Efficacy and Safety of Oral BG00012 in Relapsing-Remitting Multiple Sclerosis (DEFINE)

• ClinicalTrials.gov Identifier: NCT00420212
• Recruitment Status: Completed
• First Posted: January 11, 2007
• Results First Posted: June 2, 2014
• Last Update Posted: January 26, 2015
• Sponsor: Biogen
• Information provided by (Responsible Party): Biogen

Tracking Information

• First Submitted Date: January 8, 2007
• First Posted Date: January 11, 2007
• Results First Submitted Date: May 5, 2014
• Results First Posted Date: June 2, 2014
• Last Update Posted Date: January 26, 2015
• Study Start Date: January 2007
• Actual Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: May 5, 2014)

Proportion of Subjects Relapsed [ Time Frame: 2 years ]

A protocol-defined relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted at least 24 hours, and were separated by at least 30 days from onset of a preceding relapse. All protocol-defined relapses were evaluated by an independent neurolgic evaluation committee. The proportion of subjects with a relapse was estimated using the Kaplan-Meier method, which was based on the time-to-first-relapse survival distribution.

• Original Primary Outcome Measures (submitted: January 9, 2007): To determine if BG00012 is effective in reducing the proportion of relapsing subjects at 2 years.

Current Secondary Outcome Measures (submitted: May 5, 2014)

• Number of New or Newly Enlarging T2 Hyperintense Lesions [ Time Frame: 2 years ]
  The number of new or newly enlarging T2 hyperintense lesions at 2 years that developed in each subject compared to baseline assessed on brain magnetic resonance imaging (MRI) scans. The estimates of mean T2 lesion count were calculated from a negative binomial regression model adjusted for region and baselineT2 lesion volume
• Number of Gadolinium-enhancing T1-weighted Lesions [ Time Frame: 2 years ]
  The number of Gd-enhancing lesions was assessed using brain MRI scans following administration of gadolinium, a contrast agent. The mean number of Gd-enhancing lesions at 2 years was the average of the number of lesions at 2 years in a treatment group.
• Number of Subjects With Gadolinium (Gd)-Enhancing Lesions [ Time Frame: 2 years ]
  Note: This outcome measure represents the categorical analysis for the previously listed secondary outcome measure "Number of Gadolinium-enhancing T1-weighted lesions"
• Annualized Relapse Rate [ Time Frame: 2 years ]
  A protocol-defined relapse was defined as new or recurrent neurologic symptoms not associated with fever or infection that lasted at least 24 hours, and were separated by at least 30 days from onset of a preceding relapse. All protocol-defined relapses were evaluated by an independent neurologic evaluation committee. The adjusted annualized relapse rate was calculated from a negative binomial regression model, adjusted for baseline EDSS (≤ 2.0 vs. >2.0), age (<40 versus ≥40 years), region, and the number of relapses in the 1 year prior to enrollment.
• Proportion of Subjects Experiencing Progression of Disability Assessed Using the Expanded Disability Status Scale (EDSS) [ Time Frame: 2 years ]
  The EDSS is based on a standardized neurological examination and focuses on symptoms that commonly occur in MS. EDSS scores range from 0.0 (normal) to 10.0 (death due to MS). Disability progression was defined as ≥ 1.0 point increase in subjects with a baseline EDSS of ≥1.0, or a ≥1.5 point increase in subjects with a baseline EDSS = 0, and required that the increase from baseline was confirmed ≥12 weeks later. The proportion of subjects with confirmed (12-week) disability progression was estimated using the Kaplan-Meier method, which was based on the time-to-first-progression survival distribution.

• Original Secondary Outcome Measures (submitted: January 9, 2007): There are multiple secondary outcomes.
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Oral BG00012 in Relapsing-Remitting Multiple Sclerosis
• Official Title: A Randomized, Multicenter, Double-Blind, Placebo-Controlled, Dose-Comparison Study to Determine the Efficacy and Safety of BG00012 in Subjects With Relapsing-Remitting Multiple Sclerosis

Brief Summary

To determine if treatment with BG00012 can decrease the number of MS relapses during a certain time period. To determine if, over time, BG00012 treatment can decrease the number of certain types of brain lesions commonly seen in MS patients and slow down the time it takes for the disease to get worse.

The purpose of this study is also to determine the safety of BG00012 and how well it is tolerated. Another goal is to see what effect BG00012 may have on tests and evaluations used to assess MS.

• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Relapsing-Remitting Multiple Sclerosis

Intervention

• Drug: BG00012
  Other Names:

  • dimethyl fumarate
  • Tecfidera®
• Drug: Placebo

Study Arms

• Placebo Comparator: Placebo
  Participants received two placebo capsules orally three times daily (TID)
  Intervention: Drug: Placebo
• Experimental: BG00012 240 mg Twice Daily (BID)
  Participants received two 120 mg BG00012 capsules orally twice daily (BID) and two placebo capsules orally once daily (QD)
  Intervention: Drug: BG00012
• Experimental: BG00012 240 mg 3 Times Daily (TID)
  Participants received two 120 mg BG00012 capsules orally three times daily (TID)
  Intervention: Drug: BG00012

