Practice Patterns and Outcomes of ACTHar use in Children with Nephrotic Syndrome

Transcription

1 Page 1 of 16 Practice Patterns and Outcomes of ACTHar use in Children with Nephrotic Syndrome MANUAL OF OPERATIONS VERSION 1.0 March 10, 2016

2 Page 2 of 16 STUDY PERSONNEL CONTACT INFORMATION Principal Investigator: Lead Study Coordinator: NAPRTCS Contact: Mark Benfield, MD Pediatric Nephrology of Alabama, P.C Richard Arrington Jr. Blvd. South Suite 206 Birmingham, Alabama Phone: Fax: benfield@pednephal.com Michelle Benfield RN, BSN, CCRC Pediatric Nephrology of Alabama, P.C Richard Arrington Jr. Blvd. South Suite 206 Birmingham, Alabama Phone: Fax: embenfield@pednephal.com Danielle Lang Executive Director NAPRTCS 1 Autumn St. Box 729 Boston, MA Phone: Fax: lang@naprtcs.org DCC Director: DCC Senior Statistician And Database Manager: Traci Leong, PhD Medalytics Phone: medalyticsgroup@gmail.com Courtney McCracken, PhD Medalytics Phone: medalyticsgroup@gmail.com

3 Page 3 of 16 SCIENTIFIC ADVISORY COMMITTEE MEMBERS: Mark Benfield, MD Pediatric Nephrology of Alabama, P.C Richard Arrington Jr. Blvd. South Suite 206 Birmingham, Alabama Phone: Fax: Larry Greenbaum, MD Marcus Professor of Pediatrics Division of Pediatric Nephrology Emory University School of Medicine 2015 Uppergate Dr. NE Atlanta, Georgia, Phone: Fax: Paul Grimm, MD Professor of Pediatrics Medical Director, Pediatric Kidney Transplant Program Stanford University School of Medicine G306, MC Pasteur Drive Stanford, CA Phone: Fax: Kenneth Lieberman, MD Chief, Pediatric Nephrology Joseph M. Sanzari Children s Hospital Hackensack University Medical Center Professor of Pediatrics Rutgers New Jersey Medical School Phone: Fax:

4 Page 4 of 16 ROLES AND RESPONSIBILITIES Principal Investigator: The PI will be responsible for development of processes, forms, and conduct of study; site recruitment; development and management of scientific advisory committee, working with Medalytics for data analysis and preparation of publications. Lead Study Coordinator: The study coordinator will be responsible for developing regulatory documents and compliance, working with each of the sites during site recruitment, site initiation, patient recruitment, enrollment and data entry. Their role will be assure clear and effective communication, assist with queries during study development, initiation, and conduct. Data Coordinating Center: Medalytics will be the data coordinating center. They will be responsible for developing data entry forms; training sites to use web-based data entry system; data entry and integrity; data analysis. Interim analyses will be conducted yearly but analyses for the primary publication will be conducted at the end of the study. Participating centers can submit requests for special studies and analysis to further investigate and report on data in the registry. These analyses will be approved by the scientific advisory committee and all analyses performed with the assistance of Medalytics. NAPRTCS: NAPRTCS will be the study coordinating center. They will be responsible for coordinating site initiating and assuring appropriate contracting and IRB regulatory documents have been completed. All contracts with sites and data coordinating center will be as a subcontract of NAPRTCS. Scientific Advisory Committee: The role of the scientific advisory committee is to develop data forms and update as needed, disseminate information regarding registry and recruitment, work with data coordinating center to develop first data analysis at 1 year and be authors on initial manuscript(s).

