PDF: DEFINE
(2012)Objective
To evaluate the efficacy and safety of oral BG-12 (dimethyl fumarate) compared with placebo in patients with relapsing-remitting multiple sclerosis
Study Summary
• Both BG-12 regimens reduced disability progression by 34-38% compared to placebo
• BG-12 was well-tolerated with flushing and GI events as main side effects
Intervention
BG-12 (dimethyl fumarate) 240 mg twice daily or 240 mg three times daily vs placebo
Inclusion Criteria
Age 18-55 years, relapsing-remitting MS per McDonald criteria, EDSS 0-5.0, at least one relapse within 12 months or gadolinium-enhancing lesion on MRI within 6 weeks
Study Design
Arms: BG-12 240 mg twice daily, BG-12 240 mg three times daily, Placebo
Patients per Arm: 410 twice-daily BG-12, 416 thrice-daily BG-12, 408 placebo
Outcome
• ARR reduced by 53% (BID) and 48% (TID) vs placebo
• Disability progression reduced by 38% (BID, P=0.005) and 34% (TID, P=0.01)
Bottom Line
Both BG-12 regimens (240 mg twice daily and 240 mg three times daily) significantly reduced the proportion of patients with relapse, annualized relapse rate, disability progression, and MRI lesion burden compared to placebo in RRMS patients over 2 years.
Major Points
- BG-12 reduced the proportion of patients with relapse at 2 years by approximately 50% compared to placebo (27% and 26% vs 46%)
- Annualized relapse rate was reduced by 53% (twice-daily) and 48% (thrice-daily) compared to placebo
- Risk of confirmed disability progression sustained for 12 weeks was reduced by 38% (twice-daily) and 34% (thrice-daily)
- New or enlarging T2 lesions were reduced by 85% (twice-daily) and 74% (thrice-daily)
- Gadolinium-enhancing lesions were reduced by 90% (twice-daily) and 73% (thrice-daily)
- Main adverse events were flushing and gastrointestinal symptoms, highest in first month
- Lymphocyte counts decreased by approximately 28% at 1 year but remained within normal limits
- No opportunistic infections were observed
Study Design
- Study Type
- Randomized, double-blind, placebo-controlled phase 3 trial
- Randomization
- Yes
- Blinding
- Double-blind; separate examining and treating neurologists at each site remained unaware of assignments; patients instructed to take study drug at least 4 hours before visits to avoid revealing flushing
- Sample Size
- 1234
- Follow-up
- 2 years (96 weeks)
- Centers
- 198
- Countries
- 28 countries (not individually specified)
Primary Outcome
Definition: Proportion of patients who had a relapse by 2 years (protocol-defined relapses confirmed by independent neurologic evaluation committee)
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 46% | - | - | <0.001 for both comparisons |
Limitations & Criticisms
- No active comparator arm - comparison to approved MS therapies requires cross-trial comparisons
- MRI cohort was a subgroup (540 patients) rather than the full study population
- Approximately 23% of patients withdrew from the study, though balanced across groups
- Unknown long-term safety profile beyond 2 years
- Both BG-12 doses showed similar efficacy, leaving optimal dosing unclear
- Cannot determine whether therapeutic effect stems predominantly from immunomodulatory or neuroprotective mechanisms
- Short duration may not capture full disability progression effects
Citation
N Engl J Med 2012;367:1098-107