Time to first relapse as an endpoint in multiple sclerosis clinical trials

Background: The increasing number of effective therapies in multiple sclerosis (MS) raises ethical concerns for using placebo in clinical trials, suggesting that new design strategies are needed. Objectives: To evaluate time to first relapse as an endpoint for MS clinical trials. Methods: A recently developed model fitting the distribution of time to first relapse in MS was used for simulations estimating the sample sizes of trials using this outcome, and for comparisons with the size of trials using annualized relapse rate (ARR) as primary outcome. Results: Trials based on time to first relapse resulted feasible, requiring sample sizes similar or even smaller than if based on ARR. In case of low ARR (0.4 relapses/year), as expected in future trials, one-year trials designed to detect a treatment effect of 30% with 90% power require less patients when based on time to first relapse (470 patients/arm) than when based on ARR (540 patients/arm). Conclusions: Our simulations show that time to first relapse is not less powerful than ARR in MS trials. Thus, this measure is a potentially useful primary outcome offering the advantage of an ethically sound design, where patients randomized to placebo can switch to the active drug once they relapse. Potential drawback is the loss of information for other endpoints collected at fixed time points.