5 Page 5 of 16 ABBREVIATIONS AE CRF DCC FSGS GFR IRB ADVERSE EVENT CASE REPORT FORM DATA COORDINATING CENTER FOCAL SEGMENTAL GLOMERULAR SCLEROSIS GLOMERULAR FULTRATION RATE INSTITUTIONAL REVIEW BOARD MCNS MINIMAL CHANGE DISEASE MPGN MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS NS SAE SDNS SLE SSNS SRNS UP/C NEPHROTIC SYNDROME SERIOUS ADVERSE EVENT STEROID DEPENDENT NEPHROTIC SYNDROME SYSTEMIC LUPUS ERYTHEMATOSUS STEROID SENSITIVE NEPHROTIC SYNDROME STEROID RESISTANT NEPHROTIC SYNDROME URINE PROTEIN CREATININE RATIO DEFINITIONS 1. Nephrotic Syndrome (Diagnosis requires all 3) a. Proteinuria urine protein/creatinine ratio > 3 or 24 Hr urine > 3000 mg b. Hypoalbuminemia Serum albumin less than 2.5 c. Edema clinical diagnosis 2. Steroid (or other therapy) Responsive NS (Diagnosis requires all 3 when available. Labs that are not done do not effect definition. However parameters checked but outside of range should be evaluated as below. E.g. if albumin not done it could be steroid responsive. If albumin done and <3.5 it would be a partial response) a. Proteinuria Urine protein/creatinine ratio decrease to < 0.5 or dipstick less than 1+ for 3 consecutive days

6 Page 6 of 16 b. Hypoalbuminemia serum albumin increased to > 3.5 c. Edema no clinical edema 3. Partially Responsive NS (Diagnosis requires any 1 of 3) a. Proteinuria Urine protein/creatinine ratio decreased by > 50% b. Hypoalbuminemia serum albumin increase by > 0.5 c. Edema no clinical edema 4. Steroid dependent NS a. Relapse during steroid taper or within 2 weeks of stopping steroids. 5. Steroid resistant NS/Non-responsive NS a. Unresponsive to 4 weeks of high dose steroid or other therapy 6. Relapse in patient with complete response (Diagnosis requires any 1 of 3 usually only #1) a. Proteinuria 2-4+ dipstick proteinuria for 3 consecutive days (This can be home, office, or hospital monitoring), Pro/Cr > 3 b. Hypoalbuminemia - Serum albumin less than 2.5 c. Edema clinical diagnosis 7. Relapse in patient with partial response (Diagnosis requires any 1 of 3) a. Proteinuria worsening of urine protein/creatinine ratio b. Hypoalbuminemia - Serum albumin decreased by 0.5 c. Edema clinical diagnosis 8. Infrequently relapsing NS a. 3 or fewer relapses per year 9. Frequently relapsing NS a. 4 or more relapses per year b. 2 or more relapses in a 6 month period 10. Oral Steroid Course a. High Dose daily divided steroids for induction of remission (not dependent on subsequent response)

7 Page 7 of 16 REGULATORY REQUIREMENTS Centers participating in this registry must follow applicable regulatory and institutional requirements and Good Clinical Practice (GCP) guidelines. Documentation of participant consent and source documentation for all data must be on file at the participating site. Sites are responsible for ensuring that all data submitted are collected from source documents and entered accurately into the system. PATIENT POPULATION Children 6 months to 21 years of age, with nephrotic syndrome of any cause, and treated with ACTHar therapy (patients who have received one dose of ACTHar will be able to be included in the registry) will be eligible for enrollment (including but not limited to idiopathic NS, FSGS, MPGN, IgA Nephropathy, Membranous Nephropathy, SLE). Nephrotic syndrome is very rare in children less than 1 year of age and treatment failures of traditional therapies often encompass several years. However it is important to capture all children treated with ACTHar and if local clinical decisions lead to the use of this therapy in infancy, it would be important to collect and analyze these data. The NIH and FDA define pediatrics as up to the 21st birthday. We will make every effort to transition all young adult patients to the adult registry of ACTHar use when they transition their care from pediatric nephrology to adult based care. This represents a very small number of patients and it is difficult to accurately estimate the number that will be treated with ACTHar. However it is likely that patients per year will be enrolled. There will be 25 sites for this registry. Although goal enrollment for each site is 2, we hope all sites are able to enroll all patients who have been treated with ACTHar. STUDY DESIGN This study will be an observational study utilizing a data registry of practice patterns and clinical outcomes in children with NS treated with ACTHar. We will utilize the infrastructure, clinical trial network, and experience of the North American Pediatric Trials and Collaborative Studies (NAPRTCS) and the data coordinating center Medalytics. NAPRTCS was founded in 1987 initially as a data registry for pediatric kidney transplantation. However it is now a 501 c 3 organization studying outcomes in children with CKD, Dialysis and Transplantation. This organization now includes 120 centers in the United States, Canada and Mexico. For the purposes of this study we would only utilize US centers. Utilizing this network will allow for efficient development and implementation of the data registry of ACTHar use, access to a large number of centers with a long track record of involvement with data registries, an existing web-based data entry system, and the guidance, oversight, data acquisition and analysis of an established data coordinating center. This study will have very limited traditional inclusion and exclusion criteria. This will not be a treatment study and inclusion/exclusion criteria do not pertain to decisions to use ACTHar. Our goal will be to capture as many patients as possible who have been treated with ACTHar for Nephrotic Syndrome. We propose to collect data from both incident and prevalent patients treated with ACTHar (this can be either retrospective or prospective), at the time of first ACTHar use, 1 month following initiating of therapy, follow-up forms every 6 months, and with any relapse of NS.

