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Neurology. 2013 Oct 1;81(14):1215-21. doi: 10.1212/WNL.0b013e3182a6cb9b. Epub 2013 Aug 21.

Clinical and MRI activity as determinants of sample size for pediatric multiple sclerosis trials.

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From the Pediatric Demyelinating Disease Program (L.H.V.), Program in Neuroscience & Mental Health, The Hospital for Sick Children, University of Toronto, Canada; Biostatistics Unit (A.S., M.P.S.), Department of Health Sciences, University of Genova, Italy; Department of Neurology & Neurosurgery (D.L.A., A.B.-O.), Montreal Neurological Institute and Hospital, McGill University, Montreal; Department of Neurology and Division of Medical Genetics (A.D.S.), University of British Columbia, Vancouver; Departments of Internal Medicine and Community Health Sciences (R.A.M.), Winnipeg Health Sciences Centre, University of Manitoba, Winnipeg, Canada; and Division of Neurology (B.B.), Department of Pediatrics, The Children's Hospital of Philadelphia, University of Pennsylvania.



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.


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.


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 (ϑ), 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 ϑ, 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.


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.

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