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.
Neurology. 2013 Oct 1;81(14):1215-21. doi: 10.1212/WNL.0b013e3182a6cb9b. Epub 2013 Aug 21.
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.
利用新的 T2 病灶计数、年复发率（ARR）和首次复发时间（TTFR）终点来估算小儿多发性硬化症（MS）试验的样本量。
对纳入全国前瞻性队列研究的 42 例 MS 患儿的新 T2 病灶和复发计数数据进行泊松和负二项式模型拟合，对 TTFR 数据进行负二项式时间事件和指数模型拟合。通过从新 T2 病灶计数、复发次数或 TTFR 的最佳拟合模型中重新抽样，在不同的效果大小、试验持续时间和模型参数假设下进行模拟。
假设新 T2 病灶在 6 个月内减少 50%，则需要 90 例/组，而治疗效果为 40%时则需要 165 例/组。使用与复发相关的终点进行 2 年试验的样本量小于 1 年试验。对于 2 年试验和过度离散（ϑ）的保守假设，样本量范围为 70 例/组（使用 ARR）至 105 例/组（TTFR），用于减少 50%的复发，以及 230 例/组（ARR）至 365 例/组（TTFR），用于减少 30%的复发。假设不那么保守的 ϑ，使用 ARR 的 2 年试验需要减少 50%的复发，需要 45 例/组（TTFR 为 60 例/组），减少 30%的复发需要 145 例/组（TTFR 为 200 例/组）。
在儿科 MS 人群中，使用新的 T2 病灶计数作为终点的 6 个月 II 期试验是可行的；然而，基于 ARR 或 TTFR 的试验需要持续 2 年，并且需要多中心合作。
