table For subjects who have been unable to progress to the predicted maximum dosage, the table includes the lower possible dosages available during titration and maintenance. Subjects will have their weekly dosage tapered at a rate of approximately 75% of the dosage achieved during maintenance during the first five days, followed by approximately 50% for the next five days, and approximately 25% the final four days. To achieve this while maintaining the double blind, all subjects will continue to receive 2 matching capsules each day. Subjects who have been on study drug less than three full weeks will not require a weaning period. Table Weaning Period Dosage Plan Maximum dosage achieved Week Week Week Week Week Week Week Week Day Day Day Day Day Day Placebo AM PM AM PM AM PM AM PM No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug Amitriptyline AM PM AM PM AM PM AM PM No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug Topiramate AM PM AM PM AM PM AM PM No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug No drug

150 CHAMP Study Protocol Version Concomitant Interventions Allowed Rescue Medications For acute headache treatment, subjects will be educated on effective use of allowable rescue medications to stop individual attacks. This will be guided by each site investigator, but will include the importance of early treatment with doses of medications demonstrated to be effective in acute headache management, while avoiding the development of medication overuse. With the exception of almotriptan (for year olds) and rizatriptan (6-17 years old), these medications have not been approved by the FDA for the acute treatment of migraine in children and will need to be guided by the individual site investigators. Therapeutic options will be available for use at the discretion of the site investigator. 5.7 Prohibited Interventions Acute Medications Treatment with narcotic medications is prohibited, including butalbital containing compounds and codeine compounds and derivatives Preventative Medications During the trial, no other preventative medication should be used including pharmaceutical, nutraceutical or any herbal treatments suspected to have headache prevention effects (i.e., stand alone supplements of Riboflavin, CoEnzyme Q10, and Magnesium.). Psychological intervention for headaches including biofeedback assisted relaxation therapy, or any other treatments intended for headache prevention proven or unproven (i.e., acupuncture, chiropractic manipulation) are also prohibited. Subjects who are using these agents at the time of consent may elect to stop usage and add an additional period of two weeks to the screening period to allow for wash out of these medications, supplements or therapies. The screening period may extend to -45 days before day 0 for subjects who require washout from preventative medications or supplements after consent. For these subjects, the 28 day period immediately prior to Visit 2 will be considered the baseline period for purposes of headache diary collection Specifically Excluded Medications Anticonvulsants, antidepressants including other non-selective and selective serotonin receptors, tranquilizers, transcutaneous stimulators, acetazolamide, calcium channel blockers, methysergide maleate, corticosteroids (except for inhaled steroids for treatment of the nasal mucosa, sinuses, bronchii, and lungs), beta-adrenergic blocking medications, monoamine oxidase inhibitors, chronic NSAIDs or COX inhibitors, lithium carbonate, flunarizine, nonstable doses of stimulant medication, antipsychotics (past or current), thiazide diuretics, injections for headaches (including nerve blocks and botulinum toxin), or cyproheptadine. 5.8 Handling of Study Interventions

151 CHAMP Study Protocol Version The distribution of study drug to each research site, and the directions for storage and drug accountability procedures are addressed in more detail in the pharmacy section of the Manual of Operations. Study drug will be purchased in bulk by the central pharmacy for the preparation of treatment bottles. Study drug will be provided to the research sites in blinded treatment bottles. The treatment group assignment will be retained at the central pharmacy. During titration, the bottles will contain a one month supply of study drug in four treatment bottles: an AM and a PM bottle for each two week period of supply, plus additional tablets to accommodate the supply needed for titration management or treatment during the +/- 7 day visit windows. During maintenance, the bottles will contain a one month supply of study drug in two treatment bottles: an AM and a PM bottle for each four week period of supply, plus additional tablets to accommodate the +/- 7 day visit windows. Each study site will be supplied with enrollment bottles for all weight ranges of study subjects for the initial dosing period occurring at randomization on Visit 2. Additional bottles will be supplied to the sites as needed during titration and maintenance. The study drug will be provided in an over-encapsulated form, in order to maintain blinding to treatment assignment by study staff and subjects. Unused study drug will be retained at the research site until all drug accountability procedures have been completed for the treatment bottles. Unused study drug may be destroyed per the research site s Standard Operating Procedures (SOP) after drug accountability records have been monitored and all accountability resolved, or returned to the central pharmacy if there is no SOP in place at the research site. 5.9 Adherence Assessment Adherence assessments will be conducted by the pill count method and performed by the study coordinator at the time of each study visit. Drug therapy compliance will be documented by the subject or subject s parent on the daily headache diary. The daily headache diary will be returned along with the study drug for verification of compliance at every study visit after randomization until the completion of washout. The study coordinator will complete the adherence assessment and instruct the subject or subject s parent about the study drug dosage for the next treatment period. Non-compliance issues will be reported to the site investigator during the study visit prior to the administration of further study drug. Adherence issues that are detected at the study visit will be addressed with the subject and parent at the study visit. If compliance cannot be secured, the subject may be withdrawn from study drug exposure by the site investigator (Section 6.3.3). Adherence will also be monitored by the use of batch analysis of biosamples collected at two intervals during the study and assayed for the presence of amitriptyline or topiramate Option for Future Re-contact of Subjects by Central Coordinating Center

152 CHAMP Study Protocol Version The principal investigators would like to maintain the option for future re-contact of study subjects after completion by the subject or termination of the study. The purpose for re-contact would be to invite participation in the conduct of ancillary studies with a subpopulation of study subjects. Optional future studies may include durability of treatment effect or other future investigations with biomarker analysis, or reporting of an unanticipated results from Biorepository analysis. An optional consent for re-contact will be included in the study informed consent and assent templates. 6 CLINICAL AND LABORATORY EVALUATIONS Table 3.3 summarizes the study visit and procedure schedule. A detailed listing of study procedures follows. 6.1 Informed Consent Informed consent will be obtained prior to conducting any study procedures. The informed consent process is described in Section under Definitions of Evaluations. 6.2 Evaluations Subjects, who meet ICHD-II for migraine with or without aura or ICHD-II revised for chronic migraine and meet all other inclusion/exclusion criteria, must have the following procedures completed during the Screening Visit after signing the informed consent and prior to study entry. The screening procedures may be conducted over 2 visits withall study interventions completed prior to Visit 2 if desired by the individual site investigator Screening Visit 1 (Up to Day-45 but no less than Day-30) 1. Completion of informed consent and assent (if applicable) prior to initiation of study procedures 2. Obtain urine pregnancy test for all females of childbearing potential. 3. Review baseline medical history; headache history including acute and prophylactic use and current regimen 4. Document all concomitant medications including prescribed over the counter and nutraceutical supplements 5. Determine if subject is able to swallow pills. Subjects who cannot swallow pills at the time of the screening visit will be given a training session using behavioral techniques. 6. Administer questionnaires (BRIEF, CDI, FDI, HADS, PedsQL) 7. Review the CDI questionnaire item 9 results during the visit. If suicidal ideation is identified from Item 9 of the CDI, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. 8. Obtain vital signs (height, weight, heart rate, blood pressure) 9. Obtain demographics 10. Perform physical examination

153 CHAMP Study Protocol Version Perform neurological examination including visual field exam 12. Obtain clinical laboratory tests as follows: Hematology A CHAMP Comprehensive Profile of liver and renal analytes Biorepository samples (DNA, serum, and RNA) 13. Obtain ECG. The ECG will be confirmed by the site investigator and then sent to the CCC for independent interpretation. The criteria for elongation of the QT interval will be a QT interval greater than or equal to 450 msec 46. If the central reader determines that the QT interval has been elongated and that elongation or any other serious ECG abnormality would put the subject at risk for an adverse event, then the subject would be determined to be ineligible. 14. Instruct subject and parent/guardian to discontinue all of the subject s medications being used for migraine prevention as discussed in section 5.7 for at least 2 weeks prior to start of the prospective baseline period. If the subject is not taking any migraine preventive medication they may immediately enter the Prospective Baseline Period. Subjects who are taking preventative migraine medications and who elect to discontinue the use of the medications or supplements may extend the baseline screening period to day -45 before the Visit 2 assessments. In this case, the 28 day period immediately prior to Visit 2 will be considered the baseline period for purposes of headache diary collection. 15. Instruct subject and parent/guardian with healthy habits (adequate hydration, sleep, exercise, regular meals with healthy eating) and headache diary completion Randomization - Visit 2 (30 45 Days ) Visit 2 will be conducted no less than 30 days after Visit 1 (Screening Visit).This means that the day of consent counts as day 1 with the day of the randomization visit counting as day 30. The 28 days between consent and immediately preceding the randomization visit are the days for which the diary will be reported. In the case of an extended screening period (up to 45 days), the 28 days immediately prior to the day of the randomization visit are the days for which the diary will be evaluated to determine eligibility Eligibility Determination-Headache Diary Collect and review headache diary to determine migraine frequency eligibility (Eligible: > 4-30 migraine days a month). Subjects who report a continuous headache of 28 days of duration will be determined ineligible. If the migraine frequency is appropriate to meet eligibility criteria and there are no laboratory findings restricting eligibility (i.e., identification of significant abnormalities, that in the site investigators opinion, would restrict treatment, evidence of illicit drug use, or pregnancy), the

154 CHAMP Study Protocol Version PedMIDAS disability questionnaire will be presented and scored. If the PedMIDAS score is > 10 but < 140, the visit will proceed. If these criteria are not met, the subject will be determined to have failed screening. Subjects who failed to meet eligibility criteria based on the headache diary or PedMIDAS score may be re-evaluated for study eligibility at the discretion of the site investigator after a minimum of three months if migraine frequency and PedMIDAS disability scores have changed. Confirm that subjects who could not swallow pills at the time of the screening visit have been successful with pill swallowing training. If the subject continues to be unable to swallow pills, the subject will be excluded from the study. Confirm that the subject has an acceptable ECG result from the central review which will allow participation. Upon successful completion of screening procedures, subjects who meet all inclusion/exclusion criteria will be randomized in a double-blind fashion to one of three treatment groups (amitriptyline, topiramate, or placebo) as outlined in the randomization section. The duration of the Double Blind Phase will be 26 weeks (8 week titration, 16 week maintenance, 2 week weaning off study medication). 1. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before eligibility is determined. 2. Determine if any adverse events have occurred since subject signed informed consent 3. Administer PedMIDAS and HIT-6 4. Randomize subject 5. Obtain vital signs (height, weight, heart rate, blood pressure) 6. Update demographics 7. Perform physical examination 8. Perform neurological examination including visual field exam 9. Dispense headache diary 10. Instruct subject on the use of symptom questionnaire and phone symptom screening procedure. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Baseline instrument to score any subject reports of suicidality obtained from the symptom questionnaires. 11. Review concomitant medications 12. Dispense study medication, medication instructions, and emergency contact card 13. Schedule phone symptom screening calls for week 2

155 CHAMP Study Protocol Version Titration Phase The Titration Phase will extend for 8 weeks. Clinic visits will occur at Visit 3 (4 weeks after randomization) and Visit 4 (8 weeks after randomization). Extra visits may be scheduled at the discretion of the investigator as discussed in section Visit 3 (4 Weeks ± 7 days) 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire If subject reports an adverse event, follow the adverse event procedure outlined in Section 7. If suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Obtain vital signs (height, weight, heart rate, blood pressure) 6. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 7. Update demographics 8. Perform physical examination 9. Review concomitant medications 10. Dispense headache diary for next study interval 11. Determine if subject will advance to next level of medication titration 12. Increase study medication dosage if no safety or tolerability issues. If issues are reported, the site investigator will decide to advance, hold or decrease dosage to previously tolerated level. 13. Dispense study medication; discuss revised study medication instructions 14. Schedule phone symptom screening calls for 2 weeks from visit

156 CHAMP Study Protocol Version Visit 4 (8 Weeks ± 7 days) 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire If suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Obtain vital signs (height, weight, heart rate, blood pressure) 6. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 7. Update demographics 8. Perform physical examination 9. Review concomitant medications 10. Dispense headache diary for next study interval 11. Determine if subject will advance to next level of medication titration 12. Increase study medication dosage if no safety or tolerability issues. If issues are reported, the site investigator will decide to advance, hold or decrease dosage to previously tolerated level. 13. Dispense study medication; discuss revised study medication instructions 14. Schedule phone symptom screening calls for 2 weeks from visit Maintenance Phase The Maintenance Phase extends for 16 weeks. Clinic visits will occur at Visit 5 (12 weeks after randomization) Visit 6 (16 weeks after randomization), and Visit 7 (20 weeks after randomization). Extra visits may be scheduled at the discretion of the investigator.

157 CHAMP Study Protocol Version Visit 5 (12 Weeks ± 7 days) 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire and discuss previous phone symptom screening If suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Administer Questionnaires (BRIEF, CDI, FDI, HADS, PedsQL) If suicidal ideation is identified from Item 9 of the CDI, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. 6. Administer PedMIDAS and HIT-6 7. Obtain vital signs (height, weight, heart rate, blood pressure) 8. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 9. Update demographics 10. Perform physical examination 11. Review concomitant medications 12. Perform neurological examination including visual field exam 13. Obtain laboratory tests as follows: A CHAMP Comprehensive Profile of liver and renal analytes

158 CHAMP Study Protocol Version Sample for adherence levels of Amitriptyline or Topiramate 14. Obtain ECG. The ECG will be confirmed by the site investigator and then sent to the CCC for independent interpretation. The criteria for elongation of the QT interval will be a QT interval greater than or equal to 460 msec. 46 If the central reader determines that the QT interval has been elongated and that elongation would put the subject at risk for an adverse event, then the subject would be removed from study drug exposure (Section 6.3.3). Confirm that the subject has an acceptable ECG result from the central review when this result is available to allow continued participation. 15. Dispense headache diary for next study interval 16. Determine if subject will continue on maintenance dose of medication 17. Dispense study medication 18. Schedule phone reminder call for 2 weeks from visit Visit 6 (16 Weeks ± 7 days) 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire and discuss previous phone symptom screening If suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. 5 and 6 Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Obtain vital signs (height, weight, heart rate, blood pressure) 6. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 7. Update demographics

159 CHAMP Study Protocol Version Perform physical examination 9. Review concomitant medications 10. Dispense headache diary for next study interval 11. Determine if subject will continue on maintenance dose of medication 12. Dispense study medication 13. Schedule phone reminder call for 2 weeks from visit Visit 7 (20 Weeks ± 7 days) Endpoint Visit 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire and discuss previous phone symptom screening If suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self-injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Obtain vital signs (height, weight, heart rate, blood pressure) 6. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 7. Update demographics 8. Perform physical examination 9. Review concomitant medications 10. Perform neurological examination including visual field exam 11. Dispense headache diary for next study interval 12. Determine if subject will continue on maintenance dose of medication 13. Dispense study medication 14. Schedule phone reminder call for 2 weeks from visit

160 CHAMP Study Protocol Version The endpoint visit will occur 24 weeks after randomizations +/- 7 days. Visit 8 (24 Weeks ± 7 days) 1. Distribute symptom questionnaire for completion by subject 2. Collect and review headache diary for completion of data fields 3. Collect and review symptom questionnaire and discuss previous phone symptom screening If suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4. Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 5. Administer PedMIDAS and HIT-6 6. Administer questionnaires (BRIEF, CDI, FDI, HADS, PedsQL). If suicidal ideation is identified from Item 9 of the CDI, notify the site investigator and determine if an urgent referral or outpatient followup for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. 7. Review the Healthy Habits subject handout. 8. Obtain vital signs (height, weight, heart rate, blood pressure) 9. Obtain urine pregnancy test for all females of childbearing potential. This must be a negative result before study drug is dispensed again. 10. Update demographics 11. Perform physical examination 12. Review concomitant medications 13. Perform neurological examination including visual field exam

161 CHAMP Study Protocol Version Obtain clinical laboratory tests as follows: A CHAMP Comprehensive Profile of liver and renal analytes Sample for adherence levels of Amitriptyline or Topiramate 15. Biorepository samples (serum and RNA) Dispense headache diary for next study interval 16. Dispense study medication 17. Discuss weaning procedure 18. Instruct subject on additional treatment options beyond the study for acute treatment and for preventative treatment if the subjects continue to have 1 or more migraine per month. The subject and investigator will not be unblinded to treatment assignment at the conclusion of the maintenance period or at the end of the subject s participation in the study. See section 8.3 regarding the study blind at Study Conclusion 19. Schedule phone call for 2 weeks from visit 20. Provide the subject with the CHAMP Follow up Study flyer and inform subject that they are invited to join the follow up study and that they will be contacted by a CCHMC study coordinator Final Evaluations The weaning off drug and off drug phase will extend for 6 weeks after visit 8. Subjects will wean off study medication between weeks 24 and 26 and be observed for any off drug problems. At 26 weeks subject will be off study medication. Weaning Off Drug Phase Visit 9 (26 weeks ± 7 days) conducted by phone 1. Conduct and review phone symptom questionnaire If suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow -up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject.

162 CHAMP Study Protocol Version Request subject return all remaining study drug and headache diary to the study site by mail. After study drug is received, a pill count will be performed and compliance assessed. 3. Document any ongoing or resolved adverse events; the information will be collected by phone. 4. Schedule phone symptom screening calls for 4 weeks from visit Off Drug Phase Visit 10 (30 weeks ± 7 days) conducted by phone 1. Conduct and review phone symptom questionnaire If suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, self-injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 2. If not completed after Visit 9, request subject return all remaining study drug to the study site by mail, a pill count performed and compliance will be assessed. 3. Document any ongoing or resolved adverse events; the information will be collected by phone. This will conclude the subject s involvement with the study, unless the subject has allowed permission for re-contact at a later time. 6.3 Titration Adjustment, Removal from Study Drug Exposure and Unscheduled Visits Titration Adjustment Visit A study visit may be required for subjects who require a dosage titration adjustment. If, in the opinion of the site investigator, the subject requires a dosage titration adjustment to either hold or decrease study medication due to any intolerance issues, the investigator may manage the dosage change by telephone visit or request that the subject complete a dosage titration adjustment visit in person During a telephone visit, the following interventions will be performed: 1.Conduct and review the symptom questionnaire

163 CHAMP Study Protocol Version If suicidal ideation is identified, determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through an ecrf AE report submitted urgently if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self-injury, the site investigator will develop an action plan for the immediate care needs of the subject. 2.Complete the Dosage Modification Form to document the reason for dosage titration adjustment and to communicate the revised dosage schedule to the DCC. 3.Dispense the modified dosage of study medication and allow a treatment period for the new dosage of two weeks During an in person dosage titration adjustment visit, all of the interventions listed in the telephone visit will be conducted with the addition of the following interventions: 1.Collect and review headache diary for completion of data fields 2.Dispense headache diary for next study interval if needed. 3.Collect study drug, perform pill count and drug accountability Evaluate compliance to study drug regimen and discuss adherence to regimen Counsel subject about importance of adherence 4.Obtain vital signs (height, weight, heart rate, blood pressure) 5. Obtain urine pregnancy test for all females of childbearing potential. 6.Perform physical examination 7.If, in the opinion of the investigator, other interventions are required for the safety of the subject, such as the neurological examination or study laboratory tests, these may be conducted at this visit. 8.Review concomitant medications and adverse events 9.If, in the opinion of the investigator, the subject should be discontinued from exposure to study drug, please document that decision. (Section 6.3.3) Unscheduled Visit If, in the opinion of the site investigator, the subject requires an unscheduled visit to manage safety or tolerability issues, the visit may be conducted at the investigator s discretion. The visit will be recorded in source and ecrf using the routine forms provided by the CCC and DCC.

164 CHAMP Study Protocol Version Withdrawal from Study Drug Exposure Subjects who are withdrawn from study drug exposure will be encouraged to continue to record headache diaries and headache records and maintain the visit schedule. After the study drug withdrawal visit is completed, no further laboratory samples will be collected and no ECG s will be collected. Adverse events will continue to be collected for thirty days after study drug exposure ends. Subjects who are withdrawn from study drug exposure prior to Visit 8 will not be required to attend Visits 9 or 10. For subjects who discontinue the study drug prior to Visit 9, the following interventions will be performed unless informed consent has been withdrawn. 1.Distribute symptom questionnaire for completion by subject 2.Collect and review headache diary for completion of data fields. 3.Conduct and review symptom questionnaire If suicidal ideation is identified, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through urgent ecrf AE report if any symptom is determined to be a serious adverse event. Administer the Columbia- Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. If slow thinking or cognitive difficulty is identified, or marked decline in school performance is reported, notify site investigator, determine if referral is required. If subject reports other significant symptoms or changes, such as vision changes, severe back pain, pregnancy, or self-injury, notify the site investigator who will develop an action plan for the immediate care needs of the subject. 4.Collect study drug 5.Perform final drug accountability 6.Administer PedMIDAS and HIT-6 7.Administer questionnaires (BRIEF, CDI, FDI, HADS, PedsQL) If suicidal ideation is identified from Item 9 of the CDI, notify the site investigator and determine if an urgent referral or outpatient follow-up for psychiatric care is needed. Make the appropriate clinical decision to ensure subject safety. Notify the sponsor through urgent ecrf AE report if any symptom is determined to be a serious adverse event. Administer the Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit instrument to score any subject reports of suicidality. 8.Obtain vital signs (height, weight, heart rate, blood pressure) 9.Obtain ECG if withdrawal from study drug exposure occurs at Visit 5 or if subject reports cardiac adverse events as a reason for withdrawal

165 CHAMP Study Protocol Version from study drug exposure. The ECG will be interpreted by the site investigator and then sent to the CCC for independent interpretation. 10. Perform physical examination 11. Obtain clinical laboratory tests as follows: A CHAMP Comprehensive Profile of liver and renal analytes Sample for adherence levels of Amitriptyline or Topiramate Biorepository samples (serum and RNA) 12. Perform neurological examination including visual field exam 13. Review concomitant medications and adverse events 14. Dispense headache diary for next study interval and schedule next visit if subject agrees to continue to collect study data and to avoid migraine preventative agents. 15. Document reason for withdrawal from study drug exposure Pregnancy A urine pregnancy test will be performed at each face to face study visit for females of child bearing potential. Subject pregnancy must be reported by the investigational staff within 1 working day of their knowledge of the event using the urgent ecrf AE report. Any subject who becomes pregnant during the study must be promptly withdrawn from study drug exposure, but will continue to be followed on the protocol at regularly scheduled visits, or with unscheduled visits or phone follow up. Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the infant will be required and reported through the adverse event reporting system for tracking purposes only. 6.4 Special Instructions and Definitions of Evaluations Informed Consent Research conducted in this project will be reviewed and approved by the appropriate Institutional Review Board (IRB) for each site. Following local IRB approval, the site principal investigator or their IRB approved designee will discuss the study with the family and obtain written informed consent (and assent if required by the local IRB) using the locally approved consent form. The informed consent process will be documented in source. All NIH, federal, and local IRB regulations and guidelines will be followed. Recruitment will occur at the clinical sites The CCC will provide template consent and assent forms to investigative sites. Any modifications to the template consent and assent will be reviewed by the CCC Regulatory Staff prior to submission to the local IRB. The CCC Regulatory Staff will ensure the required elements for consent are contained within each form, and that all forms are HIPAA compliant.

