Article
Benefits of fingolimod likely outweigh harms for patients with relapsing remitting MS – a benefit harm balance modelling study based on FREEDOMS
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Published: | February 12, 2020 |
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Background/research question: Fingolimod is an oral agent approved by Relapsing Remitting Multiple Sclerosis (RRMS). Safety issues during a randomized trial and post marketing surveillance highlighting the need for a systematic evaluation of the benefits and harms (bra) of fingolimod. FREEDOMS, a randomized controlled trial comparing the two different dosages of fingolimod, 0.5 and 1.25 mg once a day, to matching placebo.
Methods: We estimated the health status of each individual patient over time, using a scale ranging from 0 (representing the worst possible health=death) to 100 (maximum health). The three determinants of health status were the Expanded Disability Status Scale measured at baseline and every three months in stable state, relapses and any adverse events. We considered the severity and duration of relapses and adverse events and determined a priori their impact on health status. Finally, we compared the health status between participants of the three arms using a linear mixed model that accounted for censoring. We interpreted the relevance of the difference between fingolimod 0.5 mg once daily and placebo based on a priori defined Minimal Important Difference (MID, 4.6 point difference).
Results: The main analysis showed a net benefit of fingolimod 0.5 mg when compared to placebo (two years, average health status difference of 2.7 (95% CI 2.2 to 3.2, p<0.001), with a maximum difference of ~ 4 points (end study). The sensitivity analyses that varied weights for relapses and adverse events also all favoured fingolimod 0.5 mg over placebo and the sensitivity analysis that weighted relapses most showed a differences that outweighed the MID.
Conclusion: Our results showed a statistically significant net benefit of fingolimod 0.5 mg over placebo. The difference in health status may not be clinically meaningful on a population, but the BH balance may vary substantially across patients depending on the individual perceived importance of relapses and adverse events. Our study is the first BH assessment modelling study based on individual patient data from a randomized trial for an MS drug. It may pave the way for similar analyses of other MS drugs where the benefit harm balance is debated and, thereby, provide an important and objective evidence base for guideline recommendations.
Competing interests: I declare that I have no conflict of interest.