BG00012 Monotherapy Safety and Efficacy Extension Study in Multiple Sclerosis (MS) (ENDORSE)

• ClinicalTrials.gov Identifier: NCT00835770
• Recruitment Status: Completed
• First Posted: February 4, 2009
• Results First Posted: December 31, 2020
• Last Update Posted: December 31, 2020
• Sponsor: Biogen
• Information provided by (Responsible Party): Biogen

Tracking Information

• First Submitted Date: February 2, 2009
• First Posted Date: February 4, 2009
• Results First Submitted Date: October 20, 2020
• Results First Posted Date: December 31, 2020
• Last Update Posted Date: December 31, 2020
• Actual Study Start Date: February 3, 2009
• Actual Primary Completion Date: November 8, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 7, 2020)

Number of Participants With Treatment-Emergent Adverse Events (AEs) [ Time Frame: Day 1 up to Week 561 ]

An adverse event (AE) is any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment.

• Original Primary Outcome Measures (submitted: February 3, 2009): To evaluate the long-term safety profile of BG00012 [ Time Frame: 2 years ]

Current Secondary Outcome Measures (submitted: December 7, 2020)

• Percentage of Participants Who Had Relapses [ Time Frame: Day 1 up to Week 384 ]
  Relapses were defined as new or recurrent neurologic symptoms not associated with fever or infection, lasting at least 24 hours.
• Annualized Relapse Rate (ARR) [ Time Frame: Day 1 up to Week 384 ]
  The annualized relapse rate is calculated as the total number of relapses occurred during the period for all participants, divided by the total number of participant-years followed in the period.
• Change From Baseline in the Expanded Disability Status Scale (EDSS) at Week 384 [ Time Frame: Baseline, Week 384 ]
  EDSS scale ranges from 0 (Normal neurological exam, no disability) to 10 (Death) in 0.5 unit increments that represent higher levels of disability. Scoring is based on an examination by a neurologist. Sustained disability progression was defined as at least a 1.0 point increase on the EDSS from a baseline EDSS ≥1.0 that was sustained for at least 24 weeks, or a 1.5 point increase on the EDSS from a baseline EDSS =0 that was sustained for at least 24 weeks.
• Number of Gadolinium (Gd)-Enhancing Lesions as Measured by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline up to Week 288 ]
  The Gd-enhancing lesions was evaluated using MRI technique.
• Volume of Gd-Enhancing Lesions as Measured by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline up to Week 288 ]
  The Gd-enhancing lesions was evaluated using MRI technique.
• Number of New or Newly Enlarging T2 Lesions as Measured by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline up to Week 288 ]
  The T2 lesions was evaluated using MRI technique.
• Volume of New or Newly Enlarging T2 Lesions as Measured by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline up to Week 288 ]
  The T2 lesions was evaluated using MRI technique.
• Number of T1 Hypointense Lesions as Measured by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline up to Week 288 ]
  The T1 hypointense lesions was evaluated using MRI technique.
• Volume of T1 Hypointense Lesions as Measured by Magnetic Resonance Imaging (MRI) [ Time Frame: Baseline up to Week 288 ]
  The T1 hypointense lesions was evaluated using MRI technique.
• Percent Change From Baseline in Brain Atrophy [ Time Frame: Baseline up to Week 288 ]
  Brain atrophy was measured using magnetic resonance imaging (MRI) technique.
• Percent Change From Baseline in Magnetization Transfer Ratio (MTR) [ Time Frame: Baseline up to Week 288 ]
  Magnetization Transfer Ratio (MTR) was measured using MRI technique.
• Change From Baseline in Short Form-36 Health Survey (SF-36®) at Week 384 [ Time Frame: Baseline, Week 384 ]
  The SF-36 is a brief (36-item) scale reflecting the impact of both dysfunctions and general health perception the questionnaire measures: 1.physical function (PF),2. role physical (RF),3. bodily pain (BP),4. role emotional (RE),5. social function (SF), 6. general health (GH),7. vitality (VT), 8. mental health (MH). Items 1-4 primarily contribute to the PCS score of the SF-36. Items 5-8 primarily contribute to the mental component summary (MCS) score of the SF-36. The questions related to each dimension are scored on a scale from 0 (worst score) to 100 (best score), with higher scores indicating better function.
• Change From Baseline in EuroQol 5 Dimensions Questionnaire (EQ-5D) Health Survey - EQ-5D Index Score at Week 384 [ Time Frame: Baseline, Week 384 ]
  The EQ-5D is a generic health-related quality of life instrument consisting of 2 components, EQ-5D index score and EQ-VAS. The EQ-5D provides a profile of the participant's health state in 5 dimensions (mobility, self-care, usual activities, pain/discomfort, and anxiety/depression). For each dimension, the participant is instructed to indicate whether he or she has (1) "no problems", (2) "some problems", or (3) "severe problems". A positive change from baseline indicates improvement.
• Change From Baseline in EuroQol 5 Dimensions Questionnaire (EQ-5D) Health Survey - Visual Analog Scale (VAS) at Week 384 [ Time Frame: Baseline, Week 384 ]
  The EQ-5D is a generic health-related quality of life instrument consisting of 2 components, EQ-5D index score and EQ-VAS. In EQ-VAS participants are asked to rate their current health on a 20 centimeter (cm) scale from 0 to 100 where 0 represents "worst imaginable health state" and 100 represents "best imaginable health state". A positive change from baseline indicates improvement.
• Change From Baseline in Visual Function Test Scores at Week 384 [ Time Frame: Baseline, Week 384 ]
  Participants were tested using the contrast level of 100%, 2.5%, and 1.25% charts, and the scores were defined as the number of letters identified correctly for each chart (the maximum score was 60). Higher scores indicate better functioning. A positive change from baseline indicates better functioning.