166 CHAMP Study Protocol Version Each subject s original informed consent document will be maintained in the subject s study source documents Sites will obtain written informed consent (and assent if required by the local IRB) from eligible subjects Documentation of Pediatric Migraine The diagnosis of pediatric migraine is made using a combination of clinical and diary findings. For purposes of this study, pediatric migraine is characterized by diagnosis of migraine with or without aura or chronic migraine that meets the ICHC-II criteria Migraine frequency is a key parameter in this study. It is defined in this protocol as the number of days with migraine for a given 4 week ( 28 day) period where one migraine is counted as beginning at the onset of painful migraine symptoms, not to exceed 24 hours with the clock starting at midnight. If painful symptoms last longer than 24 hours without resolution, this is considered a new and distinct migraine headache, which would result in a frequency count of two migraine days. If painful symptoms recur within 24 hours of initial onset, this is considered part of the initial migraine episode and would be counted as one migraine, or one migraine day Medical History A medical history includes chief complaint, history of migraine, past medical history A comprehensive medical history will be obtained at the screening visit and will be documented in the source documents. Subjects may provide an optional consent to allow use of their previously documented medical history to be reviewed for trial inclusion Treatment History/Prior Headache Medications At study entry, the prior history of treatment with any migraine prevention agent will be documented. Subjects who have failed adequate trials of the study medications (defined as a trial of at least 3 months duration at doses recommended for headache relief) will be excluded Physical Examination A physical examination includes central nervous system, behavioral, HEENT, cardiovascular, pulmonary, gastrointestinal, genitourinary, dermatologic, musculoskeletal assessment Physical examinations will be obtained at every clinic visit and will be documented in the source documents Vital Signs and Demographics

167 CHAMP Study Protocol Version Vital signs include height, weight, blood pressure, heart rate, and respiration Demographic information includes subject s name, address, phone, , and parent/guardian contact information, ethnicity, gender, and race Neurological Examination with Vision Examination A neurologic examination includes assessment of the subject s mental status, cranial nerve function, motor and sensory function, deep tendon reflexes, cerebellar function and gait A Funduscopic and visual field examination will be conducted Laboratory Evaluations - CBC, Renal, Liver Function, Adherence Drug Levels of Amitriptyline and Topiramate and Biorepository A random non-fasting sample of blood obtained on the day of the clinic visit will be analyzed for complete blood count (Visit 1 only), liver panel and renal function. Blood will be drawn three times during the study: Visits 1, 5 and 8. About 4 teaspoons (20 ml) of blood will be drawn from a vein for each lab test. This yields a total volume of 60 ml by the completion of the study. The 20 ml/visit is less than 5% of the total blood volume of a child ages 8-17 (3777ml 4095 ml) which would be ml. With this low volume of blood loss (about 0.5% of the total volume), no extraordinary precautions will be needed to protect the child from adverse events from blood loss Clinical laboratory tests will be performed centrally by the CCC clinical laboratory. The results will be retained in the source documentation, with the exception of the adherence drug levels of amitriptyline and topiramate which will be retained at the DCC and not provided to study sites. The ecrf will directly record the central lab result and when a value is flagged as high or low by the central laboratory. This section of the ecrf will not be accessible to the CCC or the site study staff in order to maintain the study blind A clinically significant laboratory abnormality (in the opinion of the local site principal investigator) will be considered as an adverse event The central clinical laboratory normal values for complete blood count, liver panel, renal function, and adherence drug levels for amitriptyline and topiramate will be updated annually Table summarizes the specific analytes for evaluation in the CBC, and the CHAMP Comprehensive Profile of liver and renal analytes.

168 CHAMP Study Protocol Version Table Analytes for CBC, CHAMP Comprehensive Profile of Liver and Renal analytes and Adherence Drug Levels CBC - Hematology Panel hematocrit hemoglobin platelet count red blood cell (RBC) count white blood cell (WBC) count CHAMP Comprehensive Profile of Liver and Renal Analytes albumin alkaline phosphatase ALT AST bicarbonate blood urea nitrogen (BUN) calcium chloride creatinine glucose lactic dehydrogenase (LDH) potassium Sodium total bilirubin total protein Adherence Drug Levels Amitriptyline Topiramate A CHAMP Study Biorepository will be used to retain samples for future biomarker analysis. Blood for DNA analysis, serum for biomarker analysis, and blood samples for RNA analysis will be obtained on an optional basis from consenting subjects. The samples will be obtained during regular study sample collections occurring at Visit 1, 8. A select group of sites will obtain the samples for RNA analysis ECG A twelve lead ECG will be obtained utilizing the site s ECG equipment Interpretation of ECG results will be performed by the central reader at the CCC.

169 CHAMP Study Protocol Version A focus on the QT interval will be conducted to detect elongations in the interval greater than or equal to 450 msec at Visit 1 and greater than or equal to 460msec at Visit ECG tracings will be transmitted electronically or in print to the central reader on the day of the ECG examination. The results of the interpretation will be returned to the study site and retained in the study source The central reader will be responsible for the interpretation of results to determine eligibility or exclusion or continuation in the study after the ECG exam at visit Urine Pregnancy Test A random urine sample will be obtained and the test will be performed at the site The pregnancy test results will be reviewed the site investigator prior to randomization and prior to dispensing study drug at each visit Positive pregnancy test results will be reported on an urgent ecrf AE report and be managed as an SAE for tracking purposes only Headache Diary A headache diary will be dispensed at each visit and the subject and subject s parent(s) will be instructed on the completion of the daily headache diary The headache diary will record the daily incidence, frequency, and duration of all of the subject s headaches and migraine symptoms for a period of one month The headache diary will also record any rescue medications and daily study drug use by the subject PedMIDAS The PedMIDAS scale evaluates the impact of migraines on school, home, play, and social activities. It is comprised of six items that pertain to days missed in various activities over the past 90 days. Questions are answered by the youth in consultation with their parents. The total PedMIDAS score (sum of items 1-6) will be used in this trial The PedMIDAS examination will be dispensed ate visit 2 and the subject and subject s parent(s) will be instructed on completion of the PedMIDAS to determine eligibility based on a disability score > 10, indicating at least mild disruption in daily activities and < 140, indicating extreme disability that may require more comprehensive,

170 CHAMP Study Protocol Version multi-component therapy. PedMIDAS data will be reviewed by study staff with the subject and parents The PedMIDAS will be used as a study procedure at 2 additional study timepoints after visit 2 to collect information on headache related disability that has occurred in the last 3 months For further description see the Study Questionnaire Table Secondary Measure Questionnaires The following study questionnaires will be administered to the subject and subject s parent(s) during the study visit. Table provides a summary of all study questionnaires Behavioral Rating Inventory & Executive Function (BRIEF) The BRIEF is a measure of executive function and is a questionnaire completed by the parent/guardian. It consists of two indexes, Behavioral Regulation and Metacognition, which are then used to calculate an overall composite score (Global Executive Composite; GEC). The GEC will be used in the current trial and reliability of the overall GEC score is 0.97 to Clinical Depression Inventory (CDI) The CDI is a reliable and valid 27-item scale assessing symptoms of depression. 47, 48 It yields a total score and subscale scores on negative mood, interpersonal problems, ineffectiveness, anhedonia and negative self-esteem. Separate norms are available for boys and girls ages 7-12 and 13-17, which are then converted to T-scores. The total score and a positive screen cutoff of a T-score > 65 will be used. The CDI secondary measure item 9 responses will be reviewed during the visit and the results presented to the site investigator for review during the visit. Any responses that endorse suicidality require immediate action and will be acted upon by the site investigator to ensure child safety Functional Disability Inventory (FDI) The FDI assesses children s and adolescent s self-reported difficulty in physical and psychosocial functioning due to their physical health. 49 The FDI contains 15 items related to activity limitations that are rated on a 5- point scale (0-no trouble; 4-Impossible). Scores range from 0 to 60, with higher scores indicating greater disability. The total score will be used in this trial Hospital Anxiety and Depression Scale (HADS) The HADS is a 14-item self-assessment measure of depressive and anxiety symptoms (7 items each). 50 Each item is rated on a 4-pioint scale and totaled for the respective subscale (Anxiety and Depression). Cutoffs for severity of symptoms for anxiety and depression are provided. The raw score for each respective subscale will be used in this trial.

171 CHAMP Study Protocol Version Pediatric Quality of Life Inventory (PedsQL) The PedsQL 4.0 is a measure that is commonly used for comprehensive assessment of the impact of chronic illness The 23-item pediatric self-and parent-report scales are validated for ages 5-18 and include items covering the domains of Physical, Social, Emotional and School Functioning. A total score is calculated by transforming 0-4 scaled items to scale and computing an average. The total score will be used in this trial Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Baseline The Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Baseline Version 6/23/10 is a validated instrument used for the prospective assessment of suicidality. 54 It will be used in concert with the symptom questionnaire to document any suicidal ideation or behavior of subjects Columbia-Suicide Severity Rating Scale (C-SSRS) Children s Since Last Visit(C-SSRS) Children s Since Last Visit Version 6/23/10 is a validated instrument used for the prospective assessment of suicidality. 54 It will be used at interim visits in concert with the symptom questionnaire to document any suicidal ideation or behavior of subjects HIT-6 version 1.1 (Headache Impact Test). The HIT-6 is a tool used to measure the impact headaches have on an adult s ability to function in a variety of settings. It will be used at the same intervals as the PedMIDAS, Visits 2, 5 and 8 as an exploratory secondary measure.

172 CHAMP Study Protocol Version Table Summary of Study Measures. Psychological Measure Description Construct(s) Informant (ages) Items Completion Time (mins) Data Source Reliability/ Validity Pediatric Migraine Disability Assessment (PedMIDAS) Six-item measure to assess migraine disability in school-age children and adolescents Migraine-related disability Patient report (6 items) Ages Score used: Total disability score Cronbach s coefficient alpha value of 0.77 to 0.78; test-retest reliability of 0.80 Headache Impact Test (HIT-6) Six item measure to assess migraine disability in adults (pain, social and role functioning, vitality, psychological distress, cognitive functioning). Migraine-related disability Patient Report (6 items) Ages 18 and over 6 3 Score Used: Total disability score (range 36 to 78; higher scores indicative of greater disability). Internal reliability of 0.87 to 0.90; test-retest reliability of 0.78 Behavioral Rating Inventory of Executive Functioning (BRIEF) Measures executive functioning across two scales, behavioral regulation and metacognition Behavioral functioning, executive functioning Parent report Ages Score used: Global Executive Composite (GEC) Reliability of the overall GEC score is 0.97 to 0.98 Children s Depression Inventory (CDI) Assess cognitive, affective and behavioral signs of depression in children and adolescents Depressive symptoms Ages Score used: Total Score, T-score based on age and gender Cronbach s coefficient alpha values 0.71 to 0.89; test-retest coefficients range from.74 to.83 Functional Disability Inventory (FDI) Global measure of functional disability with scores ranging from 0 to 60. Activity limitations Ages Score used: Total score (0-60) Cronbach s coefficient alpha value of 0.85 to Hospital Anxiety and Depression Scale (HADS) Self-assessment of emotions, namely anxiety and depression Anxiety (HADS-A) and Depression (HADS-D) Youth and above Scores used: Raw scores for anxiety and depression (0-21) Cronbach's coefficient alpha for HADS-A varied from.68 to.93 (mean.83) and for HADS-D from.67 to.90 (mean.82). Pediatric Quality of Life Inventory (PedsQL) Measures health-related quality of life Physical, Emotional, Social, School Functioning Child and Parent Age 8-12 Age Score used: Total Scale Score (0-100) Cronbach s coefficient alpha value of 0.89 for child report, 0.92 parent report Columbia-Suicide Severity Rating Scale (C- SSRS) Baseline Prospective assessment of suicidality Suicidality Ideation, Intensity, Behaviors, Attempts Youth Score used: Total Scale Score (1-5) Kendall s tau-b was 055,.61 and.62 (p values<0.01) Columbia-Suicide Severity Rating Scale (C- SSRS) Since Last Visit Prospective assessment of suicidality Suicidality Ideation, Intensity, Behaviors, Attempts Youth Score used: Total Scale Score (1-5) Kendall s tau-b was 055,.61 and.62 (p values<0.01)

173 CHAMP Study Protocol Version Study Drug Administration Study drug will be dispensed to eligible subjects along with medication instructions during study visits Study drug will be collected at each visit and drug accountability will be performed by pill count Compliance with medication instructions will be addressed during the study visit. Subjects will be counseled about medication compliance at every dosing visit Concomitant Treatment Any concomitant treatments will be recorded Intervisit Phone Calls The primary purpose of the intervisit phone calls conducted after visits 2, 3 and 4 is to insure subject safety; the secondary purpose is to remind subjects about diary completion and study medication adherence. The symptom screening questionnaire is to be used at these calls which should take place approximately 2 weeks after the visit, but before the next visit The purpose of the intervisit phone calls conducted after visits 5, 6, and 7 is to remind subjects to adhere to the study drug instructions and diary completion. Information about adverse events reported by the subject during these calls should be reported on the adverse event report form. These calls should take place approximately 2 weeks after the visit, but before the next visit. It is acceptable to leave a message for the subject at these intervals Adverse Events Adverse events will be solicited by the use of a standard open-ended question and the use of a targeted symptom questionnaire at each visit Adverse events will be obtained by the use of a phone symptom questionnaire administered after Visits This site investigator will review the results of the symptom questionnaires and the phone symptom questionnaire to determine if an immediate action plan is required to maintain subject safety For further detail of handling adverse events see Section 7. 7 MANAGEMENT OF ADVERSE EXPERIENCES 7.1 Adverse Event The investigator or site staff will be responsible for detecting, documenting, and reporting events that meet the definition of an Adverse Event (AE) or Serious Adverse Event (SAE). Adverse events will be collected after the ingestion of at least one dose of study

174 CHAMP Study Protocol Version drug and until the final phone contact. For subjects who are withdrawn from study drug exposure but continue on the protocol to collect diary data, adverse events will continue to be collected until 30 days after study drug exposure ends.an adverse event is any untoward medical occurrence in a patient or clinical investigation subject, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. Note: An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product. For marketed medicinal products, this also includes failure to produce expected benefits (i.e. lack of efficacy), abuse, or misuse Events meeting the definition of an AE include: a) Exacerbation of a chronic or intermittent pre-existing condition including either an increase in frequency and/or intensity of the condition. b) New conditions detected or diagnosed after investigational product administration even though it may have been present prior to the start of the study. c) Signs, symptoms, or the clinical sequelae of a suspected interaction. d) Signs, symptoms, or the clinical sequelae of a suspected overdose of either investigational product or a concomitant medication (overdose per se will not be reported as an AE/SAE). Lack of efficacy or failure of expected pharmacological action per se will not be reported as an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of efficacy will be reported if they fulfill the definition of an AE or SAE Events that do not meet the definition of an AE include: a) Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to the procedure is an AE. b) Situations where an untoward medical occurrence did not occur (social and/or convenience admission to a hospital). c) Anticipated day to day fluctuations of pre-existing disease(s) or condition(s) present or detected at the start of the study that do not worsen. d) If subjects report symptoms of migraine, the disorder being studied, migraine symptoms (i.e., head pain, nausea, vomiting, phonophobia, and photophobia) are not considered an AE.. e)inpatient treatment of status migrainosus, which may routinely be treated on an outpatient basis in many centers, will not be considered as a serious adverse event, although the presence of status migrainosus should be reported on the source and ecrf designed to capture infusion treatment for migraine.

175 CHAMP Study Protocol Version Expected Adverse Reactions Adverse Events Expected with Amitriptyline Table Common Adverse Events with Amitriptyline by Body System Body System Adverse Event Central Nervous System Dizziness Headache Somnolence Asthenia Tiredness Endocrine / Metabolic Weight Gain Gastrointestinal Abdominal Pain Constipation Xerostomia Ophthalmic Blurred Vision Table Less Common Adverse Events with Amitriptyline by Body System Body System Adverse Event Cardiovascular Blood cell or blood vessel changes Dysrhythmia Elongation of QT interval Heart rate changes Increased or decreased blood pressure Myocardial infarction Syncope Central Nervous System Seizure Dermatologic Jaundice Gastrointestinal Altered taste 7 Bloating. Hepatobiliary Decreased liver function 2 Decreased red blood cell count. Decreased white blood cell count 1Psychological Suicidal thoughts. Suicide Suicidal Thoughts with Amitriptyline Usage The onset of suicidal thoughts with amitriptyline usage will be carefully monitored for during the study by the use of the symptom questionnaire at frequent intervals by making the subjects and families aware of selfmonitoring for the onset of this possible side effect.

176 CHAMP Study Protocol Version Adverse Events Expected with Topiramate Table Common Adverse Events with Topiramate by Body System Body System Adverse Event Central Nervous System Anxiety Coordination problems Decreased concentration Difficulty with attention Dizziness Feeling nervous Hypoesthesia Insomnia Memory problems Somnolence Tingling Tiredness Endocrine/Metabolic Weight loss Gastrointestinal Abdominal pain Altered taste Diarrhea Dry Mouth Dyspepsia Loss of appetite Nausea Musculoskeletal Arthralgia Ophthalmic Blurred vision Double vision Psychological Depression Mood problems Respiratory Pharyngitis Sinusitis Body as a whole general Back pain Injury Table Less Common Adverse Events with Topiramate by Body System Body System Adverse Event Central Nervous System Confusion Headache Ophthalmic Nearsightedness Twitchy eyes Respiratory Sinusitis Upper respiratory tract infection Urinary Kidney Stones

177 CHAMP Study Protocol Version Table Rare Adverse Events with Topiramate by Body System Body System Adverse Event Hepatobiliary Liver failure Idiosyncratic Reactions 7. Psychological Erythema multiforme Decreased sweating Elevated body temperature Excessive acidity of the blood Hyperammonemia with or without encephalopathy Stevens-Johnson Syndrome Toxic epidermal necrolysis Suicidal thoughts Suicide Decreased Sweating with Topiramate Usage Decreased sweating with topiramate usage may be prevented by closely monitoring children for evidence of increased body temperature, especially during hot weather, and assuring that adequate steps are taken to maintain hydration Suicidal Thoughts with Topiramate Usage The onset of suicidal thoughts with topiramate usage will be carefully monitored for during the study by the use of the symptom questionnaire at frequent intervals by making the subjects and families aware of selfmonitoring for the onset of this possible side effect Adverse Events Related to Weight Change Decreases and increases in weight will be monitored closely during study visits. Change in weight that exceed two isobars on the normal CDC growth chart published May 30, 2000 for children ages 2-20 will be considered an adverse event and reported as a grade 2 event. A detailed report of the reason for weight change will be documented. The site investigator may determine if the subject may continue on the study drug or move to withdrawal from study drug exposure (Section 6.3.3) Adverse Events Expected with Placebo There are no expected adverse reactions associated with taking placebo. 7.3 Dose Modification Guidelines and Procedures Dose Modifications for Growth It is not anticipated that subjects will advance to the next weight group during their 34 weeks of involvement in the study; therefore there is no planned dose modification for growth.

178 CHAMP Study Protocol Version Subjects with Abnormal Laboratory Parameters For subjects with abnormal laboratory parameters, the site investigator will make a determination to repeat the abnormal laboratory parameter, and hold or decrease the dosage of study drug For subjects with liver enzymes elevated 2.5 times the upper limit of normal (ULN), the site investigator will repeat the liver enzyme panel after one month and hold or decrease the study drug. The site investigator may also, after consultation with the sponsor, order additional liver studies, such as a hepatitis profile or other tests as needed. Study drug will be discontinued for subjects with liver enzymes elevated > 5 times x upper limit of normal and for subjects with total bilirubin 2 x upper limit of normal. After two consecutive findings of either elevated liver enzymes > 5 times x upper limit of normal or bilirubin 2 x upper limit of normal, the subject will move to withdrawal from study drug exposure (Section 6.3.3) For subjects with serum bicarbonate levels of < 17mEq/L, the bicarbonate level will be repeated. In addition the site investigator may initiate more frequent testing to detect the development of metabolic acidosis For subjects in whom the repeat evaluation remains abnormal, the laboratory parameters will be considered dose limiting. The dose level will be decreased to the dose level immediately below the one in which the toxicity was observed Subjects in whom the repeat laboratory evaluations have returned to acceptable criteria may continue with the previous dose Subjects who are found to have a positive pregnancy test will have that result reported as an urgently reported serious adverse event for tracking purposes only and will be removed from study drug exposure but continue to be followed during the regularly scheduled intervals or as unscheduled visits until the outcome of pregnancy and any congenital anomaly/birth defect for the baby have been reported Laboratory results for Amitriptyline and Topiramate will be collected for adherence analysis only. These samples are biosamples and as such, the. resulting blood levels will not be revealed to investigators or subjects, but will be used for analysis to answer scientific questions at the end of the study. The samples will be retained for batch analysis Subjects with Rash Subjects who develop a rash considered by the site investigator to be related to the study drug will be carefully observed. If necessary,

179 CHAMP Study Protocol Version unscheduled visits may be scheduled to determine if withdrawal from study drug exposure is required. Subjects who develop a potentially life threatening rash (Stevens Johnson Syndrome, Toxic Epidermal Necrolysis) will be withdrawn from study drug exposure and move to early termination (Section 6.3.3). These subject s parents/guardians and the site investigator will be unblinded to treatment assignment Subjects with Intolerable Side Effects This situation is a Dose Limiting Toxicity in the titration phase; the study drug will be decreased to the dose level immediately below the one in which the toxicity was observed. a) If the subject s migraine frequency increases on a lower dosage then the subject will be determined to be a treatment failure and removed from study drug exposure(section 6.3.3). b) If the subject s adverse events continue on this lower dosage, then the subject is removed from study drug exposure(section 6.3.3). 7.4 Serious Adverse Events A serious adverse event is an important medical event which may not result in death, may not be life-threatening, nor require hospitalization, but may be considered serious when, based upon appropriate medical judgment; the adverse event may jeopardize the subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition Definition of Serious Adverse Event A Serious Adverse Event or Serious Suspected Adverse Reaction is considered serious if, in the view of either the investigator or the sponsor, it results in any of the following outcomes: death a life threatening adverse event requires inpatient hospitalization or prolongation of existing hospitalization a persistent or significant incapacity or substantial disruption of the ability to conduct normal life functions, a congenital anomaly/birth defect important medical events that may not result in death, be lifethreatening, or require hospitalization may be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. other conditions as specified in this protocol For purposes of this protocol, any report of the expression of suicidal ideation will also be considered a Serious Suspected Adverse Reaction. Such reports will be obtained through the routine use of the phone symptom screening questionnaire

180 CHAMP Study Protocol Version and the targeted symptom questionnaire administered at every visit, and through subject reports. Suicidal ideation and suicidal intent may also be reported on the CDI questionnaire as noted by a yes response to I think about killing myself but I would not do it and I want to kill myself on item #9. NOTE: In general, hospitalization signifies that the subject has been detained (usually involving at least an overnight stay) at the hospital or emergency department for observation and/or treatment that would not have been appropriate in the physician s office or out-patient setting. Complications that occur during hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, the event is serious. When in doubt as to whether hospitalization occurred or was necessary, the AE should be considered serious. Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not considered an AE. 7.5 Laboratory and Other Safety Assessment Abnormalities Reported as AEs and SAEs Any abnormal laboratory test results (hematology, clinical chemistry, or positive pregnancy test) or other safety assessments (i.e., ECGs, vital signs measurements), including those that worsen from baseline, and felt to be clinically significant by the investigator are to be recorded as AEs or SAEs. However, any clinically significant safety assessments that are associated with the underlying disease, unless judged by the investigator to be more severe than expected for the subject s condition are not to be reported as AEs or SAEs. Therefore, the occurrence of migraine headache will not be considered an adverse event, unless the subject is admitted to the hospital for longer than overnight treatment, because it is an expected baseline condition of every subject. 8 CRITERIA FOR INTERVENTION OR DISCONTINUATION 8.1 Subject Withdrawal From Study Drug Exposure Reasons for SubjectWithdrawal from Study Drug Exposure Subject participation may be withdrawn from study drug exposure for any of the following reasons: Subjects, or their parent or guardian, choose to discontinue the study Significant protocol violation, such as non-compliance with study procedures or attendance at study visits Tolerability Lengthening of the QTc interval on ECG Lost to Follow-Up Other (to be specified by site investigator)

181 CHAMP Study Protocol Version When a subject withdraws prior to completing the trial, the reason for withdrawal is to be clearly indicated on the appropriate ecrf and source document. Such subjects should have all the tests and examinations scheduled for the last study visit performed at the time of their withdrawal from study drug exposure.. Discontinued subjects will not be replaced. Study drug assigned to a withdrawn subject may not be assigned to another subject A Withdrawal From Study Drug Exposure Visit will be conducted if at all possible with the elements described in Section Unblinding to treatment assignment: if unblinding to treatment assignment becomes necessary due to subject safety issues or for clinical management of a serious adverse event, the site investigator, medical monitor or DSMB may request to become unblinded to a subject s treatment assignment. Site investigators who wish to pursue unblinding must make the request in writing to the study chair. After approval of unblinding for the site investigator, the subject will be discontinued from study participation. Notification will be provided by the DCC. 8.2 Site Termination An investigational site may be terminated by the CCC or DCC at any time. Investigational sites will be closed upon study completion. An investigational site is considered closed when all required documents and study supplies have been collected, the site IRB has been notified, and a site closure visit has been performed The individual site investigator may initiate site closure at any time, provided there is reasonable cause and sufficient notice is given in advance of the intended termination Reasons for the early closure of an investigational site by the CCC or DCC or by the investigator, or termination of a study by the sponsor, may include, but are not limited to: Failure of the site to meet enrollment goals after assistance efforts have been provided by the CCC Failure of the investigator to comply with the protocol, the CCC s or DCC s procedures, or good clinical practice guidelines Safety concerns Sufficient data suggesting lack of efficacy after the interim analysis inadequate recruitment of subjects by the investigator 8.3 Study Termination The study may be terminated by the study chair for any or all of the following reasons:

182 CHAMP Study Protocol Version Failure of the study to meet enrollment goals and achieve sufficient power to answer the scientific questions of the study Loss of funding Safety concerns Sufficient data suggesting lack of efficacy after interim analysis Conclusion of all planned study activities At the conclusion of the study, after all actively enrolled subjects have completed the final visit and monitoring, data analysis, and reporting activities have been concluded the investigators will provide the study results and treatment assignments to the site investigators who will provide the information to the study subjects. 9 STATISTICAL CONSIDERATIONS 9.1 Specific Aims and Hypothesis The specific aims are to: Aim 1: To test if amitriptyline (AMI) is superior to placebo in reducing migraine frequency and migraine-related disability Primary Hypothesis #1: Amitriptyline, at a target dose of 1 mg/kg/day, will result in an increased percentage of subjects meeting the primary endpoint compared to placebo Major Secondary Hypothesis #1: Amitriptyline also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to placebo Aim 2: To test if topiramate (TPM) is superior to placebo in reducing migraine frequency and migraine-related disability Primary Hypothesis #2: Topiramate, at a target dose of 2 mg/kg/day, will result in an increased percentage of subjects meeting the primary endpoint compared to placebo Major Secondary Hypothesis #2: Topiramate also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to placebo Aim 3: To compare the efficacy of amitriptyline and topiramate in reducing migraine frequency and migraine-related disability Primary Hypothesis #3: Topiramate will result in an increased percentage of subjects meeting the primary endpoint compared to amitriptyline.

183 CHAMP Study Protocol Version Major Secondary Hypothesis #3: Topiramate also will result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to amitriptyline Aim 4: To prospectively and systematically estimate the safety and tolerability profiles of each therapy Major Secondary Hypothesis #4: Amitriptyline and topiramate will be well tolerated Major Secondary Hypothesis #5: AMI and TPM will not differ from placebo on the occurrence of treatment - emergent serious adverse events. We also expect that AMI and TPM will have overall safety profiles that do not preclude determination of first line therapy for clinical practice according to our decision algorithm. 9.2 Outcomes Consistent with the overview of the trial in the precis and derived from these study aims, the CHAMP Study involves a primary endpoint and four secondary outcomes. Specifically, listed by endpoint, this trial will examine: a primary endpoint (50% or greater reduction in headache days) and four secondary endpoints (migrainerelated disability, absolute change in headache days, tolerability, and treatment-emergent serious adverse events). Comparisons will be made between amitriptyline and placebo, topiramate and placebo, and amitriptyline and topiramate. The specific details for how each of the objectives will be addressed will be fully specified in a separate Statistical Analysis Plan Primary Outcome The primary objective is to determine the best choice prevention strategy for pediatric migraine headache. We plan to test if amitriptyline and/or topiramate are superior to placebo in reducing headache frequency in children and adolescents age 8 to 17 with migraines. Specifically, we will conduct a three trials in one study to determine if there is a difference in the proportion of subjects who meet our primary outcome measure of a 50% reduction in headache frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial. Headache frequency is defined as the number of days with headache for a given 4 week period. A 20 percentage point difference from placebo in this reduction effect is considered clinically meaningful by pediatric headache experts. 27 For the primary outcome, we will employ a conservative approach and assume any subject with no visit 8 headache diary information is a failure. A set of sensitivity analyses (described in section 9.4.5) will be employed in order to assess the sensitivity of these subjects on the final study conclusions Secondary Outcome The secondary outcome measures in the study include: Reduction in migraine disability score on PedMIDAS (Time Frame: end of the week baseline period to the last 4 weeks of the 24-week trial)

184 CHAMP Study Protocol Version Tolerability of amitriptyline and topiramate (Time Frame: visit 2 until the last 4 weeks of the 24-week trial) Occurrence of treatment-emergent serious adverse events (Time Frame: visit 2 to the last 4 weeks of the 24-week trial) Reduction in absolute migraine frequency (Time Frame: 4 week baseline period to the last 4 weeks of the 24-week trial) 9.3 Data Monitoring This study is a multi-site Phase III clinical trial. Therefore, there is a need for a careful data and safety monitoring plan to ensure the well-being of the youth in this study and the scientific integrity of the project. On-site monitoring occurs throughout the duration of the study. A study site start up call will be conducted by the CCC at the time of study initiation to ensure that the site has been completely trained in protocol procedures and Good Clinical Practices (GCP)and that facilities and personnel are adequate. Onsite monitoring visits will be conducted by the DCC monitoring staff. Scheduled monitoring will occur once per year during the conduct of the trial, with the option of making a second visit to selected centers each year, if needed, to address overenrollment, under-enrollment, or protocol deviation issues. The Monitoring Plan details the frequency and level of intensity of on-site monitoring visits. In general, sites will be monitored for all subjects at a level of 100% of study data gathered for inclusion and exclusion criteria, informed consent procedures, and adverse events. Depending on the goals of the study, a certain percentage of the study data are monitored against the study s database. The DCC will collaborate with the CCC, who may conduct remedial site training to ensure compliance with GCP and all regulations. During scheduled interim monitoring visits, the monitors will verify that the protocol is being followed and that data are being collected according to protocol requirements. The monitors will review the Study Regulatory File to determine that all required documentation is being collected and that the IRB approval for the site is current. They will then verify that each subject has signed the correct version of the informed consent document, and that this document is filed in the subject s notebook. At each visit, the monitor performs an audit of the case report forms in the subject s notebook by checking them against the database and source documents. Adverse event documentation is checked for completeness and accuracy. Drug and supplies accountability will also be monitored. At the study closeout, the monitors confirm that all data have been reviewed, all source documents have been verified, and all required documents are present in the Study Regulatory File. Table 9.3 below describes the variables to be reviewed during monitoring visits. Table 9.3. Variables to be Reviewed During Monitoring Visits. Variable % of Records Reviewed Informed consents 100% Eligibility criteria for all screened subjects 100% Adverse events 100%

185 CHAMP Study Protocol Version Drug accountability 20% of active subjects Protocol adherence 20% of active subjects Verification of ecrfs with source documents 20% of active subjects Verification of ecrfs with headache diaries 100% Central study files-inclusion of all applicable documents 100% Protocol deviations/violations 100% Medical Safety Monitor Dr. David Dodick will serve as the independent medical monitor for this trial. Dr. Dodick is a Professor of Neurology at the Mayo Clinic in Arizona, President of the American Headache Society, and Editor of the journal of the International Headache Society, Cephalalgia. He will work in collaboration with the DCC to review all reported serious adverse events in near real time and evaluate them to identify the need for timely intervention. Dr. Dodick will work closely with the DCC and use the AE reporting system of the DCC. For any AE s which are characterized as serious events, an automatic will be sent to Dr. Dodick to prompt a review of the event for determination of whether the event is unanticipated and related to study drug and thus requires expedited reporting to the FDA. If deemed expedited, a MedWatch form is created electronically and submitted to the FDA. With the assistance of the coordinators at the DCC, Dr. Dodick has the option of requesting additional information about any SAE. He will complete a form for each review and this information will be entered into the data entry system. He may become unblinded upon request to the DCC based upon the results of any of his activities He will receive (A, B, C) blinded monthly tabulation reports of adverse events and serious adverse events by the type of event for the purpose of determining if any safety trends exist that may require a more frequent review by the DSMB than the planned biannual review. In the case of an immediate subject safety issue, the medical monitor will be charged with contacting the site investigator to support the safety needs of the subject. He will also actively interact with the Data Safety Monitoring Board (DSMB) and inform the DSMB of any particular concerns that may require the urgent attention of the group. This will be coordinated by the DCC and balanced by review of the DSMB Data Safety Monitoring Board (DSMB) An NIH-appointed DSMB is charged with the task of providing regular oversight of the data and safety monitoring issues as detailed in the document: NINDS Guidelines for Data and Safety Monitoring in Clinical Trials These experts will periodically review and evaluate the accumulated data for subject safety, adverse

186 CHAMP Study Protocol Version events, study conduct, and study progress. The DSMB will make recommendations to NINDS concerning continuation, modification, or termination of the study. Once a DSMB has been formed, the initial meeting will specify the frequency of future meetings and specific guidelines to be used for monitoring the study. We recommend that the DSMB conduct two face to-face meetings per year to review the ongoing study data. Given the sample size, we believe that subject accrual over six month intervals will be an adequate time period to provide sufficient information for performance and safety review. In addition, provisions will be made for emergency meetings should any SAEs require urgent review between regularly scheduled meetings. The DCC will prepare regular reports for the DSMB to review at each meeting. These reports will include overall summaries, AE and SAE summaries by treatment group in a blinded fashion, or summaries by treatment group in an unblinded fashion depending on the preferences expressed by the members of the DSMB. These reports will include a summary of the following topics: Performance Monitoring Performance monitoring will examine subject recruitment, comparison with targeted recruitment, retention, protocol adherence, and quality of data collection procedures Treatment Monitoring Treatment monitoring will examine data on treatment integrity and adherence Safety Monitoring Safety monitoring will examine data related to the safety of the subjects, including confidentiality, all adverse events or side effects related to the treatment Interim Safety Assessment All clinically significant SAEs and AEs of special interest will be reported to the medical monitor and to the DSMB. The interim safety assessment will supplement the ongoing regular safety review conducted by the medical monitor and consist of review of the tabulated monthly safety report with a trend analysis generated by the DCC for review by the medical monitor. Due to the increased concern associated with the risk of suicidal ideation, we will use data collection methods that map to the Columbia Classification Algorithm for Suicide Assessment (C-CASA) to assess suicidality, specifically the symptom questionnaire, phone symptom questionnaire and CDI questionnaire. A positive answer to selected questions on these screening forms will result in an immediate referral to address the urgent care need of the subject and the use of the C-SSRS Baseline or C-SSRS Since Last Visit questionnaire. If a statistically significant difference (at the 0.05 level) is found in the incidence of suicidal ideation between either active treatment and placebo, the DSMB

187 CHAMP Study Protocol Version will be consulted to consider whether the trial should discontinue the affected arm Efficacy Monitoring Two interim efficacy assessments will occur. The first when 225 subjects have completed their 24-week visit, the second when 450 subjects have completed their 24-week visit. For the interim analyses, the Lan-DeMets alpha spending function approach with O Brien-Fleming stopping boundaries will be used. However, the Lan-DeMets method allows for analyses at unequal intervals and does not require pre-specifying the time of any interim analyses. Therefore, the proposed method has the flexibility to adapt should the DSMB request an interim analysis at an alternative time point or if the DSMB is unavailable at the time of a scheduled interim analysis. Importantly, the placebo arm will be dropped only if both active treatments cross the stopping boundary at one of the pre-specified interim assessments. If only one crosses the boundary at the first look, both will be assessed again at the second look and the placebo arm dropped only if both cross the bound at that look Futility Monitoring Futility monitoring will be performed at each interim analysis. We will report the conditional power based on the pre-specified effect of interest. If both conditional power values fall below 20%, we will stop the trial early for futility. 9.4 Data Management and Statistical Analysis Plan Summary of Study Design This study will utilize an intent-to-treat, three-arm, randomized, double-blind, parallel design, placebo controlled study in order to simultaneously assess the impact of two medication therapies (amitriptyline and topiramate) for migraine prevention in children and adolescents. A total of 675 children and adolescents between age 8 and 17 with migraine will be enrolled into the trial at up to 40 sites across the U.S. Subjects will be randomized in a 2:2:1 fashion to receive either amitriptyline (n=270), topiramate (n=270), or placebo (n=135). Each subject will be followed for 34 weeks. All subjects will complete a headache diary during an initial 4 week baseline period, an 8 week titration period, and a 16 week constant dose period. This will be followed by a 2-week period for weaning subjects off medication, and 4 weeks off drug. Subjects will be recruited over a three year period, with an average of 17 subjects per site Randomization Randomization will be stratified by age (8-12, 13-17) and the baseline number of migraines per month (episodic: 4-14, chronic: 15 or more). Because this strategy provides four strata, we have elected not to stratify the randomization by site. The DCC will generate a randomization table for each strata using a permuted block design with random block sizes.

188 CHAMP Study Protocol Version Statistical Analysis Plan Primary Hypotheses Primary Hypotheses #1 and #2: Amitriptyline and topiramate will result in an increased percentage of subjects meeting the primary endpoint compared to placebo. Primary Hypothesis #3: Topiramate will result in an increased percentage of subjects meeting the primary endpoint compared to amitriptyline. Each of these primary hypotheses will involve a comparison of migraine frequency (percentage of days with any migraine) between the last 4 weeks of treatment (weeks 20-24) and the 4-week baseline period. A migraine episode will be defined as the period from the onset to the cessation of painful migraine symptoms, not to exceed 24 hours. If painful symptoms last > 24 hours, it will be considered a new and distinct migraine episode. If painful symptoms recur within 24 hours, it will be considered part of the initial migraine episode. Study subjects will be allowed to take acute pain medications, including OTC and triptans. A prior clinical trial of prevention medication in pediatric migraine found that the beneficial effects of topiramate over placebo increased throughout the duration of the trial, and reached the optimal outcome during the final 4 weeks. 45 Therefore, the choice was made to evaluate the final 4 weeks versus baseline as the primary analysis for the proposed trial. For each subject, the primary outcome will involve a determination of whether a 50% or greater reduction in migraine frequency was observed during the last 4 weeks of active treatment as compared with the migraine frequency during the 4-week baseline period. 3 The only exception will be that any subjects who must be removed from therapy prior to the completion of the 24-week treatment period will be considered failures with respect to the primary endpoint. The primary hypothesis will be assessed using a logistic regression model, adjusted for the two stratification variables. For example, the following model will be fit to these data: where Yi represents the binary variable indicating whether or not the i th subject met the primary outcome requirement of a 50% or greater reduction in migraine frequency, X1i is an indicator variable for the baseline age group for the i th subject (=0 if age 8-12, =1 if age 13-17), X2i is an indicator variable for the baseline number of migraines per month for the i th subject (=0 if 4-14, =1 if 15 or more), X3i is an indicator variable for whether the i th subject was randomized to the AMI group, and X4i is an indicator variable for whether the i th subject was randomized to the TPM,

189 CHAMP Study Protocol Version group. Correspondingly, the three hypotheses of interest can be assessed by performing a hypothesis test of the three pair-wise treatment comparisons of interest: Amitriptyline vs. Placebo: vs.. Topiramate vs. Placebo: vs.. Amitriptyline vs. Topiramate: vs.. Each of the primary hypotheses will be tested using a chi-square test at a significance level of (= 0.05/3). Due to randomization, it is unlikely that important covariates (such as gender) will be imbalanced in this study. However, should important imbalances occur, we will control for these additional covariates in the logistic regression model Major Secondary Hypotheses 1-3 Major Secondary Hypotheses #1 and #2: Amitriptyline and topiramate will also result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to placebo. Major Secondary Hypothesis #3: Topiramate will also result in a decrease in absolute migraine disability score (measured by PedMIDAS) compared to amitriptyline. Three of the major secondary hypotheses (see Section ) will involve a comparison of the change in absolute migraine disability score, as measured by the PedMIDAS. Each subject will have a PedMIDAS score measured at baseline (covering the three months prior to enrollment) and the 24 weeks visit (the end of the maintenance period covering three months of enrollment). The outcome measure for this comparison will be the differences in these two PedMIDAS scores. The mean change from baseline over time for the two groups will be assessed using a linear regression model, adjusted for the baseline PedMIDAS score Major Secondary Hypothesis 4 Major Secondary Hypothesis #4: Amitriptyline and topiramate will be well tolerated. Major secondary hypothesis 4 (see Section 1.1.4) will assess tolerability for the two active treatment groups. Concerns regarding tolerability will be defined as either having a percentage of subjects who complete the entire 24-week treatment period for the two active treatments arms that is significantly lower than the percentage for placebo subjects or significantly less than 65%. %. To assess tolerability, the percentage of subjects who complete the entire treatment period will be compared across the three groups and the percentage in the active treatments will be

190 CHAMP Study Protocol Version examined to see if they are significantly greater than 35%. Both analyses will be conducted using standard chi-square tests Major Secondary Hypothesis 5 Major Secondary Hypothesis #5: Amitriptyline and topiramate will not differ from placebo on the occurrence of treatment-emergent serious adverse effects. Major secondary hypothesis 5 (see Section 1.1.4) will involve a comparison of treatment-related SAE s across the three treatment groups. This will be assessed in two ways. First, the percentage of subjects who experience any treatment-related SAE in each of the three groups will be compared using a chi-square test. Then, the rates of treatment-related SAE s across the three groups will be compared using a Poisson regression model Decision Algorithm for Final Recommendation The main objective of this project is to empirically determine the best choice prevention medication for current practice. In order to accomplish this goal, we need an a priori decision making process that incorporates the novel data that will result from this 3 trials in one project. We propose a tiered approach to how the results of this trial will be used to pick a winner among the therapies tested. This algorithm is briefly described below. The first tier is based upon our primary endpoint, 50% reduction rate for migraine frequency. If both drugs are superior to placebo, but no clear winner can be identified based on the primary endpoint, we will consider the tier 2 endpoint of migraine-related disability. If one medication is superior to the other with respect to disability in tier 2, it will be declared the winner. If not, we would consider tolerability as the third tier. If no winner can be identified based upon all three criteria, then the outcome of the trial would be that both therapies are efficacious and individualized clinical decisions based on patient presentation should guide the first choice in practice. Of course, all recommendations must separately account for the safety data generated by this novel study and any safety concerns could trump the conclusions from any of the three tiers. Figure summarizes this decision making plan.

191 CHAMP Study Protocol Version Figure Decision Algorithm.

192 CHAMP Study Protocol Version Impact of Missing Data Both primary analyses will follow the intent-to-treat paradigm. As such, it will be critically important to minimize the occurrence of missing data. Obviously, the optimal strategy for dealing with missing data is to make every effort to obtain complete data during the conduct of the study. Our team will use a variety of methods in order to minimize the percentage of missing data in this trial. Nevertheless, there is likely to be a small percentage of missing data. For the primary analysis, we will employ a conservative approach and impute an outcome of failure for any subject that does not have observed visit 8 headache diary data. We then propose a series of sensitivity analyses to determine the potential dependence of the results of the primary analysis on missing values. This sensitivity analysis will generally be split into two broad categories: Observed Data: Use only subjects with non-missing visit 8 headache diary data Tolerability/Imputation: Assume all subjects terminated from the study due to tolerability issues (see Table below) are failures. For other subjects with missing visit 8 headhace diary data, outcomes will be imputed using a variety of methods. Last Observation Carried Forward: Use a multiple imputation method to impute their final outcome. This will be implemented using a model based on age and headache frequency at baseline and each intermediate time-point for all subjects with observed data. Imputed values will be derived using the MCMC method with multiple chains, adequate burn-in iterations, and a non-informative prior distribution. We will use five separate implementations of this approach, and will average the parameters across all five imputations for the final analysis. Best Case Scenario: Assume all subjects with missing visit 8 headache diary data in either the amitriptyline or topiramate group are successes; Assume all subjects in the placebo group with missing visit 8 headache diary data are failures. Worst Case Scenario: Assume all subjects with missing visit 8 headache diary data in either the amitriptyline or topiramate group are failures; Assume all subjects in the placebo group with missing visit 8 headache diary data are successes. At the time of the interim and final analyses, results will be reported from both the primary analysis and all sensitivity analyses in order to inform how robust the overall trend observed in the study is to the missing data. For example, if an interim analysis suggests that both treatments are better than placebo based on the primary endpoint, the DSMB might be more comfortable dropping the placebo arm if that finding is supported by the majority of the sensitivity analyses. On the other hand, if the finding is not supported by the sensitivity analyses, the DSMB may choose to keep the placebo arm in the study until the time of the next planned interim assessment.

193 CHAMP Study Protocol Version Table Summary of Reasons for Withdrawal From Study Drug Exposure Due to Tolerabilty / Safety Concerns End of study data collection reason Withdrawn from study drug exposure Withdrawn from study drug exposure Withdrawn from study drug exposure Withdrawn from study drug exposure Withdrawn- from study drug exposure Withdrawn from study drug exposure Withdrawn from study drug exposure Protocol reference, page # Reason Section , page 36 Dosage decrease at week 2 Section , page 36 Dosage decrease below baseline Section 6.2.4, item 14, page 49 QTc interval > 460 at visit 5 Section , page 70 Section , page 69 Section 7.3.4, page 70 Section 7.3.4, page 70 Rash related to study drug or SJS rash Repeated abnormal increased liver enzymes or bilirubin Increased migraine frequency on lower dose after toxicity Adverse events continue on lower dosage We do not anticipate issues associated with missing days for subjects with completed diaries. The daily headache diary asks a subject to respond in a yes/no manner as to whether a headache occurred on each day and to check off typical migraine symptoms when present. For days that no value is marked, staff at the study site are encouraged to contact the subject to determine whether a headache occurred on that day and if the headache had migraine features. If no determination can be made, the data for these days will be marked as unobtainable. The CCC has established that there was >97% adherence to headache diary completion in their current single-site NIH trial of Drug and Non-Drug Treatment of Pediatric Chronic Headache. The same procedures will be used in this trial to minimize occurrences of missing data Secondary Analysis A number of additional secondary analyses are planned. A comparison of the mean rate of migraines in each group will be conducted using a Poisson regression model. The percentage of subjects with a 50% or greater reduction in migraine frequency and migraine disability across each 4-week block of time will be examined using a generalized linear model. Improvement in the PedMIDAS Grade Score 32 will also be assessed. The PedMIDAS will be classified using a grading scale, with values ranging from I (best) to IV (worst). For the purposes of analysis, improvement will be defined as an improvement of 2 units or more from baseline or a reported score of I at the end of treatment. The percentage of subjects with improvement in each of the treatment groups will be compared using a chi-square test. The patient satisfaction scores among subjects within

194 CHAMP Study Protocol Version each treatment group will be compared using a rank-based nonparametric test. A chi-square test will also be used to compare the improvement in migraineassociated symptoms (nausea, vomiting, photophobia, phonophobia) across the three groups. For this comparison, the percentage of migraines within each treatment group will be compared with the associated symptom. A generalized estimating equations model will also be utilized to assess the frequency of these symptoms over time across the groups Sample Size Justification The sample for this study is 675 subjects (135 placebo, 270 amitriptyline, and 270 topiramate.) Details regarding the planning and power analysis used to determine the sample size are recorded later in this section. In order to properly determine the required sample size for the trial, the CCC investigators completed a review of the limited literature pertaining to pediatric headache research. This review revealed four applicable studies. Three of these studies evaluated topiramate versus placebo. 40,45,56 One study examined amitriptyline in a clinical database. 39 Based on this review, estimates of the proportion of subjects in each study group that will meet the primary endpoint of a 50% reduction in migraine frequency can be made. Table 9.4.3a demonstrates the percentage of subjects in existing pediatric headache prevention medication trials who achieve the primary endpoint of 50% reduction in migraine frequency. Table a Percentage of patients in existing pediatric headache prevention medication trials who achieve the primary endpoint of 50% reduction in migraine frequency. Reference PBO Response Rate TPM Response Rate Winner, % 54% Lakshmi, % 95% Lewis, % 83% The table shows an average response rate between 45% and 52% for the placebo group. There is generally more variability regarding the percentage of subjects on topiramate who achieve the primary endpoint. The average percentage of subjects achieving the primary endpoint is 77% in the topiramate group, but the effect ranges from 54% to 95% across the studies. Finally, a database from a prior study conducted at the CCC suggests that 70% of subjects taking amitriptyline will achieve a 50% or greater reduction in migraine frequency. 39 Of note, the Lakshmi sample and CCC database include representation from children with <15 and 15 migraines per month. For sample size estimation in this trial, it is critically important to keep in mind that this study essentially provides three trials in one. Hence, the chosen sample

195 CHAMP Study Protocol Version size must allow adequate power for testing all three primary hypotheses of interest. For the two comparisons with placebo, the results of our NINDS Clinical Research Collaboration survey demonstrated that the majority of responders felt that a minimum absolute increase of 20% in the percentage of subjects achieving a 50% reduction in migraine frequency was clinically meaningful and the threshold needed for the results of a placebo-controlled trial to change practice. The sample size has been chosen to ensure adequate power assuming that 50% of those on placebo versus 70% of those in each of the treatment groups will achieve a 50% or greater reduction in migraine frequency during the final 4 week endpoint evaluation of the 24-week treatment period. Clearly, smaller differences are important for the head-to-head comparison and it becomes much more difficult to define a minimum clinically meaningful effect (since one could argue that, assuming equal cost and safety profiles, any difference between two active treatments is clinically meaningful). As shown in Table 9.5.4, there is some preliminary evidence that suggests more than 85% of patients in the topiramate group may achieve the primary endpoint of 50% reduction in migraine frequency. Thus, the study is powered to detect an absolute difference of 15% or greater in the percentage of subjects achieving a 50% reduction in migraine frequency for the head-to-head comparison. As stated above, since there are three primary hypotheses, a Bonferroni correction will be applied with a plan to test each hypothesis at the level. To allow for the drop-out rate for a multi-site trial, we assume a 15% drop-out rate. This selection was based on drop-out rate observed in the Lakshmi study 40.Under these assumptions, enrolling a total of 675 subjects (135 placebo, 270 amitriptyline, and 270 topiramate) provides: At least 85% power to detect all treatment/placebo comparisons 90% power to detect a head-to-head difference of 70% of those on amitriptyline vs. 85% of those on topiramate will achieve a greater than 50% reduction in migraine frequency This demonstrates that the study has adequate power to assess each primary hypothesis of interest. However, since the main objective of the study is to provide a recommendation to clinical investigators regarding the best treatment for children with migraine, the actual power of the study may be thought of as making a correct and generalizable decision using the following algorithm employing three tiers of decision making: The first tier is based upon our primary endpoint, 50% reduction rate for migraine frequency. If both drugs beat placebo, but no clear winner can be identified based on the primary endpoint, we will consider the tier 2 endpoint of migraine-related disability. If one medication is superior to the other with respect to disability in tier 2, it will be declared the winner. If not, we would consider tolerability as the third tier. If no winner can be identified based upon all three criteria, then the outcome of the trial would be that both therapies are efficacious and individualized clinical decisions based on patient presentation should guide the first choice in practice. Of course, all recommendations must separately account for the safety data generated by this

196 CHAMP Study Protocol Version novel study and any safety concerns could trump the conclusions from any of the three tiers. To assess the ability of the trial to meet this goal, a series of simulation studies were conducted. Each simulation consisted of 10,000 replications for each of 64 conditions defined by all possible combinations of plausible values for the true response rates in the three treatment groups: placebo {40%, 45%, 50%, 55%}, amitriptyline {50%, 60%, 70%, 80%}, and topiramate {50%, 70%, 85%, 95%}. For each simulated condition, one of four possible decisions was reached: (1) amitriptyline recommended first-line therapy, (2) topiramate recommended firstline therapy, (3) both amitriptyline and topiramate are recommended as first-line therapy use secondary endpoints to decide between the two, and (4) neither can be recommended as first-line therapy. The first row in Table b demonstrates that the approach maintains the type I error level at or below the desired level of The last two rows demonstrate the advantages of the overall three-in-one approach for selecting a winner. The last row, corresponding to the specific conditions used to justify the same size for the primary hypotheses, demonstrates that the overall approach provides benefits above and beyond what can be achieved with the separate hypotheses. As the table demonstrates, if this set of conditions holds true, our study would have nearly 100% power to correctly select topiramate as the appropriate first-line treatment for children with migraine. The second row demonstrates that the combined approach provides a greater likelihood of correctly selecting the winner when the absolute difference between the favorable response rates for amitriptyline and topiramate is only 10%. Under these conditions, our study would have 91% power to correctly select topiramate as first-line treatment - a substantial improvement over the 44% power for the individual head-to-head comparison Table b Probability of picking any winner and of picking the correct winner as a function of treatment response rate. Assumes type I error rate of 0.017, sample size of 135 in placebo group and 270 in amitriptyline and topiramate groups. PBO Rate AMI Rate TPM Rate Decision Prob. of Picking Winner Prob. of Picking Correct Winner* AMI Better TPM Better Both None 50% 50% 50% 1% 1% 0% 98% 3% 97% 50% 60% 70% 0% 71% 20% 9% 91% 91% 50% 70% 85% 0% 94% 6% 0% 100% 100% *If a single drug is best, the correct winner is thought to be selected if the final decision is for either that drug or both drugs. The conclusions obtained from the simulations are only strengthened by the fact

197 CHAMP Study Protocol Version that this only examines the first tier of the decision algorithm. Assuming that disability and tolerability trends will parallel those of the primary endpoint, this should only increase the overall probability of selecting the correct winner at the end of the trial Interim Monitoring Plan Overview The interim monitoring plan for this study must take into account the complex nature of the proposed project, i.e., the fact that this is really three separate trials in one. As a result, the proposed interim monitoring plan is based on the following premises: 1) The placebo arm will only be dropped if both active treatments are proven superior to placebo during the course of the study. 2) The head-to-head comparison will be stopped early only if both active treatments have been proven superior to placebo during the course of the study Interim Monitoring Plan Specifics The following sections describe the proposed interim monitoring plan. This plan will be discussed at an initial DSMB meeting and revised accordingly Interim Analysis Focus Two interim efficacy assessments will occur when 225 and 450 subjects have completed their 24-week visit. We will use the Lan-DeMets alpha spending function approach with O Brien-Fleming stopping boundaries. Table below illustrates the proposed stopping boundaries under the assumption of three equally spaced analyses (two interim analyses and the planned final analysis). However, the Lan-DeMets method allows for analyses at unequal intervals and does not require pre-specifying the time of any interim analyses. Therefore, this method has the flexibility to adapt should the DSMB request an interim analysis at an alternative time point or if the DSMB is unavailable at the time of a scheduled interim analysis. Importantly, the placebo arm will be dropped only if both active treatments cross the stopping boundary at one of the pre-specified interim assessments. Importantly, if only one crosses the boundary at the first look, both will be assessed again at the second look and the placebo arm dropped only if both cross the bound at the second review. Table O Brien-Fleming Stopping Boundaries Assuming Three Equally Spaced Analyses. Efficacy Analysis Number of Subjects Completing 24-Week Follow-Up Nominal P-Value to Conclude Efficacy <

198 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean Futility Assessment Futility will be assessed at the time of each interim analysis. We will report the conditional power based on the pre-specified t of interest (Lan, Simon, & Halperin, 1982). If both conditional power values fall below 20%, we would recommend stopping the trial early for futility. Due to the complex nature of the study, and the fact that definitive evidence would be required if neither of the active treatments proved superior to placebo, we propose that the trial should only be stopped for futility if both treatments were simultaneously futile (which has an exceptionally low probability) Safety Assessment-Periodic Assessment Safety will be assessed in a periodic manner throughout the study. The medical monitor will receive tabulations of all AE s/sae s on a monthly basis. Safety will be assessed in two ways both the percentage of subjects who experience any AE and the rate of AE s across the three groups will be compared, by body system, using standard chi-square tests. The additional questions related to whether the AE/SAE is related to treatment, is unanticipated, or is severe will be used to subset these into a series of additional tables. This monthly review will identify any disconcerting discrepancy in the frequency of an AE/SAE between the treatment groups, with particular emphasis placed on the four AE s of most concern to practicing clinicians due to the known side effect profiles of these two treatments: (1) depression, (2) suicidal ideation, (3) fatigue, and (4) slow thinking or problems with attention. Should any such discrepancy arise, or if the medical monitor feels that an SAE should be shared on an emergency basis with the participating clinical sites, he will contact the DSMB to request a special review Safety Assessment-Data from Questionnaires Data obtained using psychometrically-sound measures of depression, attention, and cognitive functioning from the current NINDS Common Data Elements will also be available for each subject in this trial at baseline, end of drug titration (week 8), and end of maintenance (week 24). To further understand the impact of the study medications on these important outcomes beyond our prospective AE monitoring approach, each monthly report will also include a comparison of the following across the three treatment groups: (1) total score from the Child Depression Inventory (CDI), (2) frequency of subjects that answer yes to intent and ideation on question #9 from the CDI, (3) Behavior Rating Inventory of Executive Function (BRIEF) global executive composite score. This information will help supplement the AE information the medical monitor reviews on a regular basis Safety Assessment-Reports to the DSMB A DSMB closed session report will include all available safety information to allow the DSMB to monitor for trends. These unblinded reports will also include a memo from the Safety Monitor to allow the communication of any concerns or findings that may be of interest to the DSMB in their study

199 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean deliberations. In general, interim safety monitoring will rely on these interim reviews to identify any potential trends of interest. However, due to the increased concern associated with the risk of suicidal ideation, we will use a more stringent guideline to trigger a concern for this variable. If the difference in the incidence of suicidal ideation between either active treatment and placebo becomes statistically significant at the 0.05 level at any of the interim reviews, the DSMB will determine whether the trial should discontinue the affected treatment arm. 10 DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORTING 10.1 Records to be Kept Source documentation will be retained at each site in support of the Electronic Case Report Forms. Source documentation will include the report of all study examinations, procedures, laboratory results, headache diaries, PedMIDAS forms, HIT-6 forms, questionnaires, drug accountability records, concomitant medication records, ECG tracings, reports of adverse events, and essential documents Document Retention In compliance with the ICH/GCP guidelines, the investigator and study staff will maintain accurate and timely entry of source data into the ecrfs as directed in the manual of operations. All source documents that support the ecrf data collected from each subject will be retained in a secure setting with limited access by non-study staff. All remaining trial documents as specified in Essential Documents for the Conduct of a Clinical Trial and as specified by the manual of operations will be retained in a secured setting also. The investigator and study staff will take measures to prevent accidental or premature destruction of these documents. Essential documents must be retained until the sponsor has notified the investigator that they may be destroyed. These documents will be retained for a longer period if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the responsibility of the sponsor to inform the investigator as to when these documents no longer need to be retained. If the responsible investigator retires, relocates, or for other reasons withdraws from the responsibility of keeping the study records, custody must be transferred to an investigator who will accept the responsibility. In addition, in compliance with the NINDS request for a central data access point for future analyses, the study data will be retained indefinitely in a data storage repository that will allow investigators a constant source of material with all personal information removed to be used for medical scientific, educational or research purposes. Data from this long term storage site will be available to other researchers for future study of migraine as well as other diseases after the study investigators have completed their analyses and publications have been completed and accepted. The processes for other investigators to gain access to the study data are in development by the CHAMP principal investigators and the NINDS. More specifics will be included in a future protocol revision Electronic Case Report Form (ecrf) The ecrfs will be available for data entry for each subject. Data must be entered onto ecrfs in the required timeline as specified in the manual of operations. Source data must be available to support every entry into the ecrf. Source data must be recorded in English. All source

200 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean forms must be completed in black ballpoint pen and must be accurate, legible contemporaneous, objective and attributable. All source documents that support the ecrf data collected from each subject will be retained in a secure setting with limited access by non-study staff. A locked filing cabinet inside a locked room in the study center is preferable for retention of study records. Every attempt will be made to maintain the confidentiality of study subjects including use of coded numeric identities instead of subjects names Missing Data Overview Both primary analyses will follow the intent-to-treat paradigm. As such, it will be critically important to minimize the occurrence of missing data. Obviously, the optimal strategy for dealing with missing data is to make every effort to obtain complete data during the conduct of the study. The DCC and CCC Staff will use a variety of methods in order to minimize the percentage of missing data in this trial. Nevertheless, there is likely to be a small percentage of missing data Missing Data from Withdrawn Subjects For subjects who withdraw completely from study participation before their 24-week outcome can be obtained, we will use a multiple imputation method to impute their outcome. This multiple imputation will be implemented using a model based on migraine frequency at baseline and each intermediate time-point for all subjects with observed data. We will use five separate implementations of this approach, and will average the parameters across all five imputations for the final analysis. The approach described above will be used for reporting all primary study results. However, in order to test the robustness of our findings, we will employ a number of additional analyses using different approaches for handling the missing data: 1) Use a Kaplan-Meier curve to obtain the estimated percentage of subjects in each group with a 50% reduction in migraine frequency at 24 weeks. This approach adequately accounts for all censored subjects (assuming censoring is noninformative) and is valid under the assumption that once a child achieves a 50% reduction in migraine frequency, the reduction will be maintained throughout the remainder of the study. 2) Assume that all subjects with missing data would not achieve a 50% reduction in migraine frequency at 24 weeks. This is a conservative approach that should dilute any true differences between the groups if dropout is purely random Missing Data from Headache Diary The daily headache diary asks a subject to respond in a yes/no manner as to whether a headache occurred on each day and to check off typical migraine symptoms when present. For days that no value is marked, staff at the study site will contact the subject to determine whether a headache occurred on that day and if the headache had migraine features. If no determination can be made, those days will be assumed to be migrainefree Role of Data Management

201 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean Overview Successful study data management involves a partnership between study staff at each clinical site and the DCC Clinical Site Responsibilities in Data Collection and Management Every investigator and the study staff at each site are responsible for the collection of the study data as original source. Further, they are responsible for data entry from the source records onto the ecrfs. The ecrfs will be continuously available for data entry for each subject. Data must be entered onto ecrfs in the required timeline as specified in the manual of operations. For most study data points the timeline for entry onto the ecrf is within 5 business days following the completion of a study visit. Source data must be available to support every entry into the ecrf. Source data must be recorded in English. All source forms must be completed in black ballpoint pen and must be accurate, legible contemporaneous, objective and attributable Electronic Case Report Forms (ecrfs) The ecrfs are to be completed within 5 business days of the subject s visit, with the exception of results of tests performed outside the investigator s office, so that the online record will always reflect the latest observations on the subjects enrolled and active in the trial. The ecrfs will be completed according to the sponsor s instructions, from data gathered on the study source forms supplied by the sponsor. Source and ecrf will be reviewed by the DCC staff to determine ecrf acceptability. If necessary, queries will be generated and transmitted to the study site for resolution Data Management by the Data Coordinating Center (DCC) Approach to Data Management The DCC is a component of the Clinical Trials Statistical and Data Management Center (CTSDMC) at the University of Iowa. The CTSDMC has developed extensive standard operating procedures that guide the development and maintenance of our web and database systems. The CTSDMC has developed a set of core functions that have been carefully validated and can be employed in multiple applications. The development of these core functions has greatly reduced the time and effort that it takes to implement an electronic data capture and data management system Online Data Entry The CTSDMC online data entry systems have been designed and implemented using Microsoft technologies and development tools. The development environment used for creating the online data entry systems employs Microsoft Visual Studio.Net to create Active Server Pages (ASP/ASP.Net). ASP is a server-side scripting technology from Microsoft that allows web developers to generate dynamic, data-driven web applications. ASP scripts are able to connect directly to the SQL Server database by using ActiveX Data Objects (ADO). By using Microsoft products (Internet Information Server 7 and MS SQL Server 2008), the Center is able to achieve a high level of integration between our web and database systems Data Security In order to maintain strict security for data entered over the Internet, all data are encrypted using the Secure Sockets Layer (SSL) protocol. This protocol allows an

202 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean encrypted link to be established between the DCC web server and the computer at each clinical site. CTSDMC data entry systems have secure firewalls to protect from viral attacks or hacking via the Internet. In addition, all systems are protected by Norton Antivirus software and are swept daily. The web servers are monitored for any suspicious activity that would indicate an attempt to break into the system. Access to data entry screens is ID and password protected. The system requires strong passwords (a minimum of eight characters, at least two of which must be symbolic or numeric). Passwords must be changed at regular intervals, or minimum of every 6 months. Previously used passwords may not be reused. All passwords stored at the CTSDMC are encrypted to prevent unauthorized usage Secured Data Location All CTSDMC Servers are located in a secured area, with access restricted to CTSDMC Personnel only. The Servers have internal IP Security Policies that limit exposure from unauthorized sources. The Systems Coordinator carefully monitors the accounts of CTSDMC Staff with database update rights. Other CTSDMC Staff database accounts are "read-only" to prevent unauthorized modification of data. The CTSDMC database server, file server, and access server are key-locked to prevent unauthorized use Redundancy Plan for Data Security The CTSDMC strives to provide 24-hour/7-day per week coverage by maintaining replication on mission-critical web and database servers. The replication process allows data saved to the primary server to be simultaneously written to a secondary server. If a failure or service interruption occurs on the primary server, a rapid failover to the secondary server allows for application recovery. The CTSDMC maintains the primary and secondary servers in separate locations to protect against extended power outages or natural disasters Data Recovery Plan All servers are backed-up regularly utilizing Veritas Backup Exec Software on a PowerVault 124T tape unit, providing eight tapes in rotation. This package allows the CTSDMC to perform complete back-ups of all Internet, database, and file servers. A full back-up of all data is performed weekly, and incremental backups are performed the other five days. This procedure allows the CTSDMC to recover data from a number of different time points if necessary. The weekly back-up tapes are stored in a secured, offsite location to provide protection from natural disasters. In addition, a safety-deposit box is retained to store tapes of frozen datasets and electronic copies of interim, safety, and final reports Data System Compliance with 21 CRF Part 11 All data entry systems at the CTSDMC are developed to be in compliance with FDA regulations outlined in 21 CFR Part 11, and in accordance with Good Clinical Practices. The DCC will train and certify all data entry personnel in the data entry process before they are granted permission to enter data into the production database. The Center maintains an Internet-based training system in which personnel perform data entry tasks and then complete a quiz. Based on successful performance, a user is certified and assigned a role that grants them authorization to enter data into designated areas

203 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean Plan for Development of Database This trial uses a web-based data entry system. Data entry screens for ecrfs are modeled on paper case report forms that were developed as design prototypes. In order to prevent invalid values from being entered into the database, radio buttons and dropdown lists are used whenever possible. When it is necessary to enter a numeric value, such as a subject s weight, the system includes checks that question values that are outside a defined range or allow data entry personnel to override confirmed out-ofrange values. Checks are also performed for valid values, missing values, and logical consistency between items on the same form (intra-form checks) or between items from different forms (inter-form checks). Any discrepancy generates an edit screen that prompts the user to resolve the discrepancy by correcting the data or indicating that the discrepant data are valid and acceptable. Software development is automated and applications are written to build a data dictionary for each database application. The data dictionary tool contains information on all data items collected by the study, including variable names, variable types, valid values, skip-out rules, mandatory field checks, range checks, overridable fields, and value labels. Database tables and initial web screens are developed directly from the data dictionary using programming logic designed to manage the data entry tables, skipout rules, and initial variable validation checks. All application development is based on user requirement documents that are developed through a collaboration of the DCC data management team, the DCC IT team, and approved by the DCC and CCC teams After a program is written, it undergoes multiphase testing to ensure that it is working properly to test the accuracy of the code in a development environment. Next, an independent team of DCC data managers evaluates the program in a test environment using a predefined and approved testing plan. This plan includes a variety of tests, including validation of the data dictionary, evaluations of system security, faults, error messages, roles, serviceability, and system performance under a heavy volume of data (i.e., simultaneous data entry by multiple users) Validation of Database During validation testing, an application (i.e., Fogbugz) is used to document/resolve errors and to identify design issues. Following validation in the Test environment, the software is moved into a staging environment. This environment allows for a final look in a clean, stable environment that mirrors production. The software is once again validated in the staging environment. When any errors are documented and resolved, the software is ready to be moved into Production Case Report Forms Data entry screens are prepared to resemble case report forms prepared as part of the ecrf design process Training for Study Data Entry All data entry personnel are trained and certified in the data entry process prior to allowing them permission to perform data entry into the production database. The Center maintains an internet-based training system in which personnel perform data entry tasks and then complete a quiz. Based on successful performance, a user is certified and assigned a role that grants them authorization to enter data into designated areas.

204 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean A significant advantage of an internet-based data system is that it automatically provides realtime reminders of incomplete data forms and discrepant values (i.e., missing, out of range). While a data entry session can be saved at any time, the system defines required fields that must be included before a form is submitted. Each time the study web page is accessed, a list of all incomplete forms appears on the screen. After an incomplete form has been accessed, the user is directed to complete all required fields before the form may be submitted. This process greatly facilitates the timely collection and entry of study data, and greatly reduces problems associated with missing data Quality Assurance The accuracy and reliability of data are paramount to the success of this study. Actions will be taken to assure that reliable and accurate data are obtained. This will begin with the selection of qualified investigators and appropriate study centers. The second most important action to data and study quality assurance will be study staff training. Training the study staff in all of the protocol procedures prior to the beginning of study enrollment at a center, and providing ongoing training during the study as procedures are updated or the protocol is revised will be a priority. The third action for data quality assurance will be periodic monitoring visits conducted by the DCC monitoring staff to verify source data and correct entry onto the ecrf. The timing of these periodic visits and the extent of reviews will be documented in the monitoring plan contained in the study manual of operations. Regular review of ecrf data by monitoring staff will take place between the periodic visits to identify any trends or systematic errors that may occur. Case Report Forms, including questionnaires will be reviewed for accuracy and completeness by DCC monitoring staff and any discrepancies will be resolved with the investigator or study staff, as appropriate. Appropriate computer edit programs will be run to assure the accuracy of the database Access to Study Source The study quality assurance program will require access to all study records, including source documents, for inspection and comparison with the ecrfs. Subject privacy must, however, be respected. Sufficient prior notice will be provided to allow the investigator to prepare properly for a monitoring visit. Findings from routine monitoring visits will be discussed with the investigator Notification of Sponsor of External Regulatory Review Auditing procedures may also be conducted by agents of any regulatory body reviewing the results of this study. The investigators should immediately notify the sponsor if they have been contacted by any regulatory agency concerning an upcoming inspection Adverse Experience Reporting The safety of study subjects is of the utmost concern to the sponsor and investigators in this study. Reporting of complete and accurate safety information according to acceptable timelines is key to the protection of subjects, and is required by the regulatory agencies with oversight of this study. Standard Operating Procedures for adverse event reporting have been developed by the sponsor to ensure compliance with regulatory requirements, including grading of adverse events according to the NCI Common Toxicity Criteria III, and a reporting timeline of 14 days for adverse events and one business day for SAEs. Adverse events regarding changes in subject weight during the study will be determined using the CDC growth curve for children ages A change from baseline

205 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean of two isobars during the study will be determined to be a grade 2 adverse event. This study will be conducted in compliance with those procedures Adverse Event Classification Definitions Adverse Event (AE) An adverse event is defined as any untoward medical occurrence in a subject administered an investigational pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. This includes any occurrence that is new in onset or increased in severity, grade or frequency from the baseline condition, or abnormal results of diagnostic procedures including laboratory test abnormalities which are considered AEs if they: result in discontinuation from the study, require treatment or any other therapeutic intervention, require further diagnostic evaluation (excluding a repetition of the same procedure to confirm the abnormality), are associated with clinical signs or symptoms judged by the investigator to have a significant clinical impact Serious Adverse Event Any untoward medical occurrence that at any dose: results in death, is life-threatening The subject was at risk of death at the time of the event. It does not refer to an event, which hypothetically might have caused death, if it were more severe, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or is an expression of suicidal ideation or action. Inpatient or emergency department admission for the treatment of migraine headache will not be considered an SAE for this protocol. Note: Medical and scientific judgment should be exercised in deciding whether expedited reporting is appropriate in other situations, such as important medical events that may not be immediately life-threatening or result in death or hospitalization but may jeopardize the subject or may require intervention to prevent one of the outcomes listed in the definition above. For purposes of this study, subject pregnancy will be considered an important medical event and will be reported for tracking purposes only as an SAE Expectedness of Adverse Experiences Expected Adverse Event

206 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean An expected AE is one which is listed in the package insert/summary of product characteristics for amitriptyline or topiramate. The most common expected adverse events associated with both of these drugs are included in the protocol. For this study, headache and migraine headache are expected and will not be reported as adverse events. Expected Adverse Events for amitriptyline and topiramate are listed in Section Unexpected Adverse Event An unexpected AE is one for which the nature or severity is not consistent with the applicable product information (e.g., Investigator s Brochure) or package insert/summary of product characteristics for an approved product. Expectedness of serious adverse experiences will be reviewed by the Medical Monitor and final interpretations made by the sponsor or his study staff Relatedness or Attribution of Association of an Adverse Event (AE) With Use of the Study Drug An AE is considered associated with the use of the drug if the attribution is possible, probable, or definite. Table describes the attributes of each of these categories. Attribution Unrelated Unlikely Table Attribution of Adverse Events. Definition An AE which is not related to the use of the drug An AE for which an alternative explanation is more likely (e.g., concomitant drug(s), concomitant disease(s), and/or the relationship in time suggests that a causal relationship is unlikely Possible An AE which might be due to the use of the drug. An alternative explanation e.g., concomitant drug(s), concomitant disease(s) is inconclusive. The relationship in time is reasonable; therefore the causal relationship cannot be excluded Probable Definite An AE which might be due to the use of the drug. The relationship in time is suggestive. An alternative explanation is less likely e.g., concomitant drug(s), concomitant disease(s) An AE, which is listed as a possible adverse reaction and cannot be reasonably explained by an alternative explanation e.g., concomitant drug(s), concomitant disease(s). The relationship in time is very suggestive Adverse Event Procedures All Adverse Events All AEs will be reported after the first dose of study medication has been administered and through the last dose of study medication administration. SAE s occurring within a period of 30 days following the last intake of study medication will also be handled according to this procedure. Those meeting the definition of SAE must be reported using the AE Form submitted urgently. Medical events that occur between the signing of the Informed Consent and the first intake of study drug will be documented in the medical history source, but not included on the ecrf. Each subject or their parent or guardian, should voluntarily report any AEs or in response to general, non-directed questioning (e.g., How has your health been since the last visit? ). In addition a symptom questionnaire will be used at each visit and each phone visit to elicit a targeted symptom list. For each AE

207 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean volunteered by the subject or their parent or guardian, the investigator should obtain all the information required to complete the AE page of the CRF, in accordance with the guidelines that accompany it in the manual of operations. All AEs, regardless of seriousness, severity, or presumed relationship to study therapy, must be recorded using medical terminology in the source document and on the CRF. Whenever possible, diagnoses should be given when signs and symptoms are due to a common etiology (e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as upper respiratory infection ). Investigators must record on the CRF their opinion concerning the relationship of the AE to study therapy. All measures required for AE management must be recorded in the source document and reported according to sponsor instructions and timelines. Adverse events must be reported on the ecrf within 14 business days of report by the subject or observation by the study staff. The sponsor assumes responsibility for appropriate reporting of AE s to the regulatory authorities. The sponsor will also report to the investigator all serious AE s that are unexpected and associated with the use of the drug. The investigator must report these events to the appropriate IRB in accordance with local regulations Serious Adverse Events All SAEs occurring during the clinical trials must be reported within one working day of the site becoming aware of the event to the sponsor or the sponsor s study staff. The initial report of an SAE will be made via the online adverse event reporting system in the ecrf. The investigator must initially provide as much information as is available but will be required to submit the minimal information: i.e., subject ID, the date of the event, and the adverse event term within one working day. Follow-up reports may be required as additional information is learned by the site. For any adverse event meeting the definition of serious, the Independent Medical Monitor will be notified via to review the event for relatedness and expectedness. If the Independent Medical Monitor determines that the event is indeed serious, related, unexpected and life-threatening, or death, then an expedited report will be submitted to the FDA with a MedWatch form. All Adverse Events will be reported to the members of the DSMB, NINDS, and IRBs as required. All Adverse Events will be coded using MedDRA. Adverse Events will be reviewed periodically by the Independent Medical Monitor in aggregate for trends. All initial reports of an SAE must be confirmed within three business days by an updated written, more detailed report submitted in the ecrf. Instructions for completion of the SAE report are detailed in the manual of operations.

208 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean All SAEs that have not resolved by the end of the study, or that have not resolved upon discontinuation of the subject s involvement with the study, must be followed until either: the event resolves, or stabilizes, or the event returns to baseline, if a baseline value is available, or the event can be attributed to other than the study drug, or to other than study conduct Reporting Pregnancy as a Serious Adverse Event Any pregnancy that occurs during this study must be reported to the DCC utilizing the Adverse Event report form submitted urgently. This report is for tracking purposes only. All pregnancies that are identified during the study must be followed to conclusion and the outcome of each must be reported. The investigator should report all pregnancies within 24 hours (as described in section ) using the AE report form including all known information about the pregnancy, such as any completed lab tests and their results, the health status of the subject and the fetus and the plan for follow up and monitoring during the pregnancy. The initial report should include the date of permanent discontinuation of study drug. The investigator should counsel the subject and her parents about the potential risks to the fetus of study drug exposure, but should not attempt to persuade the subject regarding continuation or discontinuation of the pregnancy. A subject who becomes pregnant while on the study will be counseled to discuss her choices with her own physician. Monitoring of the subject should continue until the conclusion of the pregnancy, and a follow-up AE report form detailing the outcome of the pregnancy should be submitted within fifteen calendar days of the first knowledge of the delivery and should specifically state whether or not a congenital anomaly or birth defect has been reported in the baby. 11 HUMAN SUBJECTS 11.1 Ongoing Review of Potential Risks The risks associated with participation in this study are associated with potential side effects of study medication (amitriptyline or topiramate). Potential risks associated with side effects or adverse events will be closely monitored in this trial. In particular, some expected side effects of these medications are of particular interest to pediatric headache specialists, including increased fatigue, depressive symptoms, suicidal ideation, and cognitive and attention problems (including impact on school performance). A structured symptom checklist, in addition to an open-ended questionnaire about possible adverse health experiences, has been designed for this trial to systematically and prospectively assess potential risks to youth who are taking amitriptyline or topiramate. It is also important to assess for these specific side effects in youth taking a placebo in a blinded-study of migraine therapies. Amitriptyline has been associated with relatively minor side effects in headache studies. Our Headache Center s extensive experience in treating pediatric headache and the low level of adverse events in our current trial where every subject receives amitriptyline suggests that doses of amitriptyline at 1 mg/kg/day are generally well-tolerated by children and adolescents. Topiramate has been associated with relatively minor side effects in headache studies. Our Headache Center s extensive experience in treating pediatric headache and the few trials that have been reported using this medication in youth suggests that doses of topiramate at mg/day are generally well-tolerated by

209 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean children and adolescents. Risks to confidentiality are minimal because all data will be coded by subject number Adequacy of Protection Against Risks Recruitment and Informed Consent Potential subjects will be identified during an evaluation in the participating clinical trial site. The neurologist/physician/nurse practitioner who examines the child or adolescent will explicitly state that they will continue to receive the same high quality of care from them should they choose not to participate. If the family is interested in participating, informed consent and assent will be obtained. The neurologist / physician / nurse practitioner, research nurse/coordinator, and/or the site PI will provide a full description of the study and answer any questions that the family may have. Approved procedures and forms of the IRB for each site will be utilized (or if needed for a site, Cincinnati Children s IRB procedures and forms will be used). The purposes and the risks of the investigation and the procedures of the study will be explained. The families will be explicitly told that their medical care will not be affected if they choose not to participate. No screening or assessment procedure will occur until after written consent is obtained Protection against Risk Baseline evaluations and tests (ECG, pregnancy screening, blood testing) will be conducted and exclusion criteria applied to ensure that subjects who are enrolled are not at known risk (e.g., use of amitriptyline during pregnancy or if ECG abnormal). During the trial, these evaluations and tests will be repeated (e.g., ECG at visit 5, pregnancy screening at every visit, blood testing at visits 5 and 8) to ensure that known risks do not appear (drug toxicity, pregnancy, ECG abnormality appearing upon exposure to amitriptyline). Side effects related to the medication intervention (amitriptyline or topiramate) will be closely monitored by the study physicians/nurse practitioners and research coordinators through regularly scheduled safety visits and using the NCI Common Toxicity Criteria Version III. Study site staff will closely monitor co-morbid conditions (such as asthma, irritable bowel syndrome, depressed feelings, etc.) for the duration of the study. Adverse Events will be reported from the time of randomization until 30 days following the last day of drug exposure. Adverse events will be classified as serious based on FDA regulations (21 CFR ). Toxicity reporting will be separated into organ systems and definitions for severity will be determined according to those contained in the Common Toxicity Criteria, Version III from the National Cancer Institute (NCI). The FDA has recommended the use of the NCI Common Toxicity Criteria, Version III for other clinical trials in children conducted at Cincinnati Children s after they had determined that the definitions were appropriate for pediatric trial use. The Common Toxicity Criteria provide standardized definitions of severity for a very large list of toxicities seen in clinical trials, including both symptoms and laboratory abnormalities. If a specific event is not included in the listings of the NCI Common Toxicity Criteria, then the clinical site investigator will rate the severity according to the general definitions provided for the categories of Mild, Moderate, Severe, Life-threatening in the Common Toxicity Criteria. The use of these standard definitions will ensure that there is uniformity in assessing severity of adverse events by the medical providers involved in this trial. The investigators in this trial will complete an Adverse Event form

210 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean at each visit for every symptom or laboratory adverse event detected using the Online Adverse Event Reporting System developed by the DCC. For any adverse event meeting the definition of serious, the Independent Medical Monitor will be notified via to review the event for relatedness and expectedness. If the Independent Medical Monitor determines that the event is indeed serious, related, unexpected and life-threatening or death, then an expedited report will be submitted to the FDA with a MedWatch form. All Adverse Events will be reported to the DSMB, NINDS, and IRB as required. All Adverse Events will be coded using MedDRA. Adverse Events will be reviewed periodically by the Independent Medical Monitor in aggregate for trends Protection against the Risk of Suicidality and Possible Clinical Depression The structured symptom review that will occur at each study visit specifically asks about suicidal ideation and increased sadness. A positive response to either question regarding wanting to hurt yourself or have been hurting yourself would require the site coordinator to immediately contact the site PI and a clinical evaluation will occur during the study visit with the goal being to make the appropriate clinical decision to ensure subject safety. After subject safety has been ensured, an assessment of present lethality using either the C-SSRS Baseline or C-SSRS Since Last Visit Questionnaire will be conducted.based upon assessment of possible risk to self or others, the site PI will initiate locally appropriate emergency care for the subject and/or appropriate outpatient follow-up. Also, the Child Depression Inventory, a secondary measure in this trial which will is administered at the screening visit, Visit 5, and Visit 8, has one item that asks about suicidality (Item 9 answers of concern: I want to kill myself. or I think about killing myself but I would not do it ) is a positive screen for further clinical evaluation of a diagnosis of clinical depression. When the CDI is given, the site coordinator will review the specific response to Item 9 about suicidality. If a subject reports suicidal ideation,, the site coordinator will immediately contact the site PI and a clinical evaluation will occur during the study visit, with the goal being to make the appropriate clinical decision to ensure subject safety.. Based upon assessment of possible risk to self or others, the site PI will initiate locally appropriate emergency care for the subject and/or appropriate outpatient follow-up. If suicidality is considered to be related to the study medication, the site PI will make appropriate decisions about continuation, lowering dose, or stopping the study medication. After subject safety has been ensured, an assessment of present lethality using either the C-SSRS Baseline or C-SSRS Since Last Visit Questionnaire will be conducted. Also, within 24 hours, the CCC PIs (Drs. Powers, a psychologist, and Hershey, a neurologist) will be notified of the incident and the action plan. This situation will also be documented per the study adverse event process and the medical monitor will be notified per the SAE plan detailed above. If a subject reports increased sadness as part of the adverse event monitoring procedure that is of clinical concern to the coordinator and site PI the site coordinator will immediately contact the site PI and a clinical evaluation will occur during the study visit. Based upon assessment of depression, the site PI will initiate locally appropriate care for the subject and/or appropriate outpatient follow-up. If clinically significant depression is considered to be related to the study medication, the site PI will make appropriate decisions about continuation, lowering dose, or stopping the study medication. Also, within 24 hours, the CCC PIs (Drs.

211 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean Powers, a psychologist, and Hershey, a neurologist) will be notified of the positive screening for depression and the action plan developed. This situation will also be documented per the study adverse event process Plan for Protection against School Performance Decline If a subject reports marked decline in school performance (e.g., typical A-B student now failing tests/classes) as part of the adverse event monitoring procedure (open ended question followed by structured symptom questionnaire), the site PI will conduct a clinical evaluation and initiate appropriate local referrals. If clinically significant decline in school performance is considered to be related to the study medication, the site PI will make appropriate decisions about continuation, lowering dose, or stopping the study medication. Also, within 24 hours, the CCC PIs (Drs. Powers, a psychologist, and Hershey, a neurologist) will be notified of the incident and the action plan. This situation will also be documented per the study adverse event process Institutional Review Board (IRB) Review and Informed Consent This protocol and the informed consent document and any subsequent modifications will be reviewed and approved by the IRB or ethics committee responsible for oversight of the study. A signed consent form will be obtained from the subject. For subjects who cannot consent for themselves, such as those below the legal age, a parent, legal guardian, or person with power of attorney, must sign the consent form; additionally, the subject's assent must also be obtained if he or she is able to understand the nature, significance, and risks associated with the study. The consent form will describe the purpose of the study, the procedures to be followed, and the risks and benefits of participation. A copy of the signed consent form will be given to the subject, parent, or legal guardian, and this fact will be documented in the subject s record Subject Confidentiality All laboratory specimens, evaluation forms, reports, video recordings, and other records that leave the site will be identified only by the Study Identification Number (SID) to maintain subject confidentiality. All records will be kept in a locked file cabinet. All computer entry and networking programs will be done using SIDs only. Clinical information will not be released without written permission of the subject, except as necessary for monitoring by IRB, the FDA, the NINDS, the OHRP, the sponsor, or the sponsor s designee. A description of this clinical trial will be available on as required by U.S. law. This web site will not include information that can identify an individual subject. At most, the web site will include a summary of the results. The web site can be searched at any time Subject Compensation To help cover the costs of participating in this study, the subject s family will receive a payment per visit for the costs/inconvenience/time (for example: travel, parking, and meals) associated with participation in the research study. If the subject does not finish the whole study, reimbursement will be provided for each study visit that is completed. The study medication, the study visits, and medical testing needed for the study will be provided at no charge to the subject. The compensation guidelines will be customized for each site to ensure that the study (1) adheres to all IRB guidelines at the site and (2) accurately estimates travel costs based on the average distance subjects will travel to the site.

212 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean 11.6 Study Modification/Discontinuation The study may be modified or discontinued at any time by the IRB, the NINDS, the sponsor, the OHRP, the FDA, or other government agencies as part of their duties to ensure that research subjects are protected. All protocol amendments must be issued by the sponsor, signed and dated by the investigator, and should not be implemented without prior IRB approval, except where necessary to eliminate immediate hazards to the subjects or when the change(s) involves only logistical or administrative aspects of the trial (e.g., change in of telephone number(s)). In situations requiring a departure from the protocol, the investigator or other study staff will contact the project manager or other appropriate sponsor representative by fax or telephone. If possible, this contact will be made before implementing any departure from protocol. In all cases, contact with the sponsor must be made, as soon as possible, in order to discuss the situation and agree on an appropriate course of action. The CRF and source document will describe any departure from the protocol and the circumstances requiring it. 12 PUBLICATION OF RESEARCH FINDINGS Publication of the results of this trial will be governed by the policies and procedures developed by the Executive Committee. Any presentation, abstract, or manuscript will be made available for review by the sponsor and the NINDS prior to submission. An investigator who wishes to publish the results of this study must contact the publication committee in order to obtain permission for the required data analyses and queries of the trial database. 13 REFERENCES 1. Hershey AD, Powers SW, Winner P, and Kabbouche M. Pediatric Headaches in Clinical Practice. West Sussex, UK John WIley & Sons, Ltd., Lewis D, Ashwal S, Hershey A, Hirtz D, Yonker M, and Silberstein S. Practice parameter: pharmacological treatment of migraine headache in children and adolescents: report of the American Academy of Neurology Quality Standards Subcommittee and the Practice Committee of the Child Neurology Society. Neurology 63: , Tfelt-Hansen P, Block G, Dahlof C, Diener HC, Ferrari MD, Goadsby PJ, Guidetti V, Jones B, Lipton RB, Massiou H, Meinert C, Sandrini G, Steiner T, and Winter PB. Guidelines for controlled trials of drugs in migraine: second edition. Cephalalgia 20: , Abu-Arefeh I, and Russell G. Prevalence of headache and migraine in schoolchildren. BMJ 309: , PMCID: Stewart WF, Linet MS, Celentano DD, Van Natta M, and Ziegler D. Age- and sex-specific incidence rates of migraine with and without visual aura. Am J Epidemiol 134: , Stewart WF, Lipton RB, Celentano DD, and Reed ML. Prevalence of migraine headache in the United States. Relation to age, income, race, and other sociodemographic factors. JAMA 267: 64-69, Split W, and Neuman W. Epidemiology of migraine among students from randomly selected secondary schools in Lodz. Headache 39: , 1999.

