6/2/2017. CHAMP Trial: Design, Outcomes, Context, and Lessons Learned. Disclosures. Outline

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1 CHAMP Trial: Design, Outcomes, Context, and Lessons Learned Andrew D. Hershey, MD, PhD. FAHS Endowed Chair and Director of Neurology Co-Director, Headache Center Cincinnati Children s Hospital Medical Center Professor of Pediatrics and Neurology University of Cincinnati, College of Medicine Disclosures Support grants, contracts, honoraria NIH, CHRF research foundation, Curelator American Headache Society Board Member NIH Advisory Board, Common Data Elements Migraine Research Foundation Advisory Board Assoc Ed Headache, Cephalalgia, The Journal of Headache Pain Advisory Board Amgen, Curelator, Depomed, Impax, Lilly, Teva Outline Why - Background for development of CHAMP Who Clinical Coordinating, Data Coordinating, Sites How - Protocol development What Baseline Results Study Results Where do we go from here Implications on treatment Implications from other studies 1

2 Why Migraine Migraine prevalence 4 % of young children Up to 10.5% of children age 5-15 Up to 28% age Adults 12% (17.1% women, 5.6% men) Migraine pathophysiology Migraine as a genetic disease Early intervention may have lifetime implications Migraine Impact Up to 200,000 lost school days in US $17 billion (1998) direct and $17 billion indirect cost Individual cost (2006) Direct $127 to $7089 Indirect $709 to $4453 Chronic Mig vs Episodic Mig (2016) CM Direct ($4943), Indirect ($3300) EM Direct ($1705), Indirect ($943) Pharma CM ($3925), EM ($1196) Potential progression to refractory headaches if not treated Why Migraine Global Burden of Disease GBD 2015 Disease and Injury Incidence and Prevalence Collaborators, Lancet, Oct 8, 2016 Gaps in Prevention Termiine et al, J Headache Pain, 2011 Very limited number of studies in pediatric and adolescent headaches Translation from adults studies may be problematic Are they really generalizable Prevention does not only mean medication 2

3 Gap Identification Survey given to Pediatric-Adolescent Section Assessed current status of prevention Asked what is Clinically meaningful What they are currently using Sample questions #3 Meds used AMI, Cypro, VPA, Prop, TPM, Other #4 Dose of this medication #5 How long to tell if work #6 Effectiveness level >50% reduction HF <1/week >50% reduction in disability Ease of admin Cost Other #7 % reduction that would impact practice Gap Identification 6 6 Ranked Most important Prevention clinical effectivenes - 1 to 6 Sample questions 5 5 #3 Meds used 4 AMI, Cypro, VPA, Prop, TPM, Other 4 #4 Dose of this medication 3 #5 How long to tell if work 3 #6 Effectiveness level 2 >50% reduction HF 2 <1/week 1 >50% reduction in disability 1 Ease of admin 0 6a. 50% or > 6b. Headache 6c. Low incidence 6d. 50 % or > 6e. Ease of 6f. Cost of the 6g. Other criteria reduction in frequency of side effects reduction in administration of medicine 1 Cost 0headache reduced to < 1 headache the medicine frequency 3a. per week 3b. 3c. Depakote disability3d. Propanalol 3e. Topiramate 3f. Other 1 Other Amitriptyline Cyproheptadine #7 % reduction that would impact practice Why Children and Adolescents are impacted by migraine There are significant gaps Who How What Where 3

4 Cincinnati Children s Headache Center Established in Oct 1996 collaboration between neurology and psychology Combined Clinical and Research Program on Pediatric Headache Local, Regional, National and International referral patterns Over 700 different Zip Codes 23 different states Patients from North America, South America and Central America, Asia 11 A CCHMC partnership (Headache Center; Behavioral Medicine; Neurology; Office for Clinical and Translational Research) A inter-institution collaboration (CCHMC Clinical Coordinating Center & University of Iowa - Data Coordinating Center) A national effort (involving over 40 sites) 4

