Objective: To estimate sample sizes for pediatric multiple sclerosis (MS) trials using new T2 lesion count, annualized relapse rate (ARR), and time to first relapse (TTFR) endpoints.Methods: Poisson and negative binomial models were fit to new T2 lesion and relapse count data, and negative binomial time-to-event and exponential models were fit to TTFR data of 42 children with MS enrolled in a national prospective cohort study. Simulations were performed by resampling from the best-fitting model of new T2 lesion count, number of relapses, or TTFR, under various assumptions of the effect size, trial duration, and model parameters.Results: Assuming a 50% reduction in new T2 lesions over 6 months, 90 patients/arm are required, whereas 165 patients/arm are required for a 40% treatment effect. Sample sizes for 2-year trials using relapse-related endpoints are lower than that for 1-year trials. For 2-year trials and a conservative assumption of overdispersion (q), sample sizes range from 70 patients/arm (using ARR) to 105 patients/arm (TTFR) for a 50% reduction in relapses, and 230 patients/arm (ARR) to 365 patients/arm (TTFR) for a 30% relapse reduction. Assuming a less conservative q, 2-year trials using ARR require 45 patients/arm (60 patients/arm for TTFR) for a 50% reduction in relapses and 145 patients/arm (200 patients/arm for TTFR) for a 30% reduction.Conclusion: Six-month phase II trials using new T2 lesion count as an endpoint are feasible in the pediatric MS population; however, trials powered on ARR or TTFR will need to be 2 years in duration and will require multicentered collaboration. Therapies to treat pediatric-onset multiple sclerosis (MS) 1-4 are used off-label, because all approved pharmacologic agents for MS have been studied exclusively in adult patients. With the recent approval of the first oral disease-modifying therapies (DMTs) for MS 5,6 and several promising new therapies likely to be approved over the next 10 years, pediatric practitioners face the challenge of recommending suitable therapies for pediatric patients with MS despite a lack of evidence on safety and efficacy of these drugs in the pediatric population.7 Clinical trials for pediatric-onset MS are being planned, but data on appropriate trial endpoints and required sample sizes to inform trial design are lacking.Annualized relapse rate (ARR) is a common primary efficacy endpoint in clinical trials of adults with MS, and reduction in new T2 and gadolinium-enhancing lesions are frequently used secondary endpoints in phase III trials. 5,[8][9][10][11][12] Time to first relapse (TTFR) has recently been shown in adults with MS to be a feasible and powerful trial endpoint; using TTFR has the advantage of permitting patients initially randomized to placebo to be switched to active therapy at the time of first relapse.