Centre for International Child Health, Department of Paediatrics, Imperial College London, London, UK.
Division of Clinical Pharmacology, Division of Infectious Disease, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Int J Tuberc Lung Dis. 2018 May 1;22(5):24-33. doi: 10.5588/ijtld.17.0359.
Paediatric anti-tuberculosis treatment trials have traditionally been limited to Phase I/II studies evaluating the drug pharmacokinetics and safety in children, with assumptions about efficacy made by extrapolating data from adults. However, it is increasingly being recognised that, in some circumstances, efficacy trials are required in children. The current treatment for children with multidrug-resistant tuberculosis (MDR-TB) is long and toxic; shorter, safer regimens, using novel agents, require urgent evaluation. Given the changing pattern of drug metabolism, disease spectrum and rates of TB disease confirmation with age, decisions around inclusion criteria require careful consideration. The most straightforward MDR-TB efficacy trial would include only children with confirmed MDR-TB and no additional drug resistance. Given that it may be unclear at the time treatment is initiated whether the diagnosis will ultimately be confirmed and what the final drug resistance profile will be, this presents a unique challenge in children. Recruiting only these children would, however, limit the generalisability of such a trial, as in reality the majority of children with TB do not have bacteriologically confirmed disease. Given the good existing treatment outcomes with current routine regimens for children with MDR-TB, conducting a superiority trial may not be the optimal design. Demonstrating non-inferiority of efficacy, but superiority with regard to safety, would be an alternative strategy. Using standardised control and experimental MDR-TB treatment regimens is challenging given the wide spectrum of paediatric disease. However, using variable regimens would make interpretation challenging. A paediatric MDR-TB efficacy trial is urgently needed, and with global collaboration and capacity building, is highly feasible.
儿科抗结核治疗试验传统上仅限于评估儿童药物药代动力学和安全性的 I/II 期研究，通过从成人数据推断疗效。然而，越来越多的人认识到，在某些情况下，儿童需要进行疗效试验。目前，儿童耐多药结核病（MDR-TB）的治疗方案疗程长且毒性大；使用新药物的更短、更安全的方案需要紧急评估。鉴于药物代谢、疾病谱和 TB 确诊率随年龄的变化模式，纳入标准的决策需要仔细考虑。最简单的 MDR-TB 疗效试验仅包括确诊 MDR-TB 且无其他耐药性的儿童。鉴于在开始治疗时可能不清楚最终是否会确诊诊断，以及最终的耐药谱是什么，这在儿童中提出了一个独特的挑战。然而，仅招募这些儿童将限制此类试验的普遍性，因为实际上大多数结核病患儿的疾病没有细菌学确诊。鉴于目前针对 MDR-TB 儿童的常规方案已有良好的治疗效果，进行优越性试验可能不是最佳设计。展示疗效非劣效性，但在安全性方面具有优越性，将是一种替代策略。由于儿科疾病谱广泛，使用标准化的对照和实验性 MDR-TB 治疗方案具有挑战性。然而，使用可变的方案将使解释具有挑战性。迫切需要开展儿科 MDR-TB 疗效试验，通过全球合作和能力建设，这是高度可行的。
