Chabala Chishala, Turkova Anna, Thomason Margaret J, Wobudeya Eric, Hissar Syed, Mave Vidya, van der Zalm Marieke, Palmer Megan, Kapasa Monica, Bhavani Perumal K, Balaji Sarath, Raichur Priyanka A, Demers Anne-Marie, Hoddinott Graeme, Owen-Powell Ellen, Kinikar Aarti, Musoke Philippa, Mulenga Veronica, Aarnoutse Rob, McIlleron Helen, Hesseling Anneke, Crook Angela M, Cotton Mark, Gibb Diana M
University Teaching Hospital, Children's Hospital, Private Bag RW IX, Ridgeway, Lusaka, Zambia.
Medical Research Council Clinical Trials Unit at University College London, Institute of Clinical Trials and Methodology, High Holborn, London, WC1V 6LJ, UK.
Trials. 2018 Apr 19;19(1):237. doi: 10.1186/s13063-018-2608-5.
Tuberculosis (TB) in children is frequently paucibacillary and non-severe forms of pulmonary TB are common. Evidence for tuberculosis treatment in children is largely extrapolated from adult studies. Trials in adults with smear-negative tuberculosis suggest that treatment can be effectively shortened from 6 to 4 months. New paediatric, fixed-dose combination anti-tuberculosis treatments have recently been introduced in many countries, making the implementation of World Health Organisation (WHO)-revised dosing recommendations feasible. The safety and efficacy of these higher drug doses has not been systematically assessed in large studies in children, and the pharmacokinetics across children representing the range of weights and ages should be confirmed.
METHODS/DESIGN: SHINE is a multicentre, open-label, parallel-group, non-inferiority, randomised controlled, two-arm trial comparing a 4-month vs the standard 6-month regimen using revised WHO paediatric anti-tuberculosis drug doses. We aim to recruit 1200 African and Indian children aged below 16 years with non-severe TB, with or without HIV infection. The primary efficacy and safety endpoints are TB disease-free survival 72 weeks post randomisation and grade 3 or 4 adverse events. Nested pharmacokinetic studies will evaluate anti-tuberculosis drug concentrations, providing model-based predictions for optimal dosing, and measure antiretroviral exposures in order to describe the drug-drug interactions in a subset of HIV-infected children. Socioeconomic analyses will evaluate the cost-effectiveness of the intervention and social science studies will further explore the acceptability and palatability of these new paediatric drug formulations.
Although recent trials of TB treatment-shortening in adults with sputum-positivity have not been successful, the question has never been addressed in children, who have mainly paucibacillary, non-severe smear-negative disease. SHINE should inform whether treatment-shortening of drug-susceptible TB in children, regardless of HIV status, is efficacious and safe. The trial will also fill existing gaps in knowledge on dosing and acceptability of new anti-tuberculosis formulations and commonly used HIV drugs in settings with a high burden of TB. A positive result from this trial could simplify and shorten treatment, improve adherence and be cost-saving for many children with TB. Recruitment to the SHINE trial begun in July 2016; results are expected in 2020.
International Standard Randomised Controlled Trials Number: ISRCTN63579542 , 14 October 2014. Pan African Clinical Trials Registry Number: PACTR201505001141379 , 14 May 2015. Clinical Trial Registry-India, registration number: CTRI/2017/07/009119, 27 July 2017.
儿童结核病通常菌量少，非重症肺结核很常见。儿童结核病治疗的证据大多是从成人研究推断而来。针对涂片阴性肺结核成人患者的试验表明，治疗时间可从6个月有效缩短至4个月。最近许多国家已引入新的儿科固定剂量复方抗结核治疗药物，使得实施世界卫生组织（WHO）修订的给药建议成为可能。这些较高药物剂量的安全性和有效性尚未在针对儿童的大型研究中得到系统评估，代表不同体重和年龄范围的儿童的药代动力学情况也有待确认。
方法/设计：“SHINE”是一项多中心、开放标签、平行组、非劣效性、随机对照双臂试验，比较使用WHO修订的儿科抗结核药物剂量的4个月疗程与标准6个月疗程。我们的目标是招募1200名16岁以下患有非重症结核病、无论是否感染HIV的非洲和印度儿童。主要疗效和安全性终点是随机分组后72周无结核病生存以及3级或4级不良事件。嵌套的药代动力学研究将评估抗结核药物浓度，提供基于模型的最佳给药预测，并测量抗逆转录病毒药物暴露情况，以描述一部分HIV感染儿童中的药物相互作用。社会经济分析将评估干预措施的成本效益，社会科学研究将进一步探索这些新的儿科药物制剂的可接受性和适口性。
尽管最近针对痰菌阳性成人患者缩短结核病治疗疗程的试验未获成功，但儿童患者（主要是菌量少、非重症涂片阴性疾病）的这一问题从未得到研究。“SHINE”研究将确定无论HIV感染状况如何，缩短儿童药敏结核病治疗疗程是否有效和安全。该试验还将填补关于新抗结核制剂和常用HIV药物在结核病高负担地区的给药及可接受性方面的现有知识空白。该试验的阳性结果可能会简化和缩短治疗，提高依从性，并为许多结核病儿童节省费用。“SHINE”试验于2016年7月开始招募；预计2020年得出结果。
国际标准随机对照试验编号：ISRCTN63579542，2014年10月14日。泛非临床试验注册编号：PACTR201505001141379，2015年5月14日。印度临床试验注册，注册号：CTRI/2017/07/009119，2017年7月27日。
