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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02283853
Recruitment Status : Active, not recruiting
First Posted : November 5, 2014
Last Update Posted : May 29, 2020
Sponsor:
Information provided by (Responsible Party):
Biogen

Tracking Information
First Submitted Date  ICMJE November 3, 2014
First Posted Date  ICMJE November 5, 2014
Last Update Posted Date May 29, 2020
Actual Study Start Date  ICMJE August 28, 2014
Estimated Primary Completion Date September 8, 2025   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: May 28, 2020)
  • Proportion of Participants Free of New/Newly Enlarging T2 Hyperintense Lesions on Brain MRI Scans [ Time Frame: At week 96 ]
    Part 1
  • Number of Participants That Experience Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: Up to 7 years ]
    Part 2 will be an optional open-label extension phase in subjects who complete Part 1 and who meet the Part 2 entry criteria.
  • Number of Participants Who Discontinue Study Treatment due to an AE [ Time Frame: Up to 7 years ]
    Part 2
Original Primary Outcome Measures  ICMJE
 (submitted: November 4, 2014)
Proportion of Participants Free of New/Newly Enlarging T2 Hyperintense Lesions on Brain MRI Scans [ Time Frame: Up to Week 96 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: May 28, 2020)
  • The Number of New/Newly Enlarging T2 Hyperintense Lesions on Brain MRI Scans [ Time Frame: At Week 24 and Week 96 ]
    Part 1
  • Proportion of Participants Free of New/Newly Enlarging T2 Hyperintense Lesions on Brain MRI Scans [ Time Frame: At Week 24 and Week 48 ]
    Part 1
  • Proportion of Participants Free of New MRI Activity as measured by Brain MRI Scans [ Time Frame: At Weeks 24, 48 and 96 ]
    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
  • Time to First Relapse [ Time Frame: Up to Week 96 ]
    Part 1
  • Proportion of Participants Who Do Not Experience Relapse [ Time Frame: Up to Week 96 ]
    Part 1
  • Annualized Relapse Rate [ Time Frame: At Weeks 48 and 96 ]
    Part 1
  • Number of Participants That Experience Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Week 96 ]
    Part 1. Including prospective and follow-up of flushing, nausea, abdominal pain and diarrhea
  • Fatigue as measured by the Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue Scale Scores [ Time Frame: Up to Week 96 ]
    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.
  • Quality of Life as measured by the PedsQL [ Time Frame: Up to Week 96 ]
    Part 1
  • Change from Baseline to Week 96 in the Expanded Disability Status Scale (EDSS) Score [ Time Frame: Up to Week 96 ]
    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.
  • Vital Signs, Electrocardiograms (ECGs) and Changes in Clinical Laboratory Data, including Monitoring of Liver Function, Renal Function, Hematologic, and Coagulation Parameters [ Time Frame: Up to Week 96 ]
    Part 1
  • Annualized Relapse Rate [ Time Frame: Up to 7 years ]
    Part 2
  • Change from Baseline in EDSS Score [ Time Frame: Up to 7 years ]
    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.
  • Change from Baseline in Symbol Digit Modalities Test (SDMT) Score [ Time Frame: Up to 7 years ]
    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.
  • Change from Baseline in Brief Visuospatial Memory Test - Revised (BVMT-R) Score [ Time Frame: Up to 7 years ]
    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.
  • Change from Baseline in School Progression Query [ Time Frame: Up to 7 years ]
    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?"
