Wednesday, 11 March 2015

The efficacy of DMF across two studies

How much torture can the data withstand before we say enough is enough? #MSBlog #MSResearch

"Does 1+1=2 or does 1+1=3? The following study assesses the effect of dimethyl fumarate (DMF) across both populations of the the two phase 3 pivotal clinical trials (DEFINE and CONFIRM). If both studies were positive do we expect the combined analysis to be positive or negative?"

"Where the combined analysis may help is where one study was positive and the second negative; for example in relation to disability progression, subgroup analyses (naive vs. 2nd-line exposure) and the impact of DMF on brain atrophy Surprise, surprise, when you add the two studies together you get more power (ability to detect a difference between active and placebo treated MSers), which tells is that DMF had a robust impact on disease progression. We will need to wait to see the other combined subgroup analyses, but they are likely to be positive."


"Does this study add anything to the literature? Do you feel more confident that DMF is effective in RRMS?"

"When I did my PhD, my mentor. Professor Ed Thompson used to say if you need to torture the data it is not really meaningful. He also used to say if the data said the opposite to what you expected it was almost certainly correct. This data simply states what the original two trials said but with smaller or more significant p-values. A closer look at the data, by combining them the two studies into one adds little to the efficacy profile of DMF; DMF continues to be a blockbuster drug that will have more than $3,000,000,000 of sales in 2015. In my book 1+1=2; 1+1 does not equal 3."





Viglietta et al. Efficacy of delayed-release dimethyl fumarate in relapsing-remitting multiple sclerosis: integrated analysis of the phase 3 trials. Ann Clin Transl Neurol. 2015 Feb;2(2):103-18. doi: 10.1002/acn3.148. Epub 2014 Dec 4.

OBJECTIVE: Obtain a more precise estimate of the efficacy of delayed-release dimethyl fumarate (DMF; also known as gastro-resistant DMF) in relapsing MS and examine the consistency of DMF's effects across MSer subgroups stratified by baseline demographic and disease characteristics.


METHODS: A prespecified integrated analysis of the randomized, double-blind, placebo-controlled, Phase 3 DEFINE and CONFIRM trials was conducted.

RESULTS: The intent-to-treat population comprised 2301 MSers randomized to receive placebo (n = 771) or DMF 240 mg twice daily (BID; n = 769) or three times daily (TID; n = 761). At 2 years, DMF BID and TID reduced the annualized relapse rate by 49% and 49% (both P < 0.0001), risk of relapse by 43% and 47% (both P < 0.0001), risk of 12-week confirmed disability progression by 32% (P = 0.0034) and 30% (P = 0.0059), and risk of 24-week confirmed disability progression by 29% (P = 0.0278) and 32% (P = 0.0177), respectively, compared with placebo. In a subset of MSers (MRI cohort), DMF BID and TID reduced the mean number of new/enlarging T2-hyperintense lesions by 78% and 73%, gadolinium-enhancing lesion activity by 83% and 70%, and mean number of new nonenhancing T1-hypointense lesions by 65% and 64% (all P < 0.0001 vs. placebo). Effects were generally consistent across MSer subgroups.

INTERPRETATION: The integrated analysis provides a more precise estimate of DMF's efficacy. DMF demonstrated a robust reduction in disease activity and a consistent therapeutic effect across MSer subgroups.

CoI: multiple

6 comments:

  1. Giovannoni, sir, do you have any intentions of writing a non-fiction book on your thoughts of medicine and neurology? I get the sense something is brewing and that you'll go all-Siddhartha Mukherjee on us soon.

    Siddhartha Mukherjee's book is amazing, though.

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    1. Creative writing is not my strong point. I think I will stick to what I am doing at the moment. Seeing patients and trying to improve the lives of MSers through research and public engagement. Thanks for the recommendation I will buy Siddhartha Mukherjee's book to read on my summer vacation. The sad thing is that holidays are the only time I get to read books.

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  2. These are the kind of studies that drive me crazy. I can't speak for other patients but enough already with these meaningless studies. Just reading the interpretation : "The integrated analysis provides a more precise estimate of DMF's efficacy. DMF demonstrated a robust reduction in disease activity and a consistent therapeutic effect across MSer subgroups." makes me feel more confident that their $3 billion drug will be a windfall for the company.

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  3. So do we lack data for atrophy reduction or it does not have effect? Been trying to find out all evening, any info much appreciated.

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