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.
• Fox RJ, Gold R, Phillips JT, Okwuokenye M, Zhang A, Marantz JL. Efficacy and Tolerability of Delayed-release Dimethyl Fumarate in Black, Hispanic, and Asian Patients with Relapsing-Remitting Multiple Sclerosis: Post Hoc Integrated Analysis of DEFINE and CONFIRM. Neurol Ther. 2017 Dec;6(2):175-187. doi: 10.1007/s40120-017-0077-5. Epub 2017 Aug 2.
• Fernandez O, Giovannoni G, Fox RJ, Gold R, Phillips JT, Potts J, Okwuokenye M, Marantz JL. Efficacy and Safety of Delayed-release Dimethyl Fumarate for Relapsing-remitting Multiple Sclerosis in Prior Interferon Users: An Integrated Analysis of DEFINE and CONFIRM. Clin Ther. 2017 Aug;39(8):1671-1679. doi: 10.1016/j.clinthera.2017.06.012. Epub 2017 Jul 25.
• Fox RJ, Chan A, Zhang A, Xiao J, Levison D, Lewin JB, Edwards MR, Marantz JL. Comparative effectiveness using a matching-adjusted indirect comparison between delayed-release dimethyl fumarate and fingolimod for the treatment of multiple sclerosis. Curr Med Res Opin. 2017 Feb;33(2):175-183. doi: 10.1080/03007995.2016.1248380. Epub 2016 Nov 10.
• 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.
• Giovannoni G, Gold R, Fox RJ, Kappos L, Kita M, Yang M, Sarda SP, Zhang R, Viglietta V, Havrdova E. Relapses Requiring Intravenous Steroid Use and Multiple-Sclerosis-related Hospitalizations: Integrated Analysis of the Delayed-release Dimethyl Fumarate Phase III Studies. Clin Ther. 2015 Nov 1;37(11):2543-51. doi: 10.1016/j.clinthera.2015.09.011. Epub 2015 Oct 31.
• Nakamura K, Brown RA, Narayanan S, Collins DL, Arnold DL; Alzheimer's Disease Neuroimaging Initiative. Diurnal fluctuations in brain volume: Statistical analyses of MRI from large populations. Neuroimage. 2015 Sep;118:126-32. doi: 10.1016/j.neuroimage.2015.05.077. Epub 2015 Jun 3.
• Kita M, Fox RJ, Gold R, Giovannoni G, Phillips JT, Sarda SP, Kong J, Viglietta V, Sheikh SI, Okwuokenye M, Kappos L. Effects of delayed-release dimethyl fumarate (DMF) on health-related quality of life in patients with relapsing-remitting multiple sclerosis: an integrated analysis of the phase 3 DEFINE and CONFIRM studies. Clin Ther. 2014 Dec 1;36(12):1958-1971. doi: 10.1016/j.clinthera.2014.08.013. Epub 2014 Oct 12. Erratum In: Clin Ther. 2018 Mar 7;:
• Fox RJ, Kita M, Cohan SL, Henson LJ, Zambrano J, Scannevin RH, O'Gorman J, Novas M, Dawson KT, Phillips JT. BG-12 (dimethyl fumarate): a review of mechanism of action, efficacy, and safety. Curr Med Res Opin. 2014 Feb;30(2):251-62. doi: 10.1185/03007995.2013.849236. Epub 2013 Oct 22.
• Gold R, Kappos L, Arnold DL, Bar-Or A, Giovannoni G, Selmaj K, Tornatore C, Sweetser MT, Yang M, Sheikh SI, Dawson KT; DEFINE Study Investigators. Placebo-controlled phase 3 study of oral BG-12 for relapsing multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1098-107. doi: 10.1056/NEJMoa1114287. Erratum In: N Engl J Med. 2012 Dec 13;367(24):2362.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 5, 2014): 1234
• Original Enrollment (submitted: January 9, 2007): 1011
• Actual Study Completion Date: February 2011
• Actual Primary Completion Date: February 2011 (Final data collection date for primary outcome measure)

Eligibility Criteria

Key Inclusion Criteria:

• Unless otherwise specified, to be eligible to participate in this study, candidates must meet the following eligibility criteria at the time of the randomization:
• Must have a confirmed diagnosis of RRMS according to McDonald criteria #1-4.
• Must have a baseline EDSS between 0.0 and 5.0, inclusive.
• Must have relapsing-remitting disease course.

Key Exclusion Criteria:

• Unless otherwise specified, candidates will be excluded from study entry if any of the following exclusion criteria exist at randomization:
• Other chronic disease of the immune system, malignancies, acute urologic, pulmonary, gastrointestinal disease.
• Pregnant or nursing women.

Note: Other protocol-defined inclusion/exclusion criteria may apply.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 55 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Austria, Belgium, Bosnia and Herzegovina, Canada, Croatia, Czech Republic, France, Germany, Greece, Guatemala, India, Israel, Italy, Macedonia, The Former Yugoslav Republic of, Mexico, Moldova, Republic of, Netherlands, New Zealand, Poland, Romania, Serbia, Slovakia, South Africa, Switzerland, Ukraine, United Kingdom, United States, Virgin Islands (U.S.)
• Removed Location Countries: Belarus, Bulgaria, Kazakhstan, Russian Federation, Sweden, Turkey

Administrative Information

• NCT Number: NCT00420212
• Other Study ID Numbers: 109MS301
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Biogen
• Original Responsible Party: Not Provided
• Current Study Sponsor: Biogen
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Biogen

• PRS Account: Biogen
• Verification Date: January 2015