213 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean 8. Stang PE, Crown WH, Bizier R, Chatterton ML, and White R. The family impact and costs of migraine. Am J Manag Care 10: , Bille B. A 40-year follow-up of school children with migraine. Cephalalgia 17: ; discussion 487, Stewart WF, Ricci JA, Chee E, Morganstein D, and Lipton R. Lost productive time and cost due to common pain conditions in the US workforce. JAMA 290: , Victor S, and Ryan SW. Drugs for preventing migraine headaches in children. Cochrane Database Syst Rev CD002761, Schwedt TJ, and Shapiro RE. Funding of research on headache disorders by the National Institutes of Health. Headache 49: , PMCID:PMC Journal-In Process. 13. Svensson DA, Larsson B, Bille B, and Lichtenstein P. Genetic and environmental influences on recurrent headaches in eight to nine-year-old twins. Cephalalgia 19: , Russell MB, Iselius L, and Olesen J. Migraine without aura and migraine with aura are inherited disorders. Cephalalgia 16: , Russell MB, and Olesen J. Migrainous disorder and its relation to migraine without aura and migraine with aura. A genetic epidemiological study. Cephalalgia 16: , Ashkenazi A, Silberstein S, Jakubowski M, and Burstein R. Improved identification of allodynic migraine patients using a questionnaire. Cephalalgia 27: , PMCID: Burstein R, Cutrer MF, and Yarnitsky D. The development of cutaneous allodynia during a migraine attack clinical evidence for the sequential recruitment of spinal and supraspinal nociceptive neurons in migraine. Brain 123 ( Pt 8): , Kropp P, Siniatchkin M, and Gerber WD. On the pathophysiology of migraine--links for "empirically based treatment" with neurofeedback. Appl Psychophysiol Biofeedback 27: , Bigal M. Migraine chronification--concept and risk factors. Discov Med 8: , PMCID:PMCID:PMC Journal-In Process. 20. Cohen AS, and Goadsby PJ. Functional neuroimaging of primary headache disorders. Expert Rev Neurother 6: , Goadsby PJ. Neuroimaging in headache. Microsc Res Tech 53: , Goadsby PJ. Migraine pathophysiology. Headache 45 Suppl 1: S14-24, Bigal ME, Lipton RB, Winner P, Reed ML, Diamond S, and Stewart WF. Migraine in adolescents: association with socioeconomic status and family history. Neurology 69: 16-25, Galli F, Patron L, Russo PM, Bruni O, Ferini-Strambi L, and Guidetti V. Chronic daily headache in childhood and adolescence: clinical aspects and a 4-year follow-up. Cephalalgia 24: , Guidetti V, Galli F, Fabrizi P, Giannantoni AS, Napoli L, Bruni O, and Trillo S. Headache and psychiatric comorbidity: clinical aspects and outcome in an 8-year follow-up study. Cephalalgia 18: , Koenig MA, Gladstein J, McCarter RJ, Hershey AD, and Wasiewski W. Chronic daily headache in children and adolescents presenting to tertiary headache clinics. Headache 42: , Hershey AD, Powers SW, Nelson TD, Kabbouche MA, Winner P, Yonker M, Linder SL, Bicknese A, Sowel MK, and McClintock W. Obesity in the pediatric headache population: a multicenter study. Headache 49: , PMCID:PMC Journal-In Process. 28. Lipton RB, Stewart WF, Diamond S, Diamond ML, and Reed M. Prevalence and burden of migraine in the United States: data from the American Migraine Study II. Headache 41: , 2001.

214 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean 29. Welch KM, Nagesh V, Aurora SK, and Gelman N. Periaqueductal gray matter dysfunction in migraine: cause or the burden of illness? Headache 41: , Lewis DW, Ashwal S, Dahl G, Dorbad D, Hirtz D, Prensky A, and Jarjour I. Practice parameter: evaluation of children and adolescents with recurrent headaches: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 59: , Powers SW, Patton SR, Hommel KA, and Hershey AD. Quality of life in childhood migraines: clinical impact and comparison to other chronic illnesses. Pediatrics 112: e1-5, Hershey AD, Powers SW, Vockell AL, LeCates SL, Segers A, and Kabbouche MA. Development of a patient-based grading scale for PedMIDAS. Cephalalgia 24: , Hershey AD, Powers SW, Vockell AL, LeCates S, Kabbouche MA, and Maynard MK. PedMIDAS: development of a questionnaire to assess disability of migraines in children. Neurology 57: , Powers SW, Patton SR, Hommel KA, and Hershey AD. Quality of life in paediatric migraine: characterization of age-related effects using PedsQL 4.0. Cephalalgia 24: , Stang PE, and Osterhaus JT. Impact of migraine in the United States: data from the National Health Interview Survey. Headache 33: 29-35, Crawford MJ, Lehman L, Slater S, Kabbouche MA, LeCates SL, Segers A, Manning P, Powers SW, and Hershey AD. Menstrual migraine in adolescents. Headache 49: , PMCID:PMCID:PMC Journal-In Process. 37. Lewis DW, Diamond S, Scott D, and Jones V. Prophylactic treatment of pediatric migraine. Headache 44: , Gherpelli JL. New migraine prophylactic drug options. Rev Hosp Clin Fac Med Sao Paulo 57: , Hershey AD, Powers SW, Bentti AL, and Degrauw TJ. Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache 40: , Lakshmi CV, Singhi P, Malhi P, and Ray M. Topiramate in the prophylaxis of pediatric migraine: a double-blind placebo-controlled trial. J Child Neurol 22: , Apostol G, Cady RK, Laforet GA, Robieson WZ, Olson E, Abi-Saab WM, and Saltarelli M. Divalproex extended-release in adolescent migraine prophylaxis: results of a randomized, double-blind, placebo-controlled study. Headache 48: , PMCID:PMC Journal- In Process. 42. Jones MW. Topiramate--safety and tolerability. Can J Neurol Sci 25: S13-15, Hershey AD. Current approaches to the diagnosis and management of paediatric migraine. Lancet Neurol 9: , PMCID:PMC Journal-In Process. 44. Dodick DW, Freitag F, Banks J, Saper J, Xiang J, Rupnow M, Biondi D, Greenberg SJ, and Hulihan J. Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs. Clin Ther 31: , PMCID:PMC Journal-In Process. 45. Lewis D, Winner P, Saper J, Ness S, Polverejan E, Wang S, Kurland CL, Nye J, Yuen E, Eerdekens M, and Ford L. Randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of topiramate for migraine prevention in pediatric subjects 12 to 17 years of age. Pediatrics 123: , PMCID:PMC Journal-In Process. 46. Pearl W. Effects of gender, age, and heart rate on QT intervals in children. Pediatr Cardiol 17: , Kovacs M. Rating scales to assess depression in school-aged children. Acta Paedopsychiatr 46: , Kovacs M. Children's Depression Inventory. North Tonawanda, NY: Multi-Health Systems Inc., 1992.

215 The CHAMP Study CHAMP Study Protocol DSMB Approved Version 3.2_ _clean 49. Walker LS, and Greene JW. The functional disability inventory: measuring a neglected dimension of child health status. J Pediatr Psychol 16: 39-58, Zigmond AS, and Snaith RP. The hospital anxiety and depression scale. Acta Psychiatr Scand 67: , Varni JW, Burwinkle TM, Seid M, and Skarr D. The PedsQL 4.0 as a pediatric population health measure: feasibility, reliability, and validity. Ambul Pediatr 3: , Varni JW, Seid M, and Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care 39: , Varni JW, Seid M, and Rode CA. The PedsQL: measurement model for the pediatric quality of life inventory. Med Care 37: , Mundt JC, Greist JH, Gelenberg AJ, Katzelnick DJ, Jefferson JW, and Modell JG. Feasibility and validation of a computer-automated Columbia-Suicide Severity Rating Scale using interactive voice response technology. J Psychiatr Res 44: , Winner P, Pearlman EM, Linder SL, Jordan DM, Fisher AC, and Hulihan J (2005). Topiramate for migraine prevention in children: arandomized, double-blind, placebo-controlled trial. Headache. 45(10):

216 The Childhood and Adolescent Migraine Prevention (CHAMP) Study STATISTICAL ANALYSIS PLAN Principal Investigators Andrew D. Hershey, MD, PhD, FAHS Scott W. Powers, PhD, ABPP, FAHS Study Statisticians Christopher S. Coffey, PhD Jon Yankey, MS Elizabeth Zahn, MS Supported By: National Institute of Neurological Disorders and Stroke (NINDS) Grant Numbers: U01NS (Cincinnati Children s) U01NS (U. Iowa) Investigational Drug Application (IND) Holder: Andrew D. Hershey, MD, PhD, FAHS IND # 112,220 VERSION 1.0 November 5,

217 PREFACE This Statistical Analysis Plan (SAP) describes the planned analyses for the Childhood and Adolescent Migraine Prevention (CHAMP) study (National Institute of Neurological Disorders and Stroke (NINDS) grant # s U01NS (Cincinnati Children s) and U01NS (U. Iowa). The planned analyses identified in this SAP are intended to support the completion of the Final Study Report (FSR) and will be included in regulatory submissions and/or future manuscripts. All interim analyses will involve only the primary study endpoint, and will be performed once the specified number of subjects have been enrolled and completed the full study period. All final, planned analyses identified in this SAP will be performed only after the last subject has been enrolled and completed the full study period. Once all data have been cleaned and verified, a locked version of the data will be used for reporting the final study results. Key statistics and study results will be made available to the CCC following database lock and prior to completion of the final FSR. 1. STUDY DESIGN This is a phase III, intent to treat, three-arm, multi-center, randomized, double-blind, placebo-controlled safety and efficacy study to simultaneously assess the impact of two medication therapies (amitriptyline and topiramate ) for headache prevention in children and adolescents with a diagnosis of migraine. The global objective of the study is to determine the optimal medication for the prevention of headaches in children and adolescents. A total of 675 children and adolescents between age 8 and 17 diagnosed with migraine, migraine with aura, and/or chronic migraine will be enrolled into the trial at up to 40 sites across the United States. Subjects will be randomized in a 2:2:1 fashion to either amitriptyline (n=270), topiramate (n=270), or placebo (n=135). Stratification will occur based on age at screening (8-12, 13-17) and the baseline number of headaches per month (episodic: 4-14, chronic: 15 or more). Subjects will be involved for approximately 34 weeks in the various phases of the study, with visits, time lines, and interventions as indicated in the flow chart: Screen Randomize Titrate Treat Washout/Final V 3, 4 Visit 1 V 2 V 5, 6, 7 V 8 Phone 1 & 2 4 weeks 0 weeks 8 weeks 12 weeks 4 weeks 6 weeks After informed consent (and assent where appropriate) has been obtained, subjects will maintain a headache diary during a 4 week baseline period. If eligiblity criteria are met, subjects will be randomized to one of the three treatment arms and will enter into an 8-week titration period with study drug. This titration phase will be modifiable based on tolerability and effectiveness. This will be followed by a 16-week constant dose or maintenance phase. Subjects will complete a daily headache diary during the titration and maintenace periods. At the conclusion of maintenance, a 6 week period will ensue to wean off medication (2 weeks) and conduct follow-up safety phone calls (4 weeks). Safety labs will be collected along with repository specimens at three intervals during the study. Physical exams will be conducted at each study visit. A PedMIDAS disability score will be collected every 3 months during the study. Neurological exams will be conducted at the screening and baseline exams, at the end of dose titration, at the end of the maintenance period, and at the study endpoint. Electrocardiograms (ECG) will be collected at screening and after the completion of dose titration. A targeted symptom questionnaire will be conducted at every visit and a brief version of the symptom questionnaire will be conducted by phone between visits. Subjects describing suicidal ideation in response to the symptom questionnaires will be evaluated, and if deemed at risk to themselves or others, will be directed immediately for psychiatric evaluation and management. The Columbia Suicide Severity Rating Scale (CSSRS) instruments will be used to score subject reports of suicidality that were clinically referred for immediate psychiatric evaluation and management. Adverse events and the use of concomitant medications will be recorded at each study visit. Study drug compliance will be ascertained by pill count and subject report on the daily headache diary and batched biosample analysis. Questionnaires will be completed by subjects at screening, the end of titration, and at the study endpoint. 2

218 Based upon the findings of this 3 in 1 clinical trial, our overall goal is to determine, using a specified a priori tiered approach, which of these therapies is superior in the prevention of headaches. The tiers used to make this decision are: First Tier Primary Endpoint: 50% or greater reduction in rate of headache frequency. Second Tier Headache Disability Third Tier - Tolerability If superiority cannot be determined through this tiered approach, then the outcome of the trial would be that both therapies are efficacious and individualized clinical decisions based on subject presentation should guide the first choice in practice. All final recommendations must separately account for the safety data generated by this novel study. Safety concerns could trump the conclusions from any of the three tiers Primary Objective Primary Objective 1: Determine if amitriptyline (AMI) and/or topiramate (TPM) are superior to placebo in reducing headache frequency (defined as the number of days with headache for a given 4 week period) from 4 week baseline period to the last 4 weeks of this trial, in children and adolescents. Primary Objective 2: Conduct a comparative effectiveness study of the two therapies with respect to reducing headache frequency (defined as the number of days with headache for a given 4 week period) from 4 week baseline period to the last 4 weeks of this trial. We will determine if there is a difference in the proportion of subjects with a 50% reduction in headache frequency from the 4 week baseline period to the last 4 weeks of this 24-week trial between AMI and placebo, and between TPM and placebo. These hypotheses were powered to detect a 20 percentage point improvement from placebo, which is considered a clinically meaningful difference by headache experts (Hershey et al, 2009a). For the comparative effectiveness study, we will determine if there is a difference in the proportion of subjects with a 50% reduction in headache frequency from the 4 week baseline period to the last 4 weeks of this 24- week trial between AMI and TPM. This hypothesis was powered to detect a 15 percentage point or greater difference for the comparison of two active interventions Major Secondary Objectives Major Secondary Objective 1: Determine if AMI and/or TPM will result in a decrease in absolute headache disability score (measured by PedMIDAS) from the end of the 4 week baseline period to the last 4 weeks of this trial, compared to placebo. Major Secondary Objective 2: Determine if AMI and TPM differ with respect to change in absolute headache disability score (measured by PedMIDAS) from the end of the 4 week baseline period to the last 4 weeks of this trial. Major Secondary Objective 3: Determine if AMI and/or TPM will result in a decrease in absolute headache days per 28 day period, measured by the change in absolute headache days from the 4 week baseline period to the last 4 weeks of the trial, compared to placebo. Major Secondary Objective 4: Conduct a comparative effectiveness study of the two therapies with respect to headache days per 28 day period, measured by the change in absolute headache days from the 4 week baseline period to the last 4 weeks of the trial. Major Secondary Objective 5: Determine if AMI and/or TPM are well tolerated. Major Secondary Objective 6: Determine if AMI and/or TPM differ from placebo on the occurrence of treatment-emergent serious adverse events. 2. PRIMARY ENDPOINT The primary endpoint is a 50% reduction in headache frequency from the 28 days prior to randomization to the last 28 days of this 24-week trial. Headache frequency is defined as the number of days with headache for a given four week (28 day) period. 3

219 A headache diary will be dispensed at each visit, and the subject and subject s parent(s) will be instructed on the completion of the daily headache diary. The headache diary will record the daily incidence, frequency, and duration of all of the subject s headaches and migraine symptoms for a period of one month. The headache diary will also record any rescue medications and daily study drug use by the subject. A headache day will be defined as any day during which any headache occurs within a 24 hour period, starting and ending at midnight. For each subject, the primary endpoint will involve a determination of whether a 50% or greater reduction in headache frequency was observed during the last 4 weeks of active treatment as compared with the headache frequency during the 4-week baseline period (Tfelt-Hansen et al, 2000). Subjects who achieve a 50% or greater reduction in headache frequency will be considered to have had a successful primary endpoint. Those subjects whose reduction in headache frequency was less than 50% will be considered to have had a failure with respect to the primary endpoint. The only exception will be that any subjects who must be removed from therapy prior to the completion of the 24-week treatment period or do not provide headache diary data at the final maintenance visit (visit 8) will be considered failures with respect to the primary endpoint. We do not anticipate issues associated with missing days for subjects with completed diaries. The daily headache diary asks a subject to respond in a yes/no manner as to whether a headache occurred on each day and to check off typical migraine symptoms when present. For days that no value is marked, study coordinators are encouraged to contact the subject to determine whether a headache occurred on that day and if the headache had migraine features. If no determination can be made, the data for these days will be marked as unobtainable. For situations where a subject completes less than 28 headache diary days at baseline or Visit 8, we will apply the following rules: 1) If at least 21 headache diary days were completed, the available information will be standardized to the number of headache days for a 28 day period. For example, if a subject only completed 21 headache diary days and reported 3 headache episodes, the outcome for that subject would be based on 4 headache episodes over a 28 day period (since 3/21 = 4/28). 2) If less than 21 headache diary days were completed, the diary information will be considered missing for the subject. Correspondingly, this subject will be handled in the analysis according to the prespecified rules for handing missing data. 3. SECONDARY ENDPOINTS 3.1. Headache Disability One major secondary objective of the CHAMP study is to examine whether the change in absolute headache disability score, as measured by the PedMIDAS, differs between treatment groups over time. The PedMIDAS scale evaluates the impact of headaches in school, home, play, and social activities. It is comprised of six items that pertain to days missed in various activities over the past 90 days. Questions are answered by the youth in consultation with their parents. The total PedMIDAS score (sum of items 1-6) will be used in this trial. The PedMIDAS examination will be dispensed at visit 2, and the subject and subject s parent(s) will be instructed on completion of the PedMIDAS to determine eligibility based on a disability score > 10, including at least mild disruption in daily activities and < 140, indicating extreme disability that may require more comprehensive, multi-component therapy. PedMIDAS data will be reviewed by study staff with the subject and parents. The PedMIDAS will also be used as a study procedure at two additional study timepoints to collect information on headache related disability that has occurred in the last three months. Thus, each subject will have a PedMIDAS score measured at baseline (covering the three months prior to enrollment), the start of the maintenance period (covering the three months since enrollment), and the 24-week visit (the end of the maintenance period, covering three months of enrollment). The main outcome measure for this comparison will be the difference in the 24-week and baseline PedMIDAS scores Headache Days Another major secondary objective of the study is to determine if the rate of absolute number of headache days, per 28 day period, differs between treatment groups over time. This objective will be assessed longitudinally based on the actual number of headache days from the 28 days prior to randomization to the last 28 days of this 24 week trial. 4

220 3.3. Tolerability An additional major secondary objective is to assess tolerability for the two active treatment groups. To assess tolerability, the percentage of subjects who complete the entire 24-week treatment period will be estimated in each of the three groups Safety The safety of study subjects is of the utmost concern to the sponsor and investigators in this study. Reporting of complete and accurate safety information according to acceptable timelines is crucial to the protection of subjects, and is required by the regulatory agencies with oversight of this study. Standard Operating Procedures for adverse event reporting have been developed by the sponsor to ensure compliance with regulatory requirements, including grading of adverse events according to the NCI Common Toxicity Criteria III, and a reporting timeline of 14 days for adverse events and one business day for SAEs. The investigator or site staff will be responsible for detecting, documenting, and reporting events that meet the definition of an Adverse Event (AE) or Serious Adverse Event (SAE). Adverse events will be collected after the ingestion of at least one dose of study drug and until the final phone contact. For subjects who are withdrawn from study drug exposure but continue on the protocol to collect diary data, adverse events will continue to be collected until 30 days after study drug exposure ends Adverse Events An adverse event (AE) is defined as any untoward medical occurrence in a subject administered an investigational pharmaceutical product and which does not necessarily have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the medicinal (investigational) product. This includes any occurrence that is new in onset or increased in severity, grade, or frequency from the baseline condition, or abnormal results of diagnostic procedures including laboratory test abnormalities which are considered AEs if they: Result in discontinuation from the study Require treatment or any other therapeutic intervention, require further diagnostic evaluation (excluding a repetition of the same procedure to confirm the abnormality), are associated with clinical signs or symptoms judged by the investigator to have a significant clinical impact Decreases and increases in weight will be monitored closely during study visits. Change in weight that exceeds two isobars on the normal CDC growth chart published May 30, 2000 for children ages 2-20 will be considered a grade 2 AE. A detailed report of the reason for weight change will be documented Serious Adverse Events A serious adverse event (SAE) is any untoward medical occurrence that at any dose: Results in death Is life-threatening Requires inpatient hospitalization or prolongation of existing hospitalization Results in persistent or significant disability/incapacity Is a congenital anomaly/birth defect Is an expression of suicidal ideation or action Or, in the opinion of the investigators, represents other significant hazards or potentially serious harm to research participants or others. The onset of suicidal thoughts with AMI or TPM usage will be carefully monitored during the study by the use of the symptom questionnaire at frequent intervals by making the subjects and family aware of self-monitoring for the onset of this possible side effect. Suicidal ideation and suicidal intent may also be reported on the CDI 5

