PDF: CONFIRM
(2012)Objective
To evaluate the efficacy and safety of oral BG-12 (dimethyl fumarate) at two doses compared with placebo and glatiramer acetate as reference comparator in patients with relapsing-remitting multiple sclerosis
Study Summary
• No significant effect on disability progression with any active treatment
• BG-12 reduced new T2 lesions by 71-73% and new T1 lesions by 57-65% vs placebo
Intervention
BG-12 240mg twice daily vs BG-12 240mg thrice daily vs glatiramer acetate 20mg SC daily vs placebo for 96 weeks
Inclusion Criteria
RRMS (McDonald criteria), age 18-55, EDSS 0-5, ≥1 relapse in prior 12 months or ≥1 GdE lesion within 6 weeks of randomization
Study Design
Arms: Placebo vs BG-12 240mg BID vs BG-12 240mg TID vs Glatiramer acetate 20mg SC daily
Patients per Arm: 363 vs 359 vs 345 vs 350
Outcome
• Disability progression at 2 years: 17% vs 13% vs 13% vs 16% (all NS vs placebo)
• New T2 lesions reduced by 71%, 73%, 54% (all p<0.001 vs placebo)
Bottom Line
BG-12 at both doses significantly reduced annualized relapse rates by 44-51% compared to placebo at 2 years (both p<0.001), with concurrent reductions in MRI lesions. Glatiramer acetate also reduced ARR by 29% vs placebo. However, none of the active treatments significantly reduced disability progression. BG-12 was well-tolerated with flushing and GI events as main adverse effects, decreasing over time. Post hoc comparisons suggested BG-12 TID may be superior to glatiramer acetate for some endpoints, though the study was not designed for this comparison.
Major Points
- BG-12 twice-daily reduced ARR by 44% (0.22 vs 0.40, p<0.001) and thrice-daily by 51% (0.20 vs 0.40, p<0.001) compared to placebo
- Glatiramer acetate reduced ARR by 29% (0.29 vs 0.40, p=0.01) compared to placebo
- No significant reduction in 12-week confirmed disability progression with any active treatment (17% placebo vs 13% BG-12 BID vs 13% BG-12 TID vs 16% GA)
- New T2 lesions reduced by 71% (BG-12 BID), 73% (BG-12 TID), and 54% (GA) vs placebo (all p<0.001)
- New T1 hypointense lesions reduced by 57%, 65%, and 41% vs placebo, respectively
- GdE lesions reduced by 74%, 65%, and 61% vs placebo, respectively (all p<0.001)
- Post hoc BG-12 vs GA comparisons showed BG-12 TID superior for ARR (p=0.02), and both BG-12 doses superior for new T2 lesions (p<0.01)
- Flushing (28-35%) and GI events (36-41%) most common with BG-12, highest in first month then decreasing
- Lymphocyte counts decreased ~28-32% with BG-12 but remained in normal range; 4-5% had lymphocytes <0.5×10⁹/L
- No malignant neoplasms or opportunistic infections with BG-12; 4 malignancies in GA group
- Study completion rate ~80% across groups; lower placebo dropout improved by allowing switch to alternative MS therapy
Study Design
- Study Type
- Phase 3, multicenter, randomized, double-blind (for BG-12 vs placebo), rater-blinded (for GA), placebo-controlled trial with active comparator
- Randomization
- Yes
- Blinding
- Double-blind for BG-12 and placebo groups; rater-blinded for glatiramer acetate (patients knew they were receiving GA but examining neurologists were blinded). Separate treating and examining neurologists at each site. Patients instructed not to take BG-12/placebo within 4 hours before visits to prevent unblinding from flushing. MRI reading center and neurologic evaluation committee blinded to all assignments.
- Sample Size
- 1417
- Follow-up
- 96 weeks (2 years)
- Centers
- 200
- Countries
- 28 countries - not individually specified
Primary Outcome
Definition: Annualized relapse rate at 2 years, based on protocol-defined relapses confirmed by independent neurologic evaluation committee. Relapse defined as new/recurrent neurologic symptoms not associated with fever/infection, lasting ≥24 hours, with new objective neurologic findings, separated from other confirmed relapses by ≥30 days.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 0.40 (95% CI 0.33-0.49) | BG-12 BID: 0.22 (95% CI 0.18-0.28); BG-12 TID: 0.20 (95% CI 0.16-0.25); GA: 0.29 (95% CI 0.23-0.35) | - (BG-12 BID reduction: 26.0-57.7%; BG-12 TID reduction: 33.8-63.1%; GA reduction: 6.9-45.2%) | BG-12 BID: p<0.001; BG-12 TID: p<0.001; GA: p=0.01 |
Limitations & Criticisms
- Study not designed or powered to test superiority or noninferiority of BG-12 versus glatiramer acetate
- Glatiramer acetate arm was rater-blinded but not double-blind (patients knew they were receiving injections), introducing potential bias
- No significant effect on disability progression with any active treatment, possibly due to lower-than-expected placebo progression rate (17% vs 27% in DEFINE)
- Post hoc comparisons between BG-12 and glatiramer acetate should be interpreted cautiously due to lack of prespecified statistical correction
- MRI cohort was only a subset of total population (681/1417), limiting generalizability of MRI findings
- Higher discontinuation rate in placebo group (36%) than active groups (25-30%) could introduce bias
- Lymphocyte reduction with BG-12 raises long-term safety concerns, particularly for progressive multifocal leukoencephalopathy (PML) risk not captured in 2-year trial
- No direct comparison with interferon beta products, limiting positioning in treatment algorithm
- Predominantly white population (83-85%) limits generalizability to other racial groups
- Prior DMT exposure (~29%) may confound results in treatment-experienced subgroup
- Flushing mitigation strategy (avoiding dosing 4h before visits) may have affected blinding integrity
Citation
N Engl J Med 2012;367:1087-97