The DEFINE trial: BG-12 reduces relapse rate in multiple sclerosis [Classics Series]

Image: PD

1. BG-12 (dimethyl fumarate) significantly reduces relapse rates, disability progression, and image detectable lesion load over a two-year period.

2. BG-12 is associated with higher rates of transient flushing and gastrointestinal events.

Original Date of Publication: September 20, 2012

Study Rundown: In this phase 3 trial, BG-12 (dimethyl fumarate) significantly decreased the annualized relapse rate as compared to placebo regardless of the frequency of administration (i.e., BID vs. TID). Moreover, BG-12 significantly reduced the rate of progression of disability and decreased the number of new or enlarging hyperintense lesions on T2-weighted MRI. Treatment with BG-12 was associated with increased rates of flushing, though there were no significant differences in rates of discontinuation between study groups. In summary, BG-12 significantly reduces relapse rates of multiple sclerosis (MS) as compared to placebo (P<0.001), regardless of the frequency of administration. The findings of this study are very similar to those of the CONFIRM trial, which also compared BG-12 with placebo. While these results are promising, studies comparing the efficacy and safety of BG-12 with approved therapies for MS are needed.

Please click to read study in NEJM

In-Depth [randomized, controlled study]: Originally published in 2012 in NEJM, the DEFINE trial assessed the efficacy and safety of BG-12 in relapsing-remitting MS over a 96-week period. A total of 1,234 patients underwent randomization in a 1:1:1 ratio to three study arms: 1) BG-12 240 mg BID, 2) BG-12 240 mg TID, and 3) placebo. The study was conducted at 198 sites in 28 countries.

The annualized relapse rates were 0.17 (95%CI 0.14-0.21) for the BG-12 BID group and 0.19 (95%CI 0.15-0.23) for the BG-12 TID group, compared to a rate of 0.36 (95%CI 0.30-0.44) for the placebo group. The differences in relapse rates between BG-12 and placebo were significant and independent of dose frequency. Notably, 38% of the BID and 32% of the TID groups experienced flushing as an adverse event, as compared to 5% of those taking placebo. A similar number of patients in each group experienced some type of adverse event (approximately 95-96%), including MS relapse. Infection rates were also similar across all groups and did not differ with regards to frequency of BG-12 administration (65% for placebo, 64% in the BID group, and 68% in the TID group).

By Jose-Marc Techner, Andrew Cheung, M.D.

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