8 Page 8 of 16 FORMS SCHEDULE ENROLLMENT 1 MONTH (+/-7d) EVERY 6 MONTHS (+/-30d) AS INDICATED Enrollment Form X Status/follow up form X X SAE Form X AE Form X Con Med Form X X X X (update form as needed) Relapse (update X form as needed) Dosing Form X X X X Termination Form X Data entry should be completed within 30 days of study visit. ENROLLMENT Enrollment Form Informed Consent will be performed prior to collection of any data. Labs recorded for enrollment form should be pre ACTHar dose. This is a registry that reflects practice patterns of sites. Therefore labs collected will be those of each sites standard of care. Nephrotic Syndrome Classification (See Definitions) o Steroid Responsive-Infrequently relapsing o Steroid Responsive-Frequently relapsing o Steroid Dependent o Partially Responsive o Steroid Resistant/Nonresponsive If patient has had more than one transplant, please use date of most recent transplant. Upload all previous kidney biopsy reports (prior to treatment of ACTHar) If patient has diagnosis of hypertension, please report number of medications used to treat hypertension. This should not include those medications used solely for purpose of anti-proteinuric affect.

9 Page 9 of 16 ACTHar timing and dosing Information o Capture if initial dose was the target dose or if the subject is on a planned dose escalation schedule in order to reach target dose. Below is an example of a subject who started at a dose of 48 units once a week but the planned target was 48 units 3 times a week. There will be a separate training manual available to provide guidance for data entry. Previous Used IV Therapies and Oral Therapies for Nephrotic Syndrome o Enter the number of courses since diagnosis (from date of diagnosis to the date of the first dose ACTHar) and the maximum dose prescribed for this subject. o If a subject is on a therapy for NS at the initiation of ACTHar therapy, include that course in the number entered in Previous used therapies and also enter that course in the most recent therapy section. Most Recent Therapy for Nephrotic Syndrome o Enter the most recent course prior to start of ACTHar. If a subject is on a therapy for NS at the initiation of ACTHar therapy, that current therapy would be the most recent course. o Oral prednisone use is captured under the relapse history section Below are examples from a subject who had one course of solumedrol prior to first dose of ACTHar and one course of mycophenolate mofetil prior to first dose of ACTHar. These were

10 Page 10 of 16 also his/her most recent courses of these therapies.

11 Page 11 of 16 Concomitant Medications-Conmeds to be collected will be immunosuppressant medications, antihypertensive medications (including those used for antiproteinuric affect), lipid lowering agents, diuretics and albumin. o Oral Prednisone exposure is captured under Medication changes section and should not be captured on Conmed form. o Upload ConMed form This is a word document that can be updated at each visit. Please enter a new line for each dose change. Below is an example of a subject who had multiple changes in Lisinopril dose.

12 Page 12 of 16 ACTHar Dosing Form o Capture initial ACTHar dose o This form will be updated for each dose change o In order for a new dose change option to show up you must add to the number in the dose change field. See below for example.

13 Page 13 of 16 1 MONTH VISIT FROM TIME OF INITIATION OF ACTHAR (+/- 7 day window) Status Form (Follow Up form) Hospitalization since last visit o Complete SAE form Biopsy since last visit o Biopsy report will be uploaded Relapse since last visit o Update relapse form o See definitions for response to treatment Infection since last visit o Complete AE/SAE form SAE since last visit o Complete SAE form AE (those associated with ACTHar use only) o Complete AE/SAE form Concomitant Medications-Conmeds to be collected will be immunosuppressant medications, antihypertensive medications (including those used for antiproteinuric affect), lipid lowering agents, diuretics and albumin. o Oral Prednisone exposure is captured under Medication changes section and should not be captured on Conmed form. o Upload ConMed form o This is a word document that can be updated at each visit. Please enter a new line for each dose change. Lab work o This is a registry that reflects practice patterns of sites. Therefore labs collected will be those of each sites standard of care. ACTHar Dosing Form o Capture ACTHar dose changes AE Form o Those associated with ACTHar use only o Adrenal insufficiency-based on PI s judgment FOLLOW UP VISITS OCCURS EVERY 6 MONTHS FROM TIME OF INITIATION OF ACTHAR (+/- 30 day window) Status Form (Follow Up form) Hospitalization since last visit

14 Page 14 of 16 o Complete SAE form Biopsy since last visit o Biopsy report will be uploaded Relapse since last visit o Update relapse form o See definitions for response to treatment Infection since last visit o Complete AE/SAE form SAE since last visit o Complete SAE form AE o o Those associated with ACTHar use only Complete AE/SAE form Concomitant Medications-Conmeds to be collected will be immunosuppressant medications, antihypertensive medications(including those used for antiproteinuric affect), lipid lowering agents, diuretics and albumin. o Oral Prednisone exposure is captured under Medication changes section and should not be captured on Conmed form. o Upload ConMed form o This is a word document that can be updated at each visit. Please enter a new line for each dose change. Lab work o This is a registry that reflects practice patterns of sites. Therefore labs collected will be those of each sites standard of care. ACTHar Dosing Form o Capture ACTHar dose changes AE Form o Adrenal insufficiency-based on PI s judgment ADVERSE EVENTS Only adverse events associated with Nephrotic syndrome and/or ACTHar use will be reported. These will include the following: Infection (bacterial, fungal, or viral) that requires treatment with an antibiotic (systemic or topical) New behavioral changes that are interfering with school or home functioning New sleep disturbances that are viewed as significant by the parent/child Increase in blood pressure that requires a new antihypertensive medication or an increase in dose of an antihypertensive medication that the patient is already receiving Generalized increase in skin pigmentation ( bronzing ) Increase in Cushingoid symptoms such as moon facies or striae

15 Page 15 of 16 Increase in serum glucose >200mg/dL on a random sample Adrenal insufficiency-(reported based on PI s discretion) Pain, redness or swelling at ACTHar injection site AE s (Only adverse events associated with Nephrotic syndrome and/or ACTHar use will be reported) and SAE s will be collected for the entire time the subject is enrolled in the registry. SERIOUS ADVERSE EVENTS All SAE s will be reported but since this is not a drug study, it is not required that these are reported within 24 hours of the site becoming aware of the event. It is required that SAEs are reported at each of the follow up visits. Results in Death Life-threatening Hospitalization (initial or prolonged) Results in Persistent or Significant Disability or Permanent Damage Congenital Anomaly/Birth Defect Other Serious (Important Medical Events)-Report when the event does not fit the other outcomes, but the event may jeopardize the patient and may require medical or surgical intervention (treatment) to prevent one of the other outcomes. AE s (Only adverse events associated with Nephrotic syndrome and/or ACTHar use will be reported) and SAE s will be collected for the entire time the subject is enrolled in the registry. REASON FOR TERMINATION Subject requires Dialysis Subject Receives a Kidney transplant Subject Request to withdraw consent MEDICATIONS Concomitant Medications-Conmeds to be collected will be immunosuppressant medications, antihypertensive medications (including those used for anti-proteinuric affect), lipid lowering agents, diuretics and albumin. All medications will be listed by generic/common names and not by trade or brand names. The concomitant medication form is a word document. Enter a new line for all dose changes. PATIENT IDENTIFIER Patient will be identified by the site s NAPRTCS site number and then sequentially by enrollment. X X X 0 0 1

16 Page 16 of 16 NAPRTCS Site #/Enrollment#