Enhancing crossover trial design for rare diseases: limiting ineffective exposure and increasing study power by enabling patient choice to escape early.
Enhancing crossover trial design for rare diseases: limiting ineffective exposure and increasing study power by enabling patient choice to escape early.
复制标题
加强罕见疾病的交叉试验设计：通过让患者选择尽早逃避来限制无效暴露并提高研究能力。
DOI：
10.1016/j.cct.2014.05.001
复制
发表时间：
2014
影响因子：
2.2
通讯作者：
Hashkes,PhilipJ
中科院分区：
文献类型：
--
作者：
Huang,Bin;Giannini,EdwardH;Lovell,DanielJ;Ding,Lili;Liu,Yongchao;Hashkes,PhilipJ
背景解决临床试验设计中最重要的两个考虑因素，即最大限度地增加研究力量和最大限度地减少患者暴露于无效治疗的机会，对于罕见疾病的试验尤其具有挑战性。家族性地中海热(FMF)Rilonacept试验(Hashkes等，Ann Intern Med，2012；157：533-41)提出了一种新的交叉设计，使患者能够选择对罕见疾病进行早期逃脱。目的研究实施早期逃逸到交叉设计对学习能力、暴露于无效治疗臂的暴露和辍学率的影响，并提出一种贝叶斯建模方法。方法基于FMF试验数据，模拟研究比较了传统的无早期逃脱、按患者选择的早期逃脱、按患者选择的早期逃脱三种设计的学习功率和辍学率。结果与传统的假设无脱落的交叉设计相比，按患者选择或按方案设计的早期逃逸分别获得了0.89±0.12和0.78±0.20的研究效率。与按方案选择的早期逃脱相比，每个患者选择的早期逃脱可提高功率1.29±0.26，并将辍学率降低8-29%，但患者暴露在低效治疗臂的可能性更大。结论FMF试验和模拟研究的结果表明，交叉试验中允许早期逃脱的结果通过最大限度地减少患者对无效治疗臂的暴露而改进了设计，同时保持合理的研究功率，这对罕见疾病试验特别重要。在两种类型的早期逃避之间做出选择，是在学习能力和接受无效治疗之间的权衡。
BackgroundAddressing the two most important considerations in designing clinical trials, i.e. maximizing study power and minimizing patient exposure to ineffective treatment, is particularly challenging for trials of rare diseases. The familial Mediterranean fever (FMF) rilonacept trial (Hashkes et al., Ann Intern Med 2012;157:533–41) demonstrates a novel crossover design by enabling patient choice to early escape for rare disease.PurposeTo investigate the effect on study power, exposure to the ineffective treatment arm and dropout rate by implementing early escape to crossover design, and to propose a Bayesian modeling approach.MethodBased on the FMF trial data, simulation studies compared study power and dropout rate among three types of designs for crossover trial: traditional without early escape, early escape per-patient-choice, and early escape per-protocol.ResultsThe early escape per patient choice or per protocol design achieved 0.89 ± 0.12 and 0.78 ± 0.20 of the study efficiency when compared to the traditional crossover design assuming no dropout. Early escape per patient choice compared to early escape per protocol improved power by 1.29 ± 0.26, and reduced the dropout rate by 8–29%, but with greater patient exposure to the less effective treatment arm.ConclusionsThe results of the FMF trial and simulation studies suggest that allowing early escape in crossover trial enhanced the design by minimizing patient's exposure to the ineffective treatment arm while maintaining a reasonable study power, which is particularly important for rare disease trials. Choice between the two types of early escape presents tradeoff between study power and exposure to ineffective treatment.