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

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Relapsing-Remitting Multiple Sclerosis
• Intervention / Treatment: Drug: dimethyl fumarate; Drug: Interferon β-1a

• Study Type: Interventional
• Enrollment (Actual): 156
• Phase: Phase 3

Contacts and Locations

Study Locations

• Belgium
  • Brussels, Belgium, 1020
    • Research Site
  • Gent, Belgium, 9000
    • Research Site
• Bulgaria
  • Sofia, Bulgaria, 1113
    • Research Site
• Canada
  • Calgary, Canada, T3B 6A8
    • Research Site
• Czechia
  • Brno, Czechia, 656 91
    • Research Site
  • Hradec Kralove, Czechia, 500 05
    • Research Site
  • Jihlava, Czechia, 58633
    • Research Site
  • Ostrava - Poruba, Czechia, 708 52
    • Research Site
• Denmark
  • København, Denmark, 2100
    • Research Site
  • Odense, Denmark, 5000
    • Research Site
  • Århus C, Denmark, 8000
    • Research Site
• France
  • Clermont Ferrand, France, 63003
    • Research Site
  • Le Kremlin Bicêtre, France, 94275
    • Research Site
  • Lille Cedex, France, 59037
    • Research Site
  • Marseille, France, 13385
    • Research Site
  • Montpellier, France, 34295
    • Research Site
  • Bas Rhin
    • Strasbourg, Bas Rhin, France, 67098
      • Research Site
  • Cote dÝOr
    • Dijon Cedex, Cote dÝOr, France, 21033
      • Research Site
  • Ille Et Vilaine
    • Rennes cedex 09, Ille Et Vilaine, France, 35033
      • Research Site
  • Rhone
    • Bron Cedex, Rhone, France, 69677
      • Research Site
  • Somme
    • Amiens Cedex 1, Somme, France, 80054
      • Research Site
  • Vandoeuvre Les Nancy Cedex
    • Vandoeuvre les Nancy, Vandoeuvre Les Nancy Cedex, France, 54511
      • Research Site
• Germany
  • Bochum, Germany, 44791
    • Researh Site
  • Muenchen, Germany, 80337
    • Research Site
  • Bayern
    • Augsburg, Bayern, Germany, 86156
      • Research Site
• Hungary
  • Budapest, Hungary, 1083
    • Research Site
  • Budapest, Hungary, 1089
    • Research Site
• Israel
  • Jerusalem, Israel, 91120
    • Research Site
  • Petach-Tikva, Israel, 4920235
    • Research Site
  • Ramat-Gan, Israel, 52621
    • Resaerch Site
• Italy
  • Bari, Italy, 70124
    • Research Site
  • Genova, Italy, 16132
    • Research Site
  • Milano, Italy, 20132
    • Research Site
  • Napoli, Italy, 80131
    • Research Site
  • Padova, Italy, 35128
    • Research Site
  • Palermo, Italy, 90127
    • Research Site
  • Rome, Italy, 00165
    • Research Site
  • Rome, Italy, 00189
    • Research Site
  • Varese
    • Gallarate, Varese, Italy, 21013
      • Research Site
• Kuwait
  • Shuwaikh
    • Kuwait, Shuwaikh, Kuwait, 73767
      • Research Site
• Poland
  • Bialystok, Poland, 15-274
    • Research Site
  • Gdansk, Poland, 80-952
    • Research Site
  • Lodz, Poland, 93-338
    • Research Site
  • Poznan, Poland, 60-355
    • Research Site
  • Warsaw, Poland, 04-730/20
    • Research Site
• Serbia
  • Belgrade, Serbia, 11000
    • Research Site
  • Belgrade, Serbia, 11070
    • Research Site
  • Kragujevac, Serbia, 34000
    • Resaerch Site
• Spain
  • Barcelona, Spain, 8036
    • Research Site
  • Cordoba, Spain, 14011
    • Resaeach Site
  • Madrid, Spain, 28850
    • Research Site
  • Sevilla, Spain, 41009
    • Resaerch Site
• Sweden
  • Göteborg, Sweden, 41345
    • Research Site
  • Stockholm, Sweden, 17176
    • Research Site
• Turkey
  • Ankara, Turkey, 06100
    • Research Site
  • Antalya, Turkey, 07070
    • Research Site
• United Kingdom
  • London, United Kingdom, WC1N 3BG
    • Research Site
  • Greater London
    • London, Greater London, United Kingdom, SE1 7EH
      • Research Site
    • London, Greater London, United Kingdom, WC1N 3JH
      • Research Site
  • West Midlands
    • Birmingham, West Midlands, United Kingdom, B4 6NH
      • Research Site
• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Research Site
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years to 17 years (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Biogen

Publications and helpful links

General Publications

• Vermersch P, Scaramozza M, Levin S, Alroughani R, Deiva K, Pozzilli C, Lyons J, Mokliatchouk O, Pultz J, N'Dure F, Liu S, Badwan R, Branco F, Hood-Humphrey V, Franchimont N, Hanna J, Maghzi AH. Effect of Dimethyl Fumarate vs Interferon beta-1a in Patients With Pediatric-Onset Multiple Sclerosis: The CONNECT Randomized Clinical Trial. JAMA Netw Open. 2022 Sep 1;5(9):e2230439. doi: 10.1001/jamanetworkopen.2022.30439.

Study record dates

Study Major Dates

• Study Start (Actual): August 28, 2014
• Primary Completion (Anticipated): September 8, 2025
• Study Completion (Anticipated): September 8, 2025

Study Registration Dates

• First Submitted: November 3, 2014
• First Submitted That Met QC Criteria: November 4, 2014
• First Posted (Estimate): November 5, 2014

Study Record Updates

• Last Update Posted (Actual): March 2, 2023
• Last Update Submitted That Met QC Criteria: March 1, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Keywords: Pediatrics
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Physiological Effects of Drugs; Anti-Infective Agents; Antiviral Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Dermatologic Agents; Adjuvants, Immunologic; Interferons; Interferon beta-1a; Interferon-beta; Dimethyl Fumarate
• Other Study ID Numbers: 109MS306; 2013-002318-11 (EudraCT Number)