5 CHAMP Study Staff Principal Investigators Andrew Hershey, MD, PhD, FAHS Scott Powers, PhD, ABPP, FAHS Christopher Coffey, PhD Study Leadership Team Linda Porter, MD, NINDS Project Manager David Dodick, MD, Medical Safety Monitor Leigh Ann Chamberlin, CCC Project Manager Dixie Ecklund, DCC Project Manager Leslie Korbee, CCC Regulatory Manager M. Kabbouche, MD, J. Kacperski, MD, H.L. O Brien, MD, Cincinnati Children s Hospital Medical Center, Cincinnati, OH*; J. Aceves, MD, Scott and White Healthcare, Temple, TX*; D. Arun, MD, Saint Louis University, St. Louis, MO*; V. Atluru, MD, Winthrop University Hospital, Mineola, NY*; S. Aurora, MD, Stanford Hospitals and Clinics, Palo Alto, CA*; N. Bennett, MD, Preferred Clinical Research, Pittsburgh, PA*; F. Berenson MD, Atlanta Headache Specialists, Atlanta, GA*; J. Bickel, MD, Children s Mercy Hospital, Kansas City, MO*; R. Bjork, MD, Colorado Springs Neurological Associates, Colorado Springs, CO*; H. Blume, MD, Seattle Children s Hospital, Seattle, WA*; J. Cohen, MD, The Headache Institute at Roosevelt Hospital, New York, NY; D. Chrusciel, MD, Oklahoma Health Sciences, Oklahoma City, OK*; M. DiSabella, DO, Children s National Medical Center, Washington, DC; L. Matthew Frank, MD, Eastern Virginia Medical School, Norfolk, VA*; A. Gelfand, MD, P. Goadsby, MD, University of California-San Francisco Headache Center, San Francisco, CA*; H. Jacobs, MD, University of Maryland School of Medicine, Baltimore, MD*; S. Kedia, MD, Children s Hospital Colorado, Aurora, CO*; L. Kerr, MD, Primary Children s Medical Center, Salt Lake City, UT*; A. LeBel, MD, Boston Children s Hospital, Waltham, MA*; D. Lebron, MD, LeBonheur Children s Hospital, Memphis, TN*; S. Linder, MD, David B. Owen, MD, Dallas Pediatric Neurology Associates, Dallas, TX*; K. Mack, MD, Mayo Clinic, Rochester, MN; H. Markley, MD, New England Regional Headache Center, Worcester, MA*; J. McVige, MD, Dent Neurological Institute, Amherst, NY*;H. Murali, MD, Marshfield Clinic, Marshfield, WI*; A. Pakalnis, MD, Nationwide Children s Hospital, Columbus, OH*; E. Pearlman, MD, Children s Hospital at Memorial University Medical Center, Savannah, GA; K. Ridel, MD, Josephson Wallack Munshower Neurology Research, Indianapolis, IN*; D. Rothner, MD, The Children s Hospital, The Cleveland Clinic, Cleveland, OH*; J. Rothrock, MD, J. Lopez, MD, Renown Neuroscience Institute, University of Nevada, Reno School of Medicine, Reno, Nevada*; R. Simmons, MD, Schenectady Neurological Consultants, Schenectady, NY*; M. Sowell, MD, University of Louisville Health Sciences Center, Louisville, KY*; C. Szperka, MD, Children s Hospital of Philadelphia, Philadelphia, PA; M. Victorio, MD, Akron Children s Hospital, Akron, OH*; P. Winner, DO, Premiere Research Institute, West Palm Beach, FL*; M. Yonker, MD, Phoenix Children s Medical Group, Phoenix, AZ*. *denotes sites that enrolled a participant. 5

6 Why Children and Adolescents are impacted by migraine There are significant gaps Who Cincinnati Children s, Univ of Iowa, NIH NINDS and NICHD, all of our sites. How What Where Childhood and Adolescent Migraine Prevention Study A 40-site Randomized Clinical Trial U01 NS ( ) CHAMP Study Goals Outcome for Aims 1-3 reduction in migraine frequency and disability Aim 1: Determine if amitriptyline (AMI) is superior to placebo Aim 2: Determine if topiramate (TPM) is superior to placebo Aim 3: Determine superiority for AMI vs TPM Aim 4: To prospectively and systematically determine the safety and tolerability profiles of AMI, TPM and placebo 6

7 Study Design Real World Approach Subjects to reflect patients seen in typical headache, neurological and pediatric practice Subjects are children and adolescents, ages 8 to 17 years old Consistent headache frequency that indicates need for prophylaxis (>4 headaches per month) Standardized dosing of most commonly used preventative medication AMI 1 mg/kg/day TPM 2 mg/kg/day 19 Study Design Primary and Secondary Outcomes Greater than 50% reduction in migraine frequency Absolute reduction in monthly migraine frequency Reduction in migraine disability Tolerability of drug therapies 20 Inclusion Criteria 1. Diagnosis: Migraine with or without aura (International Classification of Headache Disorders, 2nd Edition (ICHD-II) or chronic migraine (ICHD-II revised.) 2. 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* * 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. 3. 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 4. Age: Females or males 8-17 years, inclusive 21 7

8 Exclusion Criteria (1) 1. Continuousmigraine definedas an unrelentingheadache for a 28 day period 2. Weight lessthan 30kg or greaterthan 120 kg 3. Unwilling to avoid taking non-specific acute medicationsuch as NSAIDS (e.g., ibuprofen), more than 3 times per week, or migraine specific acute medicationssuch as triptansmore than 6 timespermonth 4. 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 enteringthe screeningphase 5. Subjects who have previously failed an adequate trial of AMI or TPM for prophylaxis of at least 3 months durationat dosesrecommendedfor migraine reliefbecause of lack of efficacy or adverseevents* 6. Current use of disallowed medications/products: opioids, antipsychotics, antimanics, barbiturates, benzodiazepines,musclerelaxants, sedatives,tramadol, nutraceuticals, SSRIs, or SSNRIs 22 Exclusion Criteria (2) 7. Knownhistoryof allergicreactionor anaphylaxisto AMI or TPM 8. Abnormal findingsonecgatbaseline,particularlylengtheningoftheqtintervalgreaterthanorequalto440msec 9. Subjectispregnantor has a positivepregnancytest 10. Subjectissexuallyactiveandnotusingamedicallyacceptableform ofcontraception 11. Diagnosisofepilepsyor otherneurologicaldiseases. 12. History of kidneystones 13. Inabilitytoswallowpillsafter usingbehavioraltechniquesifindicatedbetweenscreeningvisitandbaselinevisit** 14. Present psychiatric disease as defined by the Diagnostic and Statistical Manual of Mental Disorders, 4th 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 opinionofthesiteinvestigator,wouldinterferewithadherencetostudyrequirementsor safeparticipationinthetrial 15. Any and all other diagnoses or conditions which in the opinion of the site investigator, that would prevent the patient frombeingasuitablecandidatefor thestudyorinterferewiththe medicalcareneedsofthestudysubject 23 Subject Selection 675 subjects Migraine without or with aura by ICHD-II Frequency allows Episodic (>4 headaches per month) Chronic (>14 headaches per month) Continuous disallowed Ages 8-17 years Up to 40 research sites across the USA 24 8

9 Study Design Flow of Events 25 Titration Methodology Dosage increases at 2 week intervals For standard titration, final dose starts at week 8 Modification allowed for tolerability Options Hold dose (no maximum number) Decrease dose (allowed once) Resume titration as tolerated If modification occurs, final dose starts at week Titration Methodology Dosage Titration Plan 6 7 Terminate from Study Dispense Study Drug Potential Dispense of Study Drug weeks +2 Weeks +4 Weeks +6 Weeks +8 Weeks +10 Weeks +12 Weeks Visit 2 Phone Visit Visit 3 Phone Visit Visit 4 Delayed Visit 4 Visit

10 Definitions Headache Frequency Headache Day any headache in 24 hour period midnight to midnight Headache Episode any headache, start to headache free Migraine Day any headache with ICHD Migraine characteristics in 24 hour period Migraine Episode any migraine from start to headache free Primary Outcome 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 29 Secondary Outcomes 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) Safety and 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) 30 10

11 Simulation Odds of significant result Why Children and Adolescents are impacted by migraine There are significant gaps Who and Where Cincinnati Children s, Univ of Iowa, NIH NINDS and NICHD, all of our sites. How NIH sponsored, U01 Multi-site study Childhood and Adolescent Migraine Prevention Study - CHAMP What Where Baseline Results Protocol - Powers, et al, Headache

12 CHAMP results Primary - > 50% reduction in headache frequency (day) 28 days prior to randomization vs 28 days prior to end of treatment phase Secondary Headache Disability PedMIDAS; compare randomization to end of treatment Tolerability whether or not subject completed entire 24 weeks Additional Secondary Absolute reduction in headache frequency Side effects CHAMP results Consort Primary (>50%) Primary all subjects without data considered failures Last Observation Carried Forward most recent visit with 28 day calendar Multiple Imputation methods with multiple chains Observed data all subjects with baseline and last 28 days 12

13 Primary (>50% distribution) Results - Secondary PedMIDAS Tolerability 50 Initial Final Imputed 100% 90% 80% % 60% 50% % 30% 20% 0 AMI TPM PLC 10% 0% AMI TPM PLC Secondary - Additional Headache Frequency Initial Final Imputed AMI TPM PLC Side Effects 852 Adverse events CDI (Child Depression Index) Baseline Visit 5 Visit in Amitriptyline 80 30% fatigue (vs 14% placebo) 419 in Topiramate 60 31% parasthesia (vs 8% placebo) in Placebo Serious adverse events 6 in amitriptyline 0 4 AMI in topiramate TPM PLC 2 in placebo 13

14 CHAMP Results Simulations Follow-Up 3, 6,12 months 18, 24, 36 months Genomics RNASeq DNASeq? Adherence Trajectory Process Migraine Characteristics response Predictors of response Why Children and Adolescents are impacted by migraine There are significant gaps Who and Where Cincinnati Children s, Univ of Iowa, NIH NINDS and NICHD, all of our sites. How NIH sponsored, U01 Multi-site study Childhood and Adolescent Migraine Prevention Study - CHAMP What Primary results all three arms treated headaches, but no difference Side effects in topiramate and amitriptyline, but not placebo Where Where do we go from here? Children and adolescents with real world migraine get better 50 to 70% with a >50% reduction in headache frequency Mean frequency at end down to almost 1 per week Thus, multidisciplinary care works Biochemical effect of medication is not the reason Is the reason expectation of response? What do we do with the 30-40% that don t get better? 14

15 Expectation of Response Cormier et al, Pain 2016 Where do we go from here? What will you do Monday when you treat your headache patients? What are the other options? What does this say about the adult studies? Thank you 15