Department of Health Sciences (DISSAL), University of Genova, Via Pastore 1, Genova, 16132, Italy.
Mult Scler. 2013 Apr;19(4):466-74. doi: 10.1177/1352458512457841. Epub 2012 Aug 22.
The increasing number of effective therapies to treat multiple sclerosis (MS) raises ethical concerns for the use of placebo in clinical trials, suggesting that new clinical trial design strategies are needed.
To evaluate time to first relapse as an endpoint for MS clinical trials.
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 as an outcome, and for comparison with the size of trials using the annualized relapse rate (ARR) as the primary outcome.
Trials based on time to first relapse were feasible, requiring sample sizes that were similar or even smaller than if the study was based on ARR instead. In the case of low ARR (0.4 relapses/year), as is expected in future trials, the 1-year trials designed to detect a treatment effect of 30%, with 90% power, require fewer patients when based on time to first relapse (470 patients/arm) than if based on ARR (540 patients/arm).
Our simulations show that time to first relapse is not less powerful than ARR in MS trials; thus, this measure would be a potentially useful primary outcome offering the advantage of an ethically sound design, as the patients randomized to placebo can then switch to the active drug, once they relapse. A potential drawback is the loss of information for other endpoints collected at fixed time points.
治疗多发性硬化症（MS）的有效疗法越来越多，这引发了临床试验中使用安慰剂的伦理问题，表明需要新的临床试验设计策略。
评估首次复发时间作为多发性硬化症临床试验的终点。
使用最近开发的一种适用于多发性硬化症首次复发时间分布的模型进行模拟，估计以此为结局的试验样本量，并与以年复发率（ARR）为主要结局的试验规模进行比较。
基于首次复发时间的试验是可行的，所需的样本量与如果研究基于 ARR 相似，甚至更小。在 ARR 较低（0.4 次复发/年）的情况下，正如未来试验所预期的那样，设计用于检测 30%治疗效果的 1 年试验，需要的患者数量少于基于 ARR 的试验（每臂 470 例患者）。
我们的模拟表明，首次复发时间在多发性硬化症试验中并不逊于 ARR；因此，这种衡量标准将是一种潜在有用的主要结局，具有合理的设计优势，因为随机分配到安慰剂的患者一旦复发，就可以转而使用活性药物。潜在的缺点是在固定时间点收集的其他终点的信息丢失。