221 questionnaire as noted by a yes response to I think about killing myself but I would not do it and I want to kill myself on item #9. Any report of the expression of suicidal ideation will be considered an SAE. Inpatient or emergency department admission for the treatment of migraine headache will not be considered an SAE for this protocol Unexpected SAE An unexpected SAE is one for which the nature or severity is not consistent with the applicable product information (e.g., Investigator s Brochure) or package insert/summary of product characteristics for an approved product. Expectedness of SAEs will be reviewed by the Medical Safety Monitor (MSM) Related SAE An SAE is considered associated with use of the drug (i.e., related or treatment-emergent) if the attribution is possible, probable, or definite. Relatedness of SAEs will be reviewed by the MSM Additional Safety Endpoints The Behavioral Rating Inventory & Executive Function (BRIEF) is a measure of executive function and is a questionnaire completed by the parent/guardian. It consists of two indexes, Behavioral Regulation and Metacognition, which are then used to calculate an overall global executive composite (GEC) score. The Clinical Depression Inventory (CDI) is a reliable and valid 27-item scale assessing symptoms of depression (Kovacs, 1981; Kovacs, 1992). It yields a total score and subscale scores on negative mood, interpersonal problems, ineffectiveness, anhedonia, and negative self esteem. Separate norms are available for boys and girls ages 7-12 and 13-17, which are then converted to T-scores. The total score and a positive screen cutoff of a T-score 80 will be used. The CDI secondary measure item 9 responses will be reviewed during the visit and the results presented to the site investigator for review. Any responses that endorse suicidality require immediate action and will be acted upon by the site investigator to ensure child safety. 4. ENROLLMENT, RANDOMIZATION, AND TREATMENT ASSIGNMENT 4.1. Enrollment of Subjects The primary methodology for identifying and recruiting subjects for this study will be through identification of potential subjects from pediatric headache medicine specialty practices, pediatric neurology practices or adult headache medicine or neurology practices that treat children and adolescents. This will include sites that are part of the NINDS Clinical Research Consortium which have contracted to conduct the study. In order to reach our expected enrollment and based on our survey of interested sites, it is anticipated that the research sites would identify at least 4 subjects per site per month, and be able to enroll at least 1 subject every 2 months Randomization Subjects who meet the eligibility criteria and have given their consent will be randomized to one of the 3 treatment arms after the initial 4 week baseline period. Randomization will be stratified by age (8-12, 13-17) and the baseline number of headaches per month (episodic: 4-14, chronic: 15 or more). Because this strategy provides four strata, we have elected not to stratify the randomization at each site. The DCC will generate a randomization table for each of the strata using a permuted block design with random block sizes Treatment Assignment After completion of all eligibility requirements, and determination of eligibility by the investigator, the eligibility Case Report Form (ecrf) will be completed by the study coordinator. The completion of this ecrf will trigger a response from the DCC to randomly assign a treatment group in keeping with the subject s age and headache frequency stratification. The notification of treatment assignment will then be delivered electronically to the central research pharmacy and to the site study staff. The study staff will receive a blinded notification of the bottle numbers to supply the assigned treatment to the subject s family to begin study drug titration. 6

222 5. PRELIMINARY TABLULATIONS All subjects who provide informed consent will be accounted for in this study. Regularly generated enrollment reports will describe: Number of subjects consented and randomized by site Ongoing study status of all randomized subjects Reasons for ineligibility Protocol deviations Early study completers The data set will also be summarized by treatment group with respect to important confounders. The distributions of categorical variables will be tabulated by treatment group and overall. Continuous variables will be summarized as mean, median, standard deviation, minimum, and maximum by treatment group and overall. Variables to be collected will include: Gender Race Ethnicity Mother s education Father s education Annual income Age Standardized BMI (standardized to account for differential growth in pediatrics) Baseline headache frequency Baseline PedMIDAS score 6. PRIMARY EFFICACY ANALYSES Primary Hypothesis 1: Amitriptyline, at a target dose of 1 mg/kg/day, will result in an increased percentage of subjects meeting the primary endpoint compared to placebo. Primary Hypothesis 2: Topiramate, at a target dose of 2 mg/kg/day will result in an increased percentage of subjects meeting the primary endpoint compared to placebo. Primary Hypothesis 3: Topiramate will result in an increased percentage of subjects meeting the primary endpoint compared to amitriptyline. Each of these primary hypotheses will involve a comparison of headache frequency (percentage of days with any headache) between the last 4 weeks of treatment (weeks 20-24) and the 4-week baseline period. A prior clinical trial of prevention medication in pediatric migraine found that the beneficial effects of TPM over placebo increased throughout the duration of the trial, and reached the optimal outcome during the final 4 weeks (Lewis et al, 2009). Therefore, the choice was made to evaluate the final 4 weeks versus baseline as the primary analysis for the proposed trial. The primary hypotheses will be assessed using a logistic regression model, adjusted for the two stratification variables, to estimate the log-odds of primary endpoint success in each group. The logistic regression model used for these purposes is stated here: where,,,, Y i represents the binary variable indicating whether or not the i th subject met the primary outcome requirement of a 50% or greater reduction in headache frequency, 7

223 X age,i is an indicator variable for the baseline age group for the i th subject (=0 if age 8-12, =1 if age 13-17) X headache,i is an indicator variable for the baseline number of headaches per month for the i th subject (=0 if 4-14, =1 if 15 or more) X AMI,i is an indicator variable for whether the i th subject was randomized to the AMI group X TPM,i is an indicator variable for whether the i th subject was randomized to the TPM group. Correspondingly, the three primary hypotheses of interest can be assessed by performing hypothesis tests of the three pair-wise treatment comparisons of interest: AMI vs. Placebo: H 0 : β 3 = 0 vs. H A : β 3 0 TPM vs. Placebo: H 0 : β 4 = 0 vs. H A : β 4 0 AMI vs. TPM: H 0 : β 3 = β 4 vs. H A : β 3 β 4 Each of the primary hypotheses will be tested using a Bonferroni corrected significance level of (= 0.05/3). Due to randomization, it is unlikely that important covariates will be imbalanced in this study. However, should important imbalances occur, we will control for these additional covariates in the logistic regression model. The odds ratio of primary endpoint success, and Bonferroni adjusted confidence intervals, will then be estimated: AMI relative to placebo: OR = exp(β 3 ), Adjusted CI: (exp( (β 3 ) ± 2.39 * SE(β 3 )) TPM relative to placebo: OR = exp(β 4 ), Adjusted CI: (exp( (β 4 ) ± 2.39 * SE(β 4 )) AMI relative to TPM: OR = exp(β 3 - β 4 ), Adjusted CI: (exp( (β 3 - β 4 ) ± 2.39 * SE(β 3 - β 4 )) Results will be summarized in the following tables (number and percent of primary endpoint success are displayed in Table 6.1, odds ratios and adjusted CI s are displayed in Table 6.2): Treatment Group Table 6.1: Number and Percent of Primary Endpoint Success Completed Visit 8 N Reduction in Reduction in Headache Headache Missing Frequency 50% Frequency < 50% N (%) N (%) N (%) Early Completer/Early Drug Withdrawal N (%) AMI XXX XXX (XX%) XXX (XX%) XXX (XX%) XXX (XX%) TPM XXX XXX (XX%) XXX (XX%) XXX (XX%) XXX (XX%) Placebo XXX XXX (XX%) XXX (XX%) XXX (XX%) XXX (XX%) Table 6.2: Odds-ratios of Primary Endpoint Success Comparison Odds-ratio p-value (Adjusted% CI) AMI vs. Placebo xx.x (xx.x, xx.x) x.xxxx TPM vs. Placebo xx.x (xx.x, xx.x) x.xxxx AMI vs. TPM xx.x (xx.x, xx.x) x.xxxx If β 3 is significantly larger than zero, we will conclude AMI to be effective for the treatment of headaches relative to placebo. If β 3 is significantly less than zero, we will conclude that AMI is less effective than placebo in the treatment of headaches. If we fail to reject the first hypothesis then we will conclude that there is no difference in the percent of primary endpoint success between the AMI and placebo groups. 8

224 Likewise, if we reject the second hypothesis we will conclude TPM to be effective for the treatment of headaches relative to placebo if β 4 is significantly larger than zero. If β 4 is significantly less than zero we will conclude that TPM is less effective than placebo in the treatment of headaches. If we fail to reject the second hypothesis then we will conclude that there is no difference in the percent of primary endpoint success between the TPM and placebo groups. In the comparison of AMI and TPM, if we reject the third hypothesis, we will conclude that AMI is more effective than TPM in the treatment of headaches if β 3 - β 4 is significantly larger than zero. We will conclude TPM to be more effective than AMI if β 3 - β 4 is significantly less than zero. If we fail to reject the third hypothesis then we will conclude that there is no significant difference in percent of primary endpoint success between the AMI and TPM groups. This analysis will be performed in accordance with the intention to treat (ITT) principle, that is, any subject who received a random treatment assignment will be included in the primary endpoint analysis. 7. IMPACT OF MISSING DATA The daily headache diary asks a subject to respond in a yes/no manner as to whether a headache occurred on each day and to check off typical migraine symptoms when present. All primary analyses will follow the intent-to-treat (ITT) paradigm. As such, it will be critically important to minimize the occurrence of missing data. Obviously, the optimal strategy for dealing with missing data is to make every effort to obtain complete data during the conduct of the study. Our team will use a variety of methods in order to minimize the percentage of missing data in this trial. Nevertheless, there is likely to be a small percentage of missing data. For the primary analysis, we will employ a conservative approach and impute an outcome of failure for any subject that either withdraws early from study drug or does not have observed visit 8 headache diary data. We then propose a series of sensitivity analyses to determine the potential dependence of the results of the primary analysis on missing values. This sensitivity analysis will employ multiple methods: Observed Data: Use only subjects with non-missing visit 8 headache diary data and who did not withdraw early from study drug Tolerability/Imputation: Assume all subjects terminated from the study due to tolerability issues are failures. For other subjects, the outcome will be obtained from the visit 8 headache diary data (even for subjects that were early drug withdrawals, if they remained in the study and completed the visit 8 headache diaries). For remaining subjects with missing visit 8 headache diary data, outcomes will be imputed using a variety of methods: o o Last Observation Carried Forward: Most recent visit with a complete 28 day headache diary period will be carried forward and used for the endpoint determination for these subjects Multiple Imputation: Impute endpoint data using a multiple imputation model based on age and headache frequency at baseline, as well as endpoint data computed at each intermediate time-point for all subjects with observed data. Imputed values will be derived using the MCMC method with multiple chains, adequate burn-in iterations, and a non-informative prior distribution. We will use five separate implementations of this approach. The logistic regression model described above will be fit to each of the five imputed data sets resulting in five separate parameter estimates, one for each of the imputed data sets.,,,,,,,,, o where the notation imp j indicates imputation j = 1,,5. The mean of the parameter estimates from the imputed data sets will be used as the estimate for the final analysis. Variances for each of the parameter estimates will be estimated using standard formulas provided by (Little & Rubin, 2002) as a function of within imputation and between imputation variance. Best Case Scenario: Assume all subjects with missing visit 8 headache diary data in either the AMI or TPM group are successes; Assume all subjects in the placebo group with missing visit 8 headache diary data are failures. 9

225 o Worst Case Scenario: Assume all subjects with missing visit 8 headache diary data in either the AMI or TPM group are failures; Assume all subjects in the placebo group with missing data are successes. At the time of the interim and final analyses, results will be reported from both the primary analysis and all sensitivity analyses in order to inform how robust the overall trend observed in the study is to the missing data. For example, if an interim analysis suggests that both treatments are better than placebo based on the primary endpoint, the DSMB might be more comfortable dropping the placebo arm if that finding is supported by the majority of the sensitivity analyses. On the other hand, if the finding is not supported by the sensitivity analyses, the DSMB may choose to keep the placebo arm in the study until the time of the next planned interim assessment. These results will be displayed in the following tables: Table 7.1: Number and Percent of Subjects with Reduction in Headache Frequency 50% Reduction in Headache Frequency 50% Imputation Method AMI N (%) TPM N (%) Placebo N (%) Primary xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) Observed xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) Tolerability, LOCF* xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) Tolerability, Multiple Imputation xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) Tolerability, Best Case xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) Tolerability, Worst Case xxx (xx.x%) xxx (xx.x%) xxx (xx.x%) * Last observation carried forward Table 7.2: Odds-ratios of Primary Endpoint Success Odds-ratios (Adjusted CI) Imputation Method AMI vs. Placebo TPM vs. Placebo AMI vs. TPM Primary x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) Observed x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) Tolerability, LOCF* x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) Tolerability, Multiple Imputation x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) Tolerability, Best Case x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) Tolerability, Worst Case x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) * Last observation carried forward 8. PRE-SPECIFIED ANALYSES OF SECONDARY OUTCOMES 8.1. Analysis of Change in PedMIDAS Score from Baseline to 24-weeks Major Secondary Hypothesis #1: Amitriptyline will result in a decrease in absolute headache disability score (measured by PedMIDAS) compared to placebo. Major Secondary Hypothesis #2: Topiramate will result in a decrease in absolute headache disability score (measured by PedMIDAS) compared to placebo. Major Secondary Hypothesis #3: Topiramate will result in a decrease in absolute headache disability score (measured by PedMIDAS) compared to amitriptyline. The mean change from baseline in PedMIDAS score over time for the three groups will be assessed using a linear regression model, adjusted for the baseline PedMIDAS score and is stated here:,,,,, where Y i represents the change in PedMIDAS score from baseline to the end of the study period for the i th subject. X age,i is an indicator variable for the baseline age group for the i th subject (=0 if age 8-12, =1 if age 13-17) 10

226 X headache,i is an indicator variable for the baseline number of headaches per month for the i th subject (=0 if 4-14, =1 if 15 or more) X AMI,i is an indicator variable for whether the i th subject was randomized to the AMI group X TPM,i is an indicator variable for whether the i th subject was randomized to the TPM group X bpm,i is the baseline PedMIDAS score for the i th subject is random error for the i th subject Correspondingly, the three hypotheses of interest can be assessed by performing a hypothesis test of the three pair-wise treatment comparisons of interest: AMI vs. Placebo: H 0,1 : β 3 = 0 vs. H A : β 3 0 TPM vs. Placebo: H 0,2 : β 4 = 0 vs. H A : β 4 0 AMI vs. TPM: H 0,3 : β 3 = β 4 vs. H A : β 3 β 4 These results will be displayed in the following table: Table 8.1.1: Change in PedMIDAS Scores from Baseline to 24 Weeks PedMIDAS Score (24 wk baseline) Mean (SD) Min. max. Missing AMI TPM Placebo Model Adjusted Difference (95% CI) xx.x (xx.x) xx xx xx xx.x (xx.x) xx xx xx xx.x (xx.x) xx xx xx AMI vs. PBO: xx.x (xx.x, xx.x) TPM vs. PBO: xx.x (xx.x, xx.x) AMI vs. TPM: xx.x (xx.x, xx.x) 8.2 Analysis of Change in Absolute Headache Days per 28 Day Period Major Secondary Hypothesis #4: Amitriptyline will result in a decrease in absolute headache days compared to placebo. Major Secondary Hypothesis #5: Topiramate will result in a decrease in absolute headache days compared to placebo. Major Secondary Hypothesis #6: Topiramate will result in a decrease in absolute headache days compared to amitriptyline. Another major secondary objective of the CHAMP study is to determine if the change in absolute headache days from baseline to week-24 differs between treatment groups. This objective will be assessed using a linear regression model, adjusted for the baseline headache frequency and is stated here:,,,, where Y i represents the change in absolute headache days from baseline (i.e., the 28 day period prior to randomization) to the last 28 days of the 24-week follow-up for the i th subject. Positive values indicate a reduction in headache days over the course of treatment. X age,i is an indicator variable for the baseline age group for the i th subject (=0 if age 8-12, =1 if age 13-17) X bhf,i is the baseline number of headache days for the i th subject X AMI,i is an indicator variable for whether the i th subject was randomized to the AMI group X TPM,i is an indicator variable for whether the i th subject was randomized to the TPM group is random error for the i th subject Correspondingly, the three hypotheses of interest can be assessed by performing a hypothesis test of the three pair-wise treatment comparisons of interest: 11

227 AMI vs. Placebo: H 0,1 : β 3 = 0 vs. H A : β 3 0 TPM vs. Placebo: H 0,2 : β 4 = 0 vs. H A : β 4 0 AMI vs. TPM: H 0,3 : β 3 = β 4 vs. H A : β 3 β 4 These results will be displayed in the following table: Table 8.2.1: Absolute Change in Headache Days per 28 Day Period from Baseline to 24 Weeks Absolute Change in Headache Days (24 wk baseline) Mean (SD) Min. max. Missing AMI TPM Placebo Model Adjusted Difference (95% CI) xx.x (xx.x) xx xx xx xx.x (xx.x) xx xx xx xx.x (xx.x) xx xx xx AMI vs. PBO: xx.x (xx.x, xx.x) TPM vs. PBO: xx.x (xx.x, xx.x) AMI vs. TPM: xx.x (xx.x, xx.x) 8.3 Analysis of Tolerability Major Secondary Hypothesis #7: Amitriptyline and topiramate will be well tolerated. Concerns regarding tolerability will be defined as either having a percentage of subjects who complete the entire 24 week treatment period for the two active treatment arms that is significantly lower than the percentage for placebo subjects, or significantly less than 65%. To first assess tolerability, we will calculate 95% confidence intervals for the proportion of subjects that completed the 24-week treatment for each treatment group. In cases where the upper bound of the confidence interval is less than 65%, the treatment will be assumed to have tolerability issues. We will also compare the percent of subjects in the active treatment groups who complete the entire 24-week treatment period to the percent of subjects in the placebo group who complete treatment. The following hypothesis test will be performed. H 0 : P AMI = P TPM = P PBO vs. H A : there is at least one pairwise difference. Here P AMI represents the proportion of subjects in the AMI group who completed the entire 24-week treatment period, P TPM and P PBO represent this proportion in the TPM and placebo groups respectively. These data will be displayed in the following table: Table 8.3.1: Number and Percent of Subjects who Completed 24-week Treatment by Group Treatment Completed 24-week Group Treatment 95% CI Percent Completed 24-week Treatment N (%) AMI xxx (xx.x%) (xx.x xx.x%) TPM xxx (xx.x%) (xx.x xx.x%) Placebo xxx (xx.x%) (xx.x xx.x%) Table 8.3.2: Odds-ratios of 24-week Study Completion Comparison Odds-ratio (Adjusted% CI) AMI vs. Placebo TPM vs. Placebo AMI vs. TPM x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) x.xx (x.xx, x.xx) A chi-square test will be used to test the null hypothesis against the alternative. If we fail to reject H 0 then we will conclude that there is no difference in the percent of subjects completing the 24-month treatment between the treatment groups. If we reject H 0, then we will perform the following separate hypothesis tests. H 0 : P AMI = P PBO vs. H A : P AMI P PBO H 0 : P TPM = P PBO vs. H A : P TPM P PBO 12

228 If the first hypothesis is rejected, and P AMI is less than P PBO, then we will conclude that AMI was not tolerated as well as placebo. Similarly, if the second hypothesis is rejected and P TPM is less than P PBO, we will conclude that TPM was not tolerated as well as placebo. The use of a chi-square test in this analysis assumes there are no observed cell counts less than five and no expected cell counts less than one. If we find that either one of these conditions are not met, then we will use a Fishers exact test. 8.4 Analysis of Treatment Related SAEs Major Secondary Hypothesis #5: Amitriptyline and topiramate will not differ from placebo on the occurrence of treatment-emergent serious adverse events. We will also compare the occurrence of treatment-related SAE s across the three treatment groups. This will be assessed in two ways. First, the percentage of subjects who experience any treatment-related SAE in each of the three groups will be compared using Fishers exact test. The following set of hypothesis tests will be performed to determine if proportion of subjects with any treatment-related SAE differs across group: H 0 : P AMI = P PBO vs. H A : P AMI P PBO H 0 : P TPM = P PBO vs. H A : P TPM P PBO H 0 : P AMI = P TPM vs. H A : P AMI P TPM Here P AMI, P TPM, and P PBO represent the proportion of subjects in the AMI, TPM, and placebo groups, respectively, who had at least one treatment related SAE. If the first hypothesis is rejected, and P AMI is greater than P PBO, we will conclude that AMI was responsible for more treatment-emergent SAE s than placebo. Similarly, if the second hypothesis is rejected and P TPM is greater than P PBO, we will conclude that TPM was responsible for more treatment-emergent SAE s than placebo. If the third hypothesis is rejected, that would imply that there was a difference between the two treatment groups with respect to the risk of treatmentemergent SAE s. The group with the lower proportion would then be determined to be the safer of the two treatment groups. These hypotheses will be repeated for assessing treatment-related SAEs by system organ class and specific type of SAE based on a classification using MedDRA preferred terms. Additionally, the rates of treatment-related SAE s across the three groups will be compared using the following Poisson regression model: log /,,,, where Y i represents the number of treatment related SAEs experienced by the i th subject. T i represents the number of the number of days between the date of randomization and the date of last follow-up for the i th subject. X age,i is an indicator variable for the baseline age group for the i th subject (=0 if age 8-12, =1 if age 13-17) X headache,i is an indicator variable for the baseline number of headaches per month for the i th subject (=0 if 4-14, =1 if 15 or more) X AMI,i is an indicator variable for whether the i th subject was randomized to the AMI group X TPM,i is an indicator variable for whether the i th subject was randomized to the TPM group is random error for the i th subject To determine if the rate of treatment related SAEs differ across group we will perform the following tests: H 0 : β 3 = 0 vs. H A : β 3 0 H 0 : β 4 = 0 vs. H A : β 4 0 H 0 : β 3 = β 4 vs. H A : β 3 β 4 13

229 8.5 Additional Secondary Analyses A number of additional secondary analyses are planned, but will not be included as part of the FSR. These additional secondary analyses include, but are not limited to: A comparison of the percentage of subjects in each group that achieve a 50% reduction in migraine frequency (defined as a migraine day). Two approaches will be considered to classify a headache as a migraine. o On the headache diary, the participant notes if a headache occurred as well as if they perceive the headache as a migraine. This data will be used to compare perceived migraines. o We will also employ International Classification of Headache Disorders, 3 rd Edition (beta) to review the diary pages for those headaches for which we have headache features and associated symptoms reported. The ICHD-3, beta will be matched to each headache episode reported, and this will yield a calculated (versus patient reported) migraine frequency. A comparison of absolute reduction in migraine frequency across treatment group (calculated for perceived migraine days and ICHD calculated migraine days) Improvement in the PedMIDAS Grade Score (Hershey et al, 2001), classified using a grading scale with values ranging from I (best) to IV (worst). For the purposes of our analysis, improvement will be defined as an improvement of 2 units or more from baseline or a reported score of I at the end of treatment. The percentage of subjects with improvement in each of the three treatment groups will be compared Comparison of patient satisfaction scores among subjects within each treatment group Compare improvement in migraine-associated symptoms (nausea, vomiting, photophobia, phonophobia) across the three treatment groups 9. DECISION ALGORITHM FOR FINAL RECOMMENDATION The main objective of this project is to empirically determine the best choice prevention medication for current practice. In order to achieve this objective, we will use an a priori decision making process that incorporates the novel data that will result from this 3 trials in one project. We propose a tiered approach for using the results of the analyses from this trial to pick a winner among the three therapies tested. The first tier is based upon our primary endpoint, 50% or greater reduction rate for headache frequency (days) between the four weeks prior to baseline and the final four weeks of treatment. This endpoint is the most relevant to current practitioners and is recommended as the key variable for migraine prevention medication trials by the International Headache Society (IHS; Tfelt-Hansen et al, 2000). In our plan, there are four possible practice recommendations: 1) TPM first choice because it is superior to placebo and AMI on primary outcome 2) AMI first choice because it is superior to placebo and TPM on primary outcome 3) Both therapies first choice because both are superior to placebo but were not different on primary outcome 4) Neither therapy first choice because neither are superior to placebo If scenario (3) occurs, and a recommendation cannot be made based upon the primary endpoint, we would need to go to a tie breaker, and we will utilize tier 2, our secondary endpoint of headache-related disability. If one medication is superior to the other on this variable, it is the winner. If not, we would go to tier 3, tolerability. If one medication was better tolerated than the other, it would be the winner. Problems with tolerability would be defined as having percentage of subjects that do not complete treatment per study protocol greater than 35%, or a rate of subjects not completing the study that is statistically worse than the other therapy. If a winner cannot be identified based upon tier 3 criteria, then the outcome of the trial would be that both therapies are efficacious and it would be individualized clinical decisions based upon subject presentation that would guide first choice in practice. Of course, recommendations will also take into account the safety data generated by this novel study. 14

230 10. SAMPLE SIZE CONSIDERATIONS Primary Hypotheses 1, 2, & 3 In order to properly determine the required sample size for the proposed trial, the CCC investigators completed a review of the limited literature pertaining to pediatric headache research. This review revealed four applicable studies. Three of these studies evaluated TPM versus placebo (Winner et al, 2005; Lakshmi et al, 2007; Lewis et al, 2009), and one study examined AMI in a clinical database (Hershey et al, 2000). Based on this review, estimates of the proportion of subjects in each study group that will meet the primary endpoint of a 50% or greater reduction in headache frequency (days) can be made. Table demonstrates the percentage of subjects in existing pediatric headache prevention medication trials who achieve the primary endpoint of 50% or greater reduction in headache frequency. Table Percentage of patients in existing pediatric headache prevention medication trials who achieve the primary endpoint of 50% or greater reduction in headache frequency. Reference PBO Response Rate TPM Response Rate Winner et al, % 54% Lakshmi et al, % 95% Lewis et al, % 83% The table shows an average response rate between 45% and 52% for the placebo group. There is generally more variability regarding the percentage of subjects on TPM who achieve the primary endpoint. The average percentage of subjects achieving the primary endpoint is 77% in the TPM group, but the effect ranges from 54% to 95% across the studies. Finally, a database from a prior study conducted at the CCC suggests that 70% of subjects taking AMI will achieve a 50% or greater reduction in headache frequency (Hershey et al, 2000). Of note, the Lakshmi sample and CCC database include representation from children with <15 and 15 headaches per month. For sample size estimation in this trial, it is critically important to keep in mind that this study essentially provides three trials in one. Hence, the chosen sample size must allow adequate power for testing all three primary hypotheses of interest. For the two comparisons with placebo, the results of our NINDS Clinical Research Collaboration survey demonstrated that the majority of responders felt that a minimum absolute increase of 20% in the percentage of subjects achieving a 50% or greater reduction in headache frequency was clinically meaningful and the threshold needed for the results of a placebo-controlled trial to change practice. Hence, the sample size has been chosen to ensure adequate power assuming that 50% of those on placebo versus 70% of those in each of the treatment groups will achieve a 50% or greater reduction in headache frequency during the final 4 week endpoint evaluation of the 24-week treatment period. Clearly, smaller differences are important for the head-to-head comparison and it becomes much more difficult to define a minimum clinically meaningful effect (since one could argue that, assuming equal cost and safety profiles, any difference between two active treatments is clinically meaningful). As shown in Table there is some preliminary evidence that suggests more than 85% of patients in the TPM group may achieve the primary endpoint of 50% reduction in headache frequency. Thus, the study is powered to detect an absolute difference of 15% or greater in the percentage of subjects achieving a 50% reduction in headache frequency for the head-to-head comparison. As stated above, since there are three primary hypotheses, a Bonferroni correction will be applied with a plan to test each hypothesis at the level. Based on the drop-out rate observed in the Lewis et al. study (2009), we assume a 15% dropout rate. Under these assumptions, enrolling a total of 675 subjects (135 placebo, 270 AMI, and 270 TPM) provides: At least 85% power to detect all treatment/placebo comparisons 90% power to detect a head-to-head difference of 70% of those on AMI vs. 85% of those on TPM will achieve a greater than 50% or greater reduction in headache frequency This demonstrates that the study has adequate power to assess each primary hypothesis of interest. However, since the main objective of the study is to provide a recommendation to clinical investigators regarding the best treatment for children with headache, the actual power of the study may be thought of as making a correct and generalizable decision using the proposed decision algorithm. 15

231 To assess the ability of the trial to meet this goal, a series of simulation studies were conducted. Each simulation consisted of 10,000 replications for each of 64 conditions defined by all possible combinations of plausible values for the true response rates in the three treatment groups: placebo {40%, 45%, 50%, 55%}, AMI {50%, 60%, 70%, 80%}, and TPM {50%, 70%, 85%, 95%}. For each simulated condition, one of four possible decisions was reached: (1) AMI recommended first-line therapy, (2) TPM recommended first-line therapy, (3) both AMI and TPM are recommended as first-line therapy use secondary endpoints to decide between the two, and (4) neither can be recommended as first-line therapy. Table summarizes a few key conditions involved in the simulation. Table : Probability of picking any winner and picking correct winner as a function of treatment response rate. Assumes type I error rate of 0.017, sample size of 135 in placebo group and 270 in AMI and TPM groups. PBO Rate AMI Rate TPM Rate Decision 16 Prob. of Picking Winner Prob. of Picking Correct Winner* AMI Better TPM Better Both None 50% 50% 50% 1% 1% 0% 98% 3% 97% 50% 60% 70% 0% 71% 20% 9% 91% 91% 50% 70% 85% 0% 94% 6% 0% 100% 100% *If a single drug is best, the correct winner is thought to be selected if the final decision is for either that drug or both drugs. The first row in Table demonstrates that the approach maintains the type I error level at or below the desired level of The last two rows demonstrate the advantages of the overall three-in-one approach for selecting a winner. The last row, corresponding to the specific conditions used to justify the same size for the primary hypotheses, demonstrates that the overall approach provides benefits above and beyond what can be achieved with the separate hypotheses. As the table demonstrates, if this set of conditions holds true, our study would have nearly 100% power to correctly select TPM as the appropriate first-line treatment for children with migraine. The second row demonstrates that the combined approach provides a greater likelihood of correctly selecting the winner when the absolute difference between the favorable response rates for AMI and TPM is only 10%. Under these conditions, our study would have 91% power to correctly select TPM as first-line treatment - a substantial improvement over the 44% power for the individual head-to-head comparison. The conclusions obtained from the simulations are only strengthened by the fact that this only examines the first tier of the decision algorithm. If the disability and tolerability trends parallel those of the primary endpoint, this should only increase the overall probability of selecting the correct winner at the end of the trial Major Secondary Hypotheses 1, 2, and 3 For major secondary hypotheses 1-3, it has been shown that the disability assessment (via PedMIDAS) is more sensitive to change than headache frequency (Hershey et al, 2009b; Lewis et al, 2009; Hershey, 2010). For this reason, the sample size chosen above to assure adequate power for the comparison of headache frequency should also provide sufficient power for the comparison of headache-related disability. For the active treatment versus placebo comparisons, our study has 85% power to detect effect sizes of 0.33, corresponding to a small to moderate effect size using the Cohen Classification. For example, Lakshmi et al (2007) showed a statistically significant difference in the reduction in the PedMIDAS score for pediatric subjects taking TPM versus placebo. The PedMIDAS score for subjects taking TPM was reduced from 50.7 ± 32.1 at baseline to 10.4 ± 6.4 at the end of the 12 week treatment period. The PedMIDAS score for subjects on placebo was reduced from 42.7 ± 27.5 at baseline to 23.7 ± 19.1 at the end of the treatment period. Because the population in the proposed study is thought to be similar, we conservatively assume that the baseline score will be approximately 40 for these subjects. We also assume that the PedMIDAS score will be reduced to 20 in the placebo group and to 10 in each of the active treatment groups by the end of the study. Under these assumptions, the proposed study has greater than 85% power to detect such differences as long as the standard deviation of the change from baseline is less than or equal to 30. For the head-to-head comparison of AMI versus TPM, our study has 80% power to detect effect sizes of 0.25 on the Cohen scale. Hence, the proposed study has greater than 85% power to detect a difference of 5 in the change from baseline, as long as the standard deviation of the change from baseline is less than or equal to 20.

232 10.3. Major Secondary Hypotheses 4, 5, and 6 For major secondary hypotheses 4 & 5, we computed a detectable effect given the proposed study sample size for a comparison of active and placebo treatment groups with respect to change in absolute headache days per 28 day period. One complication to that calculation is the need to specify an assumed standard deviation for the change in absolute headache days over time. For TPM, a recent meta-analysis for episodic migraine suggested that a reduction of 2-3 headache days with a standard deviation of 3 was fairly consistent (El-Chammas et al, 2013). The one published chronic migraine trial reported a larger change and standard deviation (Schwedt, in press). For AMI, there is much less data. In a recent assessment of AMI plus weekly education sessions, Powers et al. (2013) observed a mean reduction of 6.8 +/- 8.5 headache days (from /- 5.2 at baseline to /- 9.8 at 20 weeks). However, the mean number of baseline headaches in that study is a bit larger than the expected mean number of baseline headaches in the CHAMP study. If so, this would be expected to lead to a lower standard deviation for the change in headache frequency over time in the CHAMP study. Taken together, these data suggest a typical standard deviation of around 3 for episodic migraine and 4-8 for chronic migraine. Thus, we feel that it is reasonable to expect a standard deviation in the range of 6 for the CHAMP study. Correspondingly, we then computed the detectable effect based on the assumed standard deviation of 6, a desired level of 80% target power, and a significance level of (0.05/3 same as primary analysis, adjusting for three comparisons of interest). Based on these assumptions, the study is adequately powered to detect a difference in mean absolute reduction of 2.3 headache days for the treatment/placebo comparisons. Given that we expect 70% of treated subjects enrolled in this study to have a >=50% reduction in headache days, we believe that an assumed mean absolute headache reduction of 6-8 headache days seems reasonable for this group. Since we expect about half of our placebo group to achieve a >=50% reduction in headache days, an assumed mean absolute headache reduction of 3-5 headaches seems reasonable for the placebo group. Taken together, this seems to suggest that a reasonable assumption for the mean difference in the reduction over the course of the study for the treatment versus placebo groups is 2-5 headache days. Thus, with a detectable effect of 2.3 headache days, the study is adequately powered to detect changes in the reduction of absolute headache days across the treatment and placebo groups. For comparing the AMI and TPM groups, the study is adequately powered to detect a difference in mean absolute reduction of 1.9 headache days. Using the same assumptions that we considered for the primary power calculations, a 70% success rate in the AMI group and an 85% success rate in the TPM group, we would expect to see mean absolute headache reductions of 6-8 headache days and 8-10 headache days in the AMI and TPM groups, respectively. This suggests that a range of reduction in the magnitude of 1-3 headache days over the treatment period seems appropriate for the head-to-head comparison. With a detectable effect of 1.9 headache days, the study is adequately powered to detect differences in the middle to upper end of this expected range of differences. The power is much less on the lower end of the expected range of differences 27% for a difference of 1 headache day, and 61% for a difference of 1.5 headache days. Thus, we have reasonable power to detect moderate to large differences in change in absolute headache frequency between the AMI and TPM groups Major Secondary Hypothesis 7 Lewis et al. (2009) reported a 20% rate of placebo subjects not tolerating the medication. As detailed above, tolerability concerns will arise if more than 35% of subjects have to discontinue medication during the study (i.e., less than 65% tolerate the medication). With a sample size of 135 in the placebo group, 270 each in the two active treatment groups, and an assumed placebo tolerability rate of 80%, the study has 85% power to detect an absolute decrease of 15% or greater in the percentage of subjects who tolerate the treatment. Importantly, this assures that we have adequate power to detect increases if the rate of subjects who do not tolerate either of the active treatments is 35% or greater, which is the level of tolerability that is a priori thought to cause concerns in the decision algorithm Major Secondary Hypothesis 8 Because this is not a safety study, and the medications under study are currently widely used in the field, the trial was not powered to detect small differences in the safety profiles between the treatments and placebo. Nevertheless, the study will have adequate power to detect large differences that would dramatically affect the 17

233 choice of medication for future subjects. With a sample size of 135 in the placebo group, 270 each in the two active treatment groups, and assuming that adverse events will occur in 2% to 5% of the subjects in the placebo group, the study has at least 80% power to detect an absolute increase of 10% in the percentage of subjects who experience an adverse event. More importantly, this study will provide important information that will add to the totality of evidence regarding safety. When combined with the specified decision algorithm, this information will help to shape the final recommendations at the conclusion of this study. 11. SAFETY MONITORING Adverse Experience Reporting All AEs experience by participants during the study time frame specified in the protocol must be reported. All AE s, whether uncovered by spontaneous reporting or the structured AE interview, will be reported as quickly as possible by the clinical site. To help with this process, all AEs are collected, analyzed, and monitored using an innovative Online Adverse Event Reporting system. This system allows the site to enter data electronically for all adverse events. If a site initiates but does no submit a serious adverse event form within 24 hours of notification, an automatic notifies the DCC staff so that follow-up may occur. At the time each AE/SAE is entered into the system, the study investigator will make a determination regarding the relatedness to therapy and severity. All AE s and SAE s are coded using the MedDRA system in conjunction with a double coding system internal to the DCC Medical Safety Monitor Dr. David Dodick will serve as the independent medical monitor for this trial. Dr. Dodick will work closely with the DCC, and will use the online AE reporting system to review all reported SAEs in near real time and evaluate them to identify the need for timely intervention. For any reported SAEs, an automatic will be sent to Dr. Dodick to prompt a review of the event for determination of whether the event is unanticipated and related to study drug and thus requires expedited reporting to the FDA. If deemed expedited, a MedWatch form is created electronically and submitted to the FDA. With the assistance of the coordinators at the DCC, Dr. Dodick has the option of requesting additional information about any SAE. He will complete a form for each review and this information will be entered into the data entry system. He may become unblinded upon request to the DCC based upon the results of any of his activities. He will also receive blinded (A, B, C) monthly tabulations of all AE s/sae s on a quarterly basis for the purpose of determining if any safety trends exist that may require a more frequent review by the DSMB. Safety will be assessed in two ways both the percentage of subjects who experience any AE and the rate of AE s across the three groups will be compared, by body system, using a Fisher s exact test. The additional questions related to whether the AE/SAE is related to treatment, is unanticipated, or is severe will be used to subset these into a series of additional tables. This quarterly review will identify any disconcerting discrepancy in the frequency of an AE/SAE between the treatment groups, with particular emphasis placed on the four AE s of most concern to practicing clinicians due to the known side effect profiles of these two treatments: (1) depression, (2) suicidal ideation, (3) fatigue, and (4) slow thinking or problems with attention. Should any discrepancy arise, or if the medical monitor feels that an SAE should be shared on an emergency basis with the participating clinical sites, he will contact the DSMB to request a special review. Data obtained using psychometrically-sound measures of depression, attention, and cognitive functioning from the current NINDS Common Data Elements will also be available for each subject in this trial at baseline, end of drug titration (Visit 5 - Week 8), and end of maintenance (Visit 8 - Week 24). To further understand the impact of the study medications on these important outcomes beyond our prospective AE monitoring approach, each quarterly report will also include a comparison of the following across the treatment groups: Mean total score from the Child Depression Inventory (CDI) Percentage of subjects with total CDI score > 80 Frequency of subjects that answer yes to intent and ideation on question #9 from the CDI Behavior Rating Inventory of Executive Function (BRIEF) global executive composite score Summary of ECG readings (at baseline and Visit 5 only) 18

234 Dr. Dodick will also actively interact with the Data and Safety Monitoring Board (DSMB) and will inform the DSMB of any particular concerns that may require the urgent attention of the group. This will be coordinated by the DCC and balanced by review of the DSMB Data and Safety Monitoring Board An NIH-appointed Data and Safety Monitoring Board (DSMB) is charged with the task of providing regular oversight of the data and safety monitoring issues as detailed in the document:, NINDS Guidelines for Data and Safety Monitoring in Clinical Trials. These experts will periodically review and evaluate the accumulated data for participant safety, adverse events, study conduct, and study progress. The DSMB will make recommendations to NINDS concerning continuation, modification, or termination of the study. The Data Coordinating Center (DCC) will prepare regular reports for the DSMB to review at each meeting. These reports will include overall summaries, as well as AE & SAE summaries by treatment group in a blinded fashion. These reports will include a summary of the following topics: Performance Monitoring: Subject recruitment, comparison with targeted recruitment, retention, protocol adherence, and quality of data collection procedures. Treatment Monitoring: Data on treatment integrity and adherence. Safety Monitoring: Data related to the safety of the subjects, including confidentiality, any adverse events or side effects related to the treatment. Efficacy monitoring: Two interim efficacy analyses are to be performed when 225 and 450 of the subjects have completed their primary endpoint. Futility monitoring: Futility will be assessed at the time of each interim analysis. At the time of each DSMB meeting, a DSMB closed session report will include all available data to allow the DSMB to monitor for trends. These unblinded reports will also include a memo from the Safety Monitor to allow the communication of any concerns or findings that may be of interest to the DSMB in their study deliberations. In general, interim safety monitoring will rely on these interim reviews to identify any potential trends of interest. However, due to the increased concern associated with the risk of suicidal ideation, we propose a more stringent guideline to trigger a concern for this variable. If the difference in the incidence in suicidal ideation between either active treatment and placebo becomes statistically significant at the 0.05 level at any of the interim reviews, the DSMB will determine whether the trial should discontinue the affected treatment arm. 12. INTERIM ANALYSES The interim monitoring plan for this study must take into account the complex nature of the proposed project, i.e., the fact that this is really three separate trials in one. As a result, the proposed interim monitoring plan is based on the following premises: 1) The placebo arm will only be dropped if both active treatments are proven superior to placebo during the course of the study 2) The head-to-head comparison will be stopped early only if both active treatments have been proven superior to placebo during the course of the study With these premises in mind, we describe the interim monitoring plan below Interim Efficacy Analysis Two interim efficacy assessments will occur when 225 and 450 subjects have completed their 24 week visit. For these interim analyses, the Lan-DeMets alpha spending function approach with O Brien-Fleming stopping boundaries will be used. Table 12.1 below illustrates the proposed stopping boundaries under the assumption of three equally spaced analyses (two interim analyses and the planned final analysis). However, the Lan- DeMets method allows for analyses at unequal intervals and does not require pre-specifying the time of any interim analyses. Therefore, the proposed method has the flexibility to adapt should the DSMB request an interim analysis at an alternative time-point or if the DSMB is unavailable at the time of a scheduled interim 19

235 analysis. Importantly, the placebo arm will be dropped only if both active treatments cross the stopping boundary at one of the pre-specified interim assessments. If only one crosses the boundary at the first look, both will be assessed again at the second look and the placebo arm dropped only if both cross the bound during the second review. Table O Brien-Fleming Stopping Boundaries Assuming Three Equally Spaced Analyses. Efficacy analysis Number of Subjects Completing 24 Week Follow-Up Nominal P-Value to Conclude Efficacy < Futility Assessment Futility monitoring will be performed at each interim analysis. Due to the complex nature of the study, and the fact that definitive evidence would be required if neither of the active treatments proved superior to placebo, we propose that the trial should only be stopped for futility if both treatments were simultaneously futile (which has an exceptionally low probability). At the time of each interim analysis, we will report the conditional power based on the pre-specified effect of interest (Lan, Simon, & Halperin, 1982). If both conditional power values fall below 20%, we would recommend stopping the trial early for futility. 13. REFERENCES El-Chammas K, Keyes J, Thompson N, Vijayakumar J, Becher D, and Jackson JL (2013). Pharmacologic treatment of pediatric headaches: A meta-analysis. JAMA Pediatrics 167(3): Hershey AD (2010). Current approaches to the diagnosis and management of paediatric migraine. Lancet Neurology 9(2): Hershey A, Powers S, Bennti A, and Degrauw T. (2000). Effectiveness of amitriptyline in the prophylactic management of childhood headaches. Headache(40), Hershey AD, Powers SW, Vockell AL, LeCates S, Kabbouche MA, and Maynard MK (2001). PedMIDAS: Development of a questionnaire to assess disability of migraine in children. Neurology 57(11): Hershey A, Powers S, Winner P, & Kabbouche M (2009a). Pediatric Headaches in Clinical Practice. West Sussex, UK: John Wiley & Sons, Ltd. Hershey AD, Powers SW, Nelson TD, Kabbouche MA, Winner P, Yonker M, Linder SL, Bicknese A, Sowel MK, and McClintock W (2009b). Obesity in the pediatric headache population: A multicenter study. Headache (49): Kovacs M (1981). Rating scales to assess depression in school-age children. Acta Paedopsychiatr 46: Kovacs M (1992). Children s Depression Inventory. North Tonawanda, NY: Multi-Health System. Lakshmi C, Singhi P, Malhi P, and Ray M (2007). Topiramate in the prophylaxis of pediatric migraine: A double-blind placebo controlled trial. Journal of Child Neurology (22): Lan KK, Simon R, and Halperin (1982). Stochastically curtailed tests in long-term clinical trials theory. Communications in Statistics, Little RJ and Rubin DB (2002). Statistical Analysis with Missing Data. Hoboken, New Jersey: John Wiley & Sons, Inc. Lewis D, Winner P, Saper J, Ness S, Polverejan E, Wang S, Kurland CL, Nye J, Yuen E, Eerdekens M, and Ford L (2009). Randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of topiramate for migraine prevention in pediatric subjects 12 to 17 years of age. Pediatrics 123:

236 Powers SW, Kashikar-Zuck SM, Allen JR, LeCates SL, Slater SK, Zafar M, Kabbouche MA, O Brien HL, Shenk CE, Rausch JR, and Hershey AD (2013). Cognitive behavioral therapy plus amitriptyline for chronic migraine in children and adolescents: A randomized clinical trial. JAMA 310(24): Schwedt TJ. Chronic migraine. BMJ, in press. Tfelt-Hansen P, Block G, Dahlof C, Diener HC, Ferrari MD, Goadsby PJ, Guidetti V, Jones B, Lipton RB, Massiou H, Meinert C, Sandrini G, Steiner T, and Winter PB (2000). Guidelines for controlled trials of drugs in migraine: Second edition. Cephalagia 20: Winner P, Pearlman EM, Linder SL, Jordan DM, Fisher AC, and Hulihan J (2005). Topiramate for migraine prevention in children: A randomized, double-blind, placebo-controlled trial. Headache 45(10):

237 The Childhood and Adolescent Migraine Prevention (CHAMP) Study STATISTICAL ANALYSIS PLAN Principal Investigators Andrew D. Hershey, MD, PhD, FAHS Scott W. Powers, PhD, ABPP, FAHS Study Statisticians Christopher S. Coffey, PhD Jon Yankey, MS Elizabeth Klingner, MS Supported By: National Institute of Neurological Disorders and Stroke (NINDS) Grant Numbers: U01NS (Cincinnati Children s) U01NS (U. Iowa) Investigational Drug Application (IND) Holder: Andrew D. Hershey, MD, PhD, FAHS IND # 112,220 VERSION 2.2 September 02, 2016