High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial.
High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial.
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DOI：
10.1016/s1473-3099(16)30274-2
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发表时间：
2017-01
影响因子：
56.3
通讯作者：
Hoelscher, Michael
中科院分区：
文献类型：
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作者：
Boeree, Martin J.;Heinrich, Norbert;Aarnoutse, Rob;Diacon, Andreas H.;Dawson, Rodney;Rehal, Sunita;Kibiki, Gibson S.;Churchyard, Gavin;Sanne, Ian;Ntinginya, Nyanda E.;Minja, Lilian T.;Hunt, Robert D.;Charalambous, Salome;Hanekom, Madeleine;Semvua, Hadija H.;Mpagama, Stellah G.;Manyama, Christina;Mtafya, Bariki;Reither, Klaus;Wallis, Robert S.;Venter, Amour;Narunsky, Kim;Mekota, Anka;Henne, Sonja;Colbers, Angela;van Balen, Georgette Plemper;Gillespie, Stephen H.;Phillips, Patrick P. J.;Hoelscher, Michael
结核病是世界上最主要的传染病杀手。我们的目标是确定治疗结核病的更短，更安全的药物方案。我们进行了一项多组、多阶段设计的随机对照、开放标签试验。该试验在南非和坦桑尼亚的七个地点进行，包括医院，健康中心和临床试验中心。新诊断、利福平敏感、既往未治疗的肺结核患者以1：1：1：1：2的比例随机分配接受（全部口服）35 mg/kg利福平/天+15-20 mg/kg乙胺丁醇、20 mg/kg利福平/天+400 mg阿氟沙星、20 mg/kg利福平/天+300 mg SQ 109、10 mg/kg利福平/天+300 mg SQ 109或每日标准对照方案（10 mg/kg利福平、5 mg/kg异烟肼、25 mg/kg吡嗪酰胺和15-20 mg/kg乙胺丁醇）。每天口服5 mg/kg异烟肼和25 mg/kg吡嗪酰胺，持续12周，然后每天口服5 mg/kg异烟肼和10 mg/kg利福平，持续14周。由于较高剂量利福平导致体液变为橙子，因此无法掩盖患者和临床医生对治疗分配的认识。主要终点是12周内液体培养基中培养转化的时间。在表型试验中没有利福平耐药证据、接受至少一剂研究治疗且在治疗前或治疗前2周内在液体或固体培养基上有一次阳性培养的患者被纳入主要分析（改良意向治疗）。使用考克斯比例风险回归模型分析至事件发生时间数据，并针对最小化变量进行调整。使用Schoelfeld残差检验比例风险假设，非比例性阈值p<0.05。该试验在ClinicalTrials.gov（NCT 01785186）上注册。在2013年5月7日至2014年3月25日期间，我们招募了365例患者，并将其随机分配至不同的治疗组（利福平35 mg/kg、异烟肼、吡嗪酰胺和乙胺丁醇组63例;利福平10 mg/kg、异烟肼、吡嗪酰胺、SQ 109组59例;利福平20 mg/kg、异烟肼、吡嗪酰胺和SQ 109组57例;利福平10 mg/kg、异烟肼、吡嗪酰胺和阿托沙星组63例;对照组123例）。由于在计划的中期分析中未达到预先规定的疗效阈值，因此在含SQ 109的组中提前停止招募。在液体培养基中，35 mg/kg利福平组达到稳定培养转化的时间比对照组更快（中位数48天vs 62天，校正风险比1.78; 95% CI 1.22 - 2.58，p= 0.003），但在其他实验组中并非如此。在固体培养基上培养物转化的时间方面，任何组均无差异。11例患者在治疗后随访期间治疗失败或疾病复发：365名患者中有45名（12%）报告了3-5级不良事件，每组中的比例相似。35 mg/kg利福平剂量是安全的，减少了液体培养基中培养物转化的时间，并可能成为未来较短疗程的有希望的组成部分。我们的适应性试验设计在多中心、高结核病负担的环境中成功实施，可以以更低的成本加快方案开发。该研究由欧洲和发展中国家临床试验合作伙伴（EDCTP）、德国教育和研究部（BmBF）以及英国医学研究理事会（MRC）资助。
Tuberculosis is the world's leading infectious disease killer. We aimed to identify shorter, safer drug regimens for the treatment of tuberculosis. We did a randomised controlled, open-label trial with a multi-arm, multi-stage design. The trial was done in seven sites in South Africa and Tanzania, including hospitals, health centres, and clinical trial centres. Patients with newly diagnosed, rifampicin-sensitive, previously untreated pulmonary tuberculosis were randomly assigned in a 1:1:1:1:2 ratio to receive (all orally) either 35 mg/kg rifampicin per day with 15–20 mg/kg ethambutol, 20 mg/kg rifampicin per day with 400 mg moxifloxacin, 20 mg/kg rifampicin per day with 300 mg SQ109, 10 mg/kg rifampicin per day with 300 mg SQ109, or a daily standard control regimen (10 mg/kg rifampicin, 5 mg/kg isoniazid, 25 mg/kg pyrazinamide, and 15–20 mg/kg ethambutol). Experimental treatments were given with oral 5 mg/kg isoniazid and 25 mg/kg pyrazinamide per day for 12 weeks, followed by 14 weeks of 5 mg/kg isoniazid and 10 mg/kg rifampicin per day. Because of the orange discoloration of body fluids with higher doses of rifampicin it was not possible to mask patients and clinicians to treatment allocation. The primary endpoint was time to culture conversion in liquid media within 12 weeks. Patients without evidence of rifampicin resistance on phenotypic test who took at least one dose of study treatment and had one positive culture on liquid or solid media before or within the first 2 weeks of treatment were included in the primary analysis (modified intention to treat). Time-to-event data were analysed using a Cox proportional-hazards regression model and adjusted for minimisation variables. The proportional hazard assumption was tested using Schoelfeld residuals, with threshold p<0·05 for non-proportionality. The trial is registered with ClinicalTrials.gov (NCT01785186). Between May 7, 2013, and March 25, 2014, we enrolled and randomly assigned 365 patients to different treatment arms (63 to rifampicin 35 mg/kg, isoniazid, pyrazinamide, and ethambutol; 59 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, SQ109; 57 to rifampicin 20 mg/kg, isoniazid, pyrazinamide, and SQ109; 63 to rifampicin 10 mg/kg, isoniazid, pyrazinamide, and moxifloxacin; and 123 to the control arm). Recruitment was stopped early in the arms containing SQ109 since prespecified efficacy thresholds were not met at the planned interim analysis. Time to stable culture conversion in liquid media was faster in the 35 mg/kg rifampicin group than in the control group (median 48 days vs 62 days, adjusted hazard ratio 1·78; 95% CI 1·22–2·58, p=0·003), but not in other experimental arms. There was no difference in any of the groups in time to culture conversion on solid media. 11 patients had treatment failure or recurrent disease during post-treatment follow-up: one in the 35 mg/kg rifampicin arm and none in the moxifloxacin arm. 45 (12%) of 365 patients reported grade 3–5 adverse events, with similar proportions in each arm. A dose of 35 mg/kg rifampicin was safe, reduced the time to culture conversion in liquid media, and could be a promising component of future, shorter regimens. Our adaptive trial design was successfully implemented in a multi-centre, high tuberculosis burden setting, and could speed regimen development at reduced cost. The study was funded by the European and Developing Countries Clinical Trials partnership (EDCTP), the German Ministry for Education and Research (BmBF), and the Medical Research Council UK (MRC).