• Original Secondary Outcome Measures (submitted: February 3, 2009): To evaluate the long-term efficacy of BG00012 on clinical outcomes and MS brain lesions on MRI scans; and effects of BG00012 on quality of life measurements [ Time Frame: 2 years ]
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: BG00012 Monotherapy Safety and Efficacy Extension Study in Multiple Sclerosis (MS)
• Official Title: A Dose-Blind, Multicenter, Extension Study to Determine the Long-Term Safety and Efficacy of Two Doses of BG00012 Monotherapy in Subjects With Relapsing-Remitting Multiple Sclerosis
• Brief Summary: The primary objective of this study is to evaluate the long-term safety profile of BG00012 (dimethyl fumarate). Secondary objectives of this study are to evaluate the long-term efficacy of BG00012 using clinical endpoints and disability progression, to evaluate further the long-term effects of BG00012 on multiple sclerosis (MS) brain lesions on magnetic resonance imaging (MRI) scans in participants who had MRI scans as part of Studies 109MS301 (NCT00420212) and 109MS302 (NCT00451451) and to evaluate the long-term effects of BG00012 on health economics assessments and the visual function test.
• Detailed Description: The initial BG00012 dosage for the extension study (240 mg BID or 240 mg TID) was the same as that used in the Phase 3 Studies 109MS301 (NCT00420212) and 109MS302 (NCT00451451). Subsequent to the initiation of this study, BG00012 was approved in several countries for the treatment of MS at a dose of 240 mg BID. For this reason, all participants continuing in this study will receive the currently marketed dose of 240 mg BID.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Relapsing-Remitting Multiple Sclerosis

Intervention

• Drug: dimethyl fumarate
  BG00012 capsules
  Other Names:

  • BG00012
  • Tecfidera
  • DMF
• Drug: Placebo
  Capsules taken to maintain the blind in the 240 mg BID treatment group.

Study Arms

• Experimental: BG00012 plus placebo
  In the first phase, participants will receive BG00012 240 mg (two 120 mg capsules) twice a day (BID) and 2 placebo capsules once a day. In the second phase participants will receive open-label BG00012 240 mg BID, for atleast 8 years.
  Interventions:

  • Drug: dimethyl fumarate
  • Drug: Placebo
• Experimental: BG00012
  In the first phase participants will receive BG00012 240 mg (two 120 mg capsules) three times a day (TID). In the second phase participants will receive open-label BG00012 240 mg BID for atleast 8 years.
  Intervention: Drug: dimethyl fumarate

Publications *

• Gold R, Arnold DL, Bar-Or A, Fox RJ, Kappos L, Chen C, Parks B, Miller C. Safety and efficacy of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis: 9 years' follow-up of DEFINE, CONFIRM, and ENDORSE. Ther Adv Neurol Disord. 2020 May 12;13:1756286420915005. doi: 10.1177/1756286420915005. eCollection 2020. Erratum In: Ther Adv Neurol Disord. 2020 Oct 21;13:1756286420968357.
• Mehta D, Miller C, Arnold DL, Bame E, Bar-Or A, Gold R, Hanna J, Kappos L, Liu S, Matta A, Phillips JT, Robertson D, von Hehn CA, Campbell J, Spach K, Yang L, Fox RJ. Effect of dimethyl fumarate on lymphocytes in RRMS: Implications for clinical practice. Neurology. 2019 Apr 9;92(15):e1724-e1738. doi: 10.1212/WNL.0000000000007262. Epub 2019 Mar 27.
• Gold R, Giovannoni G, Phillips JT, Fox RJ, Zhang A, Marantz JL. Sustained Effect of Delayed-Release Dimethyl Fumarate in Newly Diagnosed Patients with Relapsing-Remitting Multiple Sclerosis: 6-Year Interim Results From an Extension of the DEFINE and CONFIRM Studies. Neurol Ther. 2016 Jun;5(1):45-57. doi: 10.1007/s40120-016-0042-8. Epub 2016 Mar 1.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: July 13, 2020): 1736
• Original Estimated Enrollment (submitted: February 3, 2009): 1700
• Actual Study Completion Date: November 8, 2019
• Actual Primary Completion Date: November 8, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

-Subjects who participated in and completed as per protocol previous BG00012 clinical studies 109MS301 (NCT00420212) or 109MS302 (NCT00451451).

Key Exclusion Criteria:

• Any significant change in medical history from 109MS301 or 109MS302 that would have excluded subject's participation from their previous study.
• Subjects from 109MS301 or 109MS302 who discontinued oral study treatment due to an AE or due to reasons other than protocol-defined relapse/disability progression.
• Subjects from 109MS301 or 109MS302 who discontinued study treatment due to disability progression or relapses and did not follow the modified visit schedule up to Week 96.

NOTE: Other protocol defined Inclusion/Exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 19 Years to 58 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Croatia, Czechia, Estonia, France, Germany, Greece, India, Ireland, Israel, Italy, Latvia, Mexico, Moldova, Republic of, Netherlands, New Zealand, North Macedonia, Poland, Puerto Rico, Romania, Serbia, Slovakia, South Africa, Spain, Switzerland, Ukraine, United Kingdom, United States
• Removed Location Countries: Czech Republic, Guatemala, Macedonia, The Former Yugoslav Republic of

Administrative Information

• NCT Number: NCT00835770
• Other Study ID Numbers: 109MS303; 2008-004753-14 ( EudraCT Number )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Biogen
• Original Responsible Party: Biogen Idec MD, Biogen Idec
• Current Study Sponsor: Biogen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Biogen

• PRS Account: Biogen
• Verification Date: December 2020