MRC Clinical Trials Unit at UCL, University College London, London, United Kingdom.
HIV and Hepatitis Department, World Health Organization, Geneva, Switzerland.
J Acquir Immune Defic Syndr. 2018 Aug 15;78 Suppl 1(1):S40-S48. doi: 10.1097/QAI.0000000000001748.
For HIV-infected children, formulation development, pharmacokinetic (PK) data, and evaluation of early toxicity are critical for licensing new antiretroviral drugs; direct evidence of efficacy in children may not be needed if acceptable safety and PK parameters are demonstrated in children. However, it is important to address questions where adult trial data cannot be extrapolated to children. In this fast-moving area, interventions need to be tailored to resource-limited settings where most HIV-infected children live and take account of decreasing numbers of younger HIV-infected children after successful prevention of mother-to-child HIV transmission. Innovative randomized controlled trial (RCT) designs enable several questions relevant to children's treatment and care to be answered within the same study. We reflect on key considerations, and, with examples, discuss the relative merits of different RCT designs for addressing multiple scientific questions including parallel multi-arm RCTs, factorial RCTs, and cross-over RCTs. We discuss inclusion of several populations (eg, untreated and pretreated children; children and adults) in "basket" trials; incorporation of secondary randomizations after enrollment and use of nested substudies (particularly PK and formulation acceptability) within large RCTs. We review the literature on trial designs across other disease areas in pediatrics and rare diseases and discuss their relevance for addressing questions relevant to HIV-infected children; we provide an example of a Bayesian trial design in prevention of mother-to-child HIV transmission and consider this approach for future pediatric trials. Finally, we discuss the relevance of these approaches to other areas, in particular, childhood tuberculosis and hepatitis.
对于感染 HIV 的儿童，新的抗逆转录病毒药物的开发、药代动力学（PK）数据和早期毒性评估至关重要；如果在儿童中证明了可接受的安全性和 PK 参数，则不一定需要有直接的疗效证据。然而，重要的是要解决无法从成人试验数据推断出儿童的问题。在这个快速发展的领域中，干预措施需要针对资源有限的环境进行调整，因为大多数感染 HIV 的儿童生活在这些环境中，并且在成功预防母婴 HIV 传播后，年幼的 HIV 感染儿童的数量正在减少。创新的随机对照试验（RCT）设计可以在同一研究中回答与儿童治疗和护理相关的几个问题。我们反思了一些关键的考虑因素，并通过示例讨论了不同 RCT 设计在解决多个科学问题方面的相对优势，包括平行多臂 RCT、析因 RCT 和交叉 RCT。我们讨论了在“篮子”试验中纳入多个人群（例如，未经治疗和预处理的儿童；儿童和成人）；在登记后进行二次随机化以及在大型 RCT 中使用嵌套子研究（特别是 PK 和配方可接受性）。我们回顾了儿科和罕见病领域其他疾病的试验设计文献，并讨论了它们在解决与感染 HIV 的儿童相关问题方面的相关性；我们提供了一个预防母婴 HIV 传播的贝叶斯试验设计的示例，并考虑将这种方法用于未来的儿科试验。最后，我们讨论了这些方法对其他领域的相关性，特别是儿童结核病和肝炎。
