Efficacy and Safety Study of Oral BG00012 With Active Reference in Relapsing-Remitting Multiple Sclerosis (CONFIRM)

• ClinicalTrials.gov Identifier: NCT00451451
• Recruitment Status: Completed
• First Posted: March 23, 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: March 21, 2007
• First Posted Date: March 23, 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: June 2007
• Actual Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)

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

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 Expanded Disability Status Scale (EDSS ) score(≤2.0 versus>2.0), age (<40 versus ≥40 years), region, and the number of relapses in the 1 year prior to enrollment.

• Original Primary Outcome Measures (submitted: March 22, 2007): To determine whether BG00012, when compared with placebo is effective in reducing the rate of clinical relapses 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 hyperintense lesion count were calculated from a negative binomial regression model adjusted for region and baseline T2 hyperintense lesion volume.
• Number of New T1 Hypointense Lesions [ Time Frame: 2 years ]
  The number of new T1 hypointense lesions at 2 years that developed in each subject compared to baseline assessed on brain magnetic resonance imaging (MRI) scans. The estimates of mean T1 hypointense lesion count were calculated from a negative binomial regression model adjusted for region and baseline T1 hypointense lesion volume.
• 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 neurologic 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.
• Proportion of Subjects Experiencing Progression of Disability Assessed Using the Expanded Disability Status Scale (EDSS) [ Time Frame: 2 years ]
  EDSS is based on a standardized neurological exam and focuses on symptoms that commonly occur in MS. 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 ≥1.5 point increase in subjects with a baseline EDSS=0, and required that the increase from baseline was confirmed ≥ 12weeks 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: March 22, 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 Study of Oral BG00012 With Active Reference in Relapsing-Remitting Multiple Sclerosis
• Official Title: A Randomized, Multicenter, Placebo-Controlled and Active Reference (Glatiramer Acetate) Comparison Study to Evaluate 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. Other goals of the study are 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 MS to get worse.

Other objectives of the study are to determine the safety and tolerability of BG00012, as well as the effect it may have on tests and evaluations used to assess MS. Additionally, glatiramer acetate is being used to compare its benefits and risks with placebo and BG00012.

• Detailed Description: Multiple sclerosis (MS) is a chronic disease of the central nervous system that affects approximately 400,000 persons in North America and 365,000 persons in Europe. It is predominantly a disease of young adults, primarily women, with disease onset typically occurring between the ages of 20 and 40.
• 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
• Drug: Glatiramer Acetate

Study Arms

• 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)
  Interventions:

  • Drug: BG00012
  • Drug: Placebo
• Experimental: BG00012 240 mg 3 Times Daily (TID)
  Participants received two 120 mg BG00012 capsules orally three times daily (TID)
  Intervention: Drug: BG00012
• Placebo Comparator: Placebo
  Participants received two placebo capsules orally three times daily (TID)
  Intervention: Drug: Placebo
• Active Comparator: Glatiramer Acetate (GA) 20 mg Injection Once Daily (QD)
  Participants received glatiramer acetate (GA) 20 mg subcutaneous injection once daily (QD)
  Intervention: Drug: Glatiramer Acetate

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.
• 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.
• Fox RJ, Miller DH, Phillips JT, Hutchinson M, Havrdova E, Kita M, Yang M, Raghupathi K, Novas M, Sweetser MT, Viglietta V, Dawson KT; CONFIRM Study Investigators. Placebo-controlled phase 3 study of oral BG-12 or glatiramer in multiple sclerosis. N Engl J Med. 2012 Sep 20;367(12):1087-97. doi: 10.1056/NEJMoa1206328. Erratum In: N Engl J Med. 2012 Oct 25;367(17):1673.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: May 5, 2014): 1417
• Original Enrollment (submitted: March 22, 2007): 1232
• Actual Study Completion Date: August 2011
• Actual Primary Completion Date: August 2011 (Final data collection date for primary outcome measure)

Eligibility 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:

Key Inclusion Criteria:

• Must have 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:

• Other chronic disease of immune system, malignancies, 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: Belarus, Belgium, Bosnia and Herzegovina, Bulgaria, Canada, Costa Rica, Croatia, Czech Republic, Estonia, France, Germany, Greece, India, Ireland, Israel, Latvia, Macedonia, The Former Yugoslav Republic of, Mexico, Moldova, Republic of, New Zealand, Poland, Puerto Rico, Romania, Serbia, Slovakia, Spain, Ukraine, United States
• Removed Location Countries: Australia, Italy, Kazakhstan, Lithuania, Russian Federation

Administrative Information

• NCT Number: NCT00451451
• Other Study ID Numbers: 109MS302
• 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