  • Number of Participants with Incidences of Clinically Relevant Vital Signs Abnormalities [ Time Frame: Up to 7 years ]
    Part 2
  • Number of Participants with Incidences of Clinically Relevant ECG Abnormalities [ Time Frame: Up to 7 years ]
    Part 2
  • Number of Participants with Incidences of Clinically Relevant Laboratory Assessment Abnormalities [ Time Frame: Up to 7 years ]
    Part 2
  • Change from Baseline in Height [ Time Frame: Up to 7 years ]
    Part 2
  • Change from Baseline in Weight [ Time Frame: Up to 7 years ]
    Part 2
  • Change from Baseline in Bone Age [ Time Frame: Up to 7 years ]
    Part 2
  • Tanner Stage [ Time Frame: Up to 7 years ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: November 4, 2014)
  • The Number of New/Newly Enlarging T2 Hyperintense Lesions on Brain MRI Scans [ Time Frame: At Week 24 and Week 96 ]
  • Proportion of Participants Free of New/Newly Enlarging T2 Hyperintense Lesions on Brain MRI Scans [ Time Frame: At Week 24 and Week 48 ]
  • Proportion of Participants Free of New MRI Activity as measured by Brain MRI Scans [ Time Frame: At Weeks 24, 48 and 96 ]
    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
  • Time to First Relapse [ Time Frame: Up to Week 96 ]
  • Proportion of Participants Who Do Not Experience Relapse [ Time Frame: Up to Week 96 ]
  • Annualized Relapse Rate [ Time Frame: At Weeks 48 and 96 ]
  • Number of Participants That Experience Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to Week 96 ]
    Including prospective and follow-up of flushing, nausea, abdominal pain and diarrhea
  • Area under the concentration-time curve from time 0 to 10 hours (AUC0-10) of BG00012 [ Time Frame: Up to Week 4 ]
    Participants receiving BG00012 who consent to participate in the PD/PK subset
  • Maximum observed plasma concentration (Cmax) of BG00012 [ Time Frame: Up to Week 4 ]
    Participants receiving BG00012 who consent to participate in the PD/PK subset
  • Time to reach maximum observed plasma concentration (Tmax) of BG00012 [ Time Frame: Up to Week 4 ]
    Participants receiving BG00012 who consent to participate in the PD/PK subset
  • Lag time of BG00012 [ Time Frame: Up to Week 4 ]
    Participants receiving BG00012 who consent to participate in the PD/PK subset
  • Elimination half-life (t½) of BG00012 [ Time Frame: Up to Week 4 ]
    Participants receiving BG00012 who consent to participate in the PD/PK subset
  • Apparent clearance (Cl/F) of BG00012 [ Time Frame: Up to Week 4 ]
    Participants receiving BG00012 who consent to participate in the PD/PK subset
  • Apparent volume of distribution (V/F) of BG00012 [ Time Frame: Up to Week 4 ]
    Participants receiving BG00012 who consent to participate in the PD/PK subset
  • Changes in the nuclear factor (erythroid derived 2) like 2 activation pathway markers nicotinamide adenine dinucleotide phosphate [NAD(P)H] dehydrogenase [ Time Frame: Up to Week 4 ]
    Participants receiving BG00012 who consent to participate in the PD/PK subset
  • Changes in the nuclear factor (erythroid derived 2) like 2 activation pathway markers Quinone 1 (NQO-1) [ Time Frame: Up to Week 4 ]
    Participants receiving BG00012 who consent to participate in the PD/PK subset
  • Changes in the nuclear factor (erythroid derived 2) like 2 activation pathway markers Heme oxygenase 1 (HO-1) [ Time Frame: Up to Week 4 ]
    Participants receiving BG00012 who consent to participate in the PD/PK subset
  • Fatigue as measured by the Pediatric Quality of Life Inventory (PedsQL) Multidimensional Fatigue Scale Scores [ Time Frame: Up to Week 96 ]
    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.
  • Quality of Life as measured by the PedsQL [ Time Frame: Up to Week 96 ]
  • Change from Baseline to Week 96 in the Expanded Disability Status Scale (EDSS) Score [ Time Frame: Up to Week 96 ]
    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.
  • Vital Signs, Electrocardiograms (ECGs) and Changes in Clinical Laboratory Data, including Monitoring of Liver Function, Renal Function, Hematologic, and Coagulation Parameters [ Time Frame: Up to Week 96 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Phase 3 Efficacy and Safety Study of BG00012 in Pediatric Subjects With Relapsing-remitting Multiple Sclerosis (RRMS)
Official Title  ICMJE 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
Brief Summary 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.
Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Relapsing-Remitting Multiple Sclerosis
Intervention  ICMJE
  • Drug: dimethyl fumarate
    administered orally
    Other Names:
    • BG00012
    • Tecfidera
  • Drug: Interferon β-1a
    administered by intramuscular injection
    Other Name: Avonex
Study Arms  ICMJE
  • Experimental: BG00012
    Participants will receive the recommended dose of 240 mg orally, twice a day
    Intervention: Drug: dimethyl fumarate
  • Active Comparator: IFN β-1a (Avonex)
    Participants will receive the recommended dose of 30 μg (weekly)
    Intervention: Drug: Interferon β-1a
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: May 28, 2020)
156
Original Estimated Enrollment  ICMJE
 (submitted: November 4, 2014)
142
Estimated Study Completion Date  ICMJE September 8, 2025
Estimated Primary Completion Date September 8, 2025   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 10 Years to 17 Years   (Child)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Belgium,   Bulgaria,   Canada,   Czechia,   Denmark,   France,   Germany,   Hungary,   Israel,   Italy,   Kuwait,   Poland,   Serbia,   Spain,   Sweden,   Turkey,   United Kingdom,   United States
Removed Location Countries Argentina,   Czech Republic,   Romania
 
Administrative Information
NCT Number  ICMJE NCT02283853
Other Study ID Numbers  ICMJE 109MS306
2013-002318-11 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Biogen
Study Sponsor  ICMJE Biogen
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Study Director: Medical Director Biogen
PRS Account Biogen
Verification Date May 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP