Phase 3 Efficacy and Safety Study of BG00012 in Pediatric Subjects With Relapsing-remitting Multiple Sclerosis (RRMS)

Study Overview
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Brief Summary
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The main objectives of Part 1 are as follows: To evaluate the safety, tolerability, and efficacy of BG00012 in pediatric subjects with RRMS, as compared with a disease-modifying treatment and to assess health outcomes and evolution of disability. The primary objective of Part 2 is to evaluate the long-term safety of BG00012 in subjects who completed Week 96 in Part 1 of Study 109MS306. The secondary objective of Part 2 is to describe the long-term MS outcomes of BG00012 in subjects who completed Week 96 in Part 1 of Study 109MS306.

Official Title
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Open-Label, Randomized, Multicenter, Multiple-Dose,Active-Controlled, Parallel-Group, Efficacy and Safety Study of BG00012 in Children From 10 to Less Than 18 Years of Age With Relapsing-Remitting Multiple Sclerosis, With Optional Open-Label Extension

Conditions
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Relapsing-Remitting Multiple Sclerosis

Intervention / Treatment
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* Drug: dimethyl fumarate
* Drug: Interferon β-1a


Participation Criteria
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Eligibility Criteria
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Key Inclusion Criteria: Must have a body weight of ≥30 kg. Must have a diagnosis of RRMS (consensus definition for pediatric RRMS [Krupp 2007]). Must be ambulatory with a baseline EDSS score between 0 and 5.5, inclusive. Must have experienced at least 1 of the following 3 conditions: a) at least 1 relapse within the last 12 months prior to Day 1 with a prior brain MRI demonstrating lesions consistent with MS; b) at least 2 relapses within the last 24 months prior to Day 1, with a prior brain MRI demonstrating lesions consistent with MS; c) evidence of Gd-enhancing lesions of the brain on an MRI performed within the 6 weeks prior to Day 1. Must be neurologically stable, with no evidence of relapse within 50 days prior to Day 1 and no evidence of corticosteroid treatment within 30 days prior to Day 1. Subjects of childbearing potential who are sexually active must be willing to practice effective contraception during the study and be willing and able to continue contraception for at least 30 days after their final dose of study treatment. Key Exclusion Criteria: Primary progressive, secondary progressive, or progressive relapsing MS (as defined by [Lublin and Reingold 1996]). These conditions require the presence of continuous clinical disease worsening over a period of at least 3 months. Subjects with these conditions may also have superimposed relapses but are distinguished from relapsing-remitting subjects by the lack of clinically stable periods or clinical improvement. Disorders mimicking MS, such as other demyelinating disorders (e.g., acute disseminated encephalomyelitis), systemic autoimmune disorders (e.g., Sjögren disease, lupus erythematosus), metabolic disorders (e.g., dystrophies), and infectious disorders. History of premalignant or malignant disease. Subjects with basal cell carcinoma that has been completely excised prior to screening will remain eligible. History of severe allergic or anaphylactic reactions, or known drug hypersensitivity to DMF, fumaric acid esters, or interferon beta-1a (IFN Beta-1a). History of abnormal laboratory results indicative of any significant endocrinologic, hematologic, hepatic, immunologic, metabolic, urologic, renal, and/or any other major disease that would preclude participation in a clinical study. History of clinically significant cardiovascular, pulmonary, GI, dermatologic, growth, developmental, psychiatric (including depression), neurologic (other than MS), and/or other major disease that would preclude participation in a clinical study. -.History of human immunodeficiency virus. An MS relapse that has occurred within 50 days prior to Day 1 AND/OR the subject has not stabilized from a previous relapse prior to Day 1. Other unspecified reasons that, in the opinion of the Investigator or Biogen Idec, make the subject unsuitable for enrollment. For the PD/PK subset of subjects: subjects unable to swallow the BG00012 capsule whole. Key Treatment history Any previous treatment with Fumaderm (fumaric acid esters) or BG00012. Prior treatment with any of the following: total lymphoid irradiation, cladribine, T-cell or T-cell receptor vaccination, any therapeutic monoclonal antibody, with the exception of rituximab or natalizumab. Prior treatment with any of the following medications within the 12 months prior to Day 1: mitoxantrone, cyclophosphamide, rituximab. Prior treatment with any of the following medications or procedures within 6 months prior to Day 1: fingolimod; teriflunomide; natalizumab; cyclosporine; azathioprine; methotrexate; mycophenolate mofetil; laquinimod; intravenous (IV) immunoglobulin; plasmapheresis or cytapheresis Treatment with any of the following medications within 30 days prior to Day 1: steroids (IV or oral corticosteroid treatment, including agents that may not act through the corticosteroid pathway [e.g.low dose naltrexone]), 4-aminopyridine or related products (except subjects on a stable dose of controlled-release fampridine for 3 months) NOTE: Other protocol-defined inclusion/exclusion criteria may apply

Ages Eligible for Study
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Minimum Age: 10 Years
Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BG00012<br>Participants will receive the recommended dose of 240 mg orally, twice a day | Drug: dimethyl fumarate<br>* administered orally<br>* Other names: Tecfidera;|
| Active Comparator: IFN β-1a (Avonex)<br>Participants will receive the recommended dose of 30 μg (weekly) | Drug: Interferon β-1a<br>* administered by intramuscular injection<br>* Other names: Avonex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Participants Free of New/Newly Enlarging T2 Hyperintense Lesions on Brain MRI Scans | Part 1 | At week 96 | 
| Number of Participants That Experience Adverse Events (AEs) or Serious Adverse Events (SAEs) | Part 2 will be an optional open-label extension phase in subjects who complete Part 1 and who meet the Part 2 entry criteria. | Up to 7 years | 
| Number of Participants Who Discontinue Study Treatment due to an AE | Part 2 | Up to 7 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Number of New/Newly Enlarging T2 Hyperintense Lesions on Brain MRI Scans | Part 1 | At Week 24 and Week 96 | 
| Proportion of Participants Free of New/Newly Enlarging T2 Hyperintense Lesions on Brain MRI Scans | Part 1 | At Week 24 and Week 48 | 
| Proportion of Participants Free of New MRI Activity as measured by Brain MRI Scans | Part 1. New MRI Activitiy includes: Gd-enhancing MRI lesions on brain MRI scans; New T2 MRI lesions on brain MRI scans and newly enlarging MRI lesions on brain MRI scans | At Weeks 24, 48 and 96 | 
| Time to First Relapse | Part 1 | Up to Week 96 | 
| Proportion of Participants Who Do Not Experience Relapse | Part 1 | Up to Week 96 | 
| Annualized Relapse Rate | Part 1 | At Weeks 48 and 96 | 
| Number of Participants That Experience Adverse Events (AEs) and Serious Adverse Events (SAEs) | Part 1. Including prospective and follow-up of flushing, nausea, abdominal pain and diarrhea | Up to Week 96 | 
| Fatigue as measured by the Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue Scale Scores | Part 1. Multidimensional Fatigue Scale scores - designed as a generic symptom-speciﬁc instrument to measure fatigue in patients with acute and chronic health conditions as well as healthy school and community populations. | Up to Week 96 | 
| Quality of Life as measured by the PedsQL | Part 1 | Up to Week 96 | 
| Change from Baseline to Week 96 in the Expanded Disability Status Scale (EDSS) Score | Part 1. The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. | Up to Week 96 | 
| Vital Signs, Electrocardiograms (ECGs) and Changes in Clinical Laboratory Data, including Monitoring of Liver Function, Renal Function, Hematologic, and Coagulation Parameters | Part 1 | Up to Week 96 | 
| Annualized Relapse Rate | Part 2 | Up to 7 years | 
| Change from Baseline in EDSS Score | Part 2. The EDSS measures the disability status of people with multiple sclerosis on a scale that ranges from 0 to 10. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability. The range of main categories include (0) = normal neurologic exam; to (5) = ambulatory without aid or rest for 200 meters; disability severe enough to impair full daily activities; to (10) = death due to MS. | Up to 7 years | 
| Change from Baseline in Symbol Digit Modalities Test (SDMT) Score | Part 2. SDMT is used to assess processing speed. Participants are given 90 seconds in which to pair specific numbers with given geometric figures using a key. The score is number of correctly coded items from 0 (worst) to 110 (best). Higher scores indicate better performance. | Up to 7 years | 
| Change from Baseline in Brief Visuospatial Memory Test - Revised (BVMT-R) Score | Part 2. BVMT-R is used to assess learning/memory. The stimulus page is presented for 10 seconds, and the participant is then asked to reproduce the designs as accurately as possible and in the same location on the page. Three learning trials are administered, followed by a delay trial approximately 20 to 40 minutes later. Immediately following the delay trial a recognition trial is administered to see whether the participant recognizes the figures that were on the display. | Up to 7 years | 
| Change from Baseline in School Progression Query | Part 2. If permitted by the local regulatory authority, participants or caregivers will be posed the following question: During the past year, did [you/the subject] progress from one [class/grade-level] to the next in school? | Up to 7 years | 
| Number of Participants with Incidences of Clinically Relevant Vital Signs Abnormalities | Part 2 | Up to 7 years | 
| Number of Participants with Incidences of Clinically Relevant ECG Abnormalities | Part 2 | Up to 7 years | 
| Number of Participants with Incidences of Clinically Relevant Laboratory Assessment Abnormalities | Part 2 | Up to 7 years | 
| Change from Baseline in Height | Part 2 | Up to 7 years | 
| Change from Baseline in Weight | Part 2 | Up to 7 years | 
| Change from Baseline in Bone Age | Part 2 | Up to 7 years | 
| Tanner Stage | Part 2. Information regarding Tanner staging will be collected at baseline for all male participants and for female participants who are premenarche and will be stopped once the participant's bone age reaches ≥16 years or once the participant is postmenarche. | Up to 7 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatrics