Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis
Efficiency and safety of the combination of moxifloxacin, pretomanid (PA-824), and pyrazinamide during the first 8 weeks of antituberculosis treatment: a phase 2b, open-label, partly randomised trial in patients with drug-susceptible or drug-resistant pulmonary tuberculosis
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DOI：
10.1016/s0140-6736(14)62002-x
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发表时间：
2015-05-02
期刊：
影响因子：
168.9
通讯作者：
Mendel, Carl M.
中科院分区：
文献类型：
--
作者：
Dawson, Rodney;Diacon, Andreas H.;Mendel, Carl M.
背景迫切需要新的抗结核治疗方案来缩短结核病治疗时间。在为期2周的研究中，我们研究了一种新的治疗方案，在治疗的前8周内对药物敏感和耐多药（MDR）结核病的疗效和安全性。方法我们进行了这项2b期杀菌活性研究-定义为显微镜涂片阳性肺结核患者痰中结核分枝杆菌菌落形成单位（CFU）的减少-在南非和坦桑尼亚的八个地点。我们招募了未经治疗的药物敏感性肺结核患者，通过计算机生成的序列将他们随机分配接受8周莫西沙星或100 mg pretomanid治疗（以前称为PA-824）和吡嗪酰胺（MPa 100 Z方案）;阿托沙星，200 mg pretomanid和吡嗪酰胺（MPa 200 Z方案）;或目前药物敏感性肺结核的标准治疗，异烟肼、利福平、PZA和乙胺丁醇（HRZE方案）。一组MDR结核患者接受MPa 200 Z（DRMPa 200 Z组）。主要结果是通过每周一次收集的每mL过夜痰液中结核分枝杆菌CFU的平均每日减少率测量的杀菌活性，联合贝叶斯非线性混合效应回归模型。我们还通过监测不良事件来评估安全性和耐受性。该研究注册于ClinicalTrials.gov，编号NCT 01498419。结果在2012年3月24日至2013年7月26日期间，我们招募了207例患者，并将其随机分配至治疗组;我们将60例患者分配至MPa 100 Z方案，62例分配至MPa 200 Z方案，59例分配至HRZE方案。我们将26例耐药结核患者非随机分配至DRMPa 200 Z方案。在药物敏感性结核病患者中，MPa 200 Z（n=54）在第0-56天的杀菌活性（0.155，95%贝叶斯可信区间0.133-0.178）显著高于HRZE（n=54，0.112，0.093-0.131）。DRMPa 200 Z（n=9）的杀菌活性为0.117（0.070-0.174）。第7-14天的杀菌活性与第7-56天的杀菌活性强烈相关。所有组中不良事件的频率与标准治疗相似。最常见的不良事件是59例（29%）患者的高尿酸血症（MPa 100 Z组17例[28%]患者，MPa 200 Z组17例[27%]患者，MPa 200 Z组17例[29%]患者）。DRMPa 200 Z组8例[31%]。其他常见的不良事件是恶心，（MPa 100 Z组14例[23%]患者，MPa 200 Z组8例[13%]患者，HRZE组7例[12%]患者，DRMPa 200 Z组8例[31%]患者）和呕吐（MPa 100 Z组7例[12%]患者，MPa 200 Z组7例[11%]患者，HRZE组7例[12%]患者和DRMPa 200 Z组4例[15%]患者）。未报告治疗期间心电图校正QT间期超过500 ms（室性快速性心律失常的潜在指标）。没有表型耐药性发展到任何的药物在regime.Interpretation的组合，氟沙星，pretomanid，吡嗪酰胺，是安全的，耐受性良好，并显示出优越的上级杀菌活性在药物敏感的结核病在8周的治疗。耐药结核和耐多药结核的结果是一致的。这种新的方案已准备好进入药物敏感性结核病和MDR结核病患者的3期试验，目的是缩短和简化治疗。
Background New antituberculosis regimens are urgently needed to shorten tuberculosis treatment. Following on from favourable assessment in a 2 week study, we investigated a novel regimen for efficacy and safety in drug-susceptible and multidrug-resistant (MDR) tuberculosis during the first 8 weeks of treatment.Methods We did this phase 2b study of bactericidal activity-defined as the decrease in colony forming units (CFUs) of Mycobacterium tuberculosis in the sputum of patients with microscopy smear-positive pulmonary tuberculosis-at eight sites in South Africa and Tanzania. We enrolled treatment-naive patients with drug-susceptible, pulmonary tuberculosis, who were randomly assigned by computer-generated sequences to receive either 8 weeks of moxifloxacin, 100 mg pretomanid (formerly known as PA-824), and pyrazinamide (MPa100Z regimen); moxifloxacin, 200 mg pretomanid, and pyrazinamide (MPa200Z regimen); or the current standard care for drug-susceptible pulmonary tuberculosis, isoniazid, rifampicin, PZA, and ethambutol (HRZE regimen). A group of patients with MDR tuberculosis received MPa200Z (DRMPa200Z group). The primary outcome was bactericidal activity measured by the mean daily rate of reduction in M tuberculosis CFUs per mL overnight sputum collected once a week, with joint Bayesian non-linear mixed-effects regression modelling. We also assessed safety and tolerability by monitoring adverse events. This study is registered with ClinicalTrials.gov, number NCT01498419.Findings Between March 24, 2012, and July 26, 2013 we enrolled 207 patients and randomly assigned them to treatment groups; we assigned 60 patients to the MPa100Z regimen, 62 to the MPa200Z regimen, and 59 to the HRZE regimen. We non-randomly assigned 26 patients with drug-resistant tuberculosis to the DRMPa200Z regimen. In patients with drug-susceptible tuberculosis, the bactericidal activity of MPa200Z (n=54) on days 0-56 (0.155, 95% Bayesian credibility interval 0.133-0.178) was significantly greater than for HRZE (n=54, 0.112, 0.093-0.131). DRMPa200Z (n=9) had bactericidal activity of 0.117 (0.070-0.174). The bactericidal activity on days 7-14 was strongly associated with bactericidal activity on days 7-56. Frequencies of adverse events were similar to standard treatment in all groups. The most common adverse event was hyperuricaemia in 59 (29%) patients (17 [28%] patients in MPa100Z group, 17 [27%] patients in MPa200Z group, 17 [29%] patients. in HRZE group, and 8 [31%] patients in DRMPa200Z group). Other common adverse events were nausea in (14 [23%] patients in MPa100Z group, 8 [13%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 8 [31%] patients in DRMPa200Z group) and vomiting (7 [12%] patients in MPa100Z group, 7 [11%] patients in MPa200Z group, 7 [12%] patients in HRZE group, and 4 [15%] patients in DRMPa200Z group). No on-treatment electrocardiogram occurrences of corrected QT interval more than 500 ms (an indicator of potential of ventricular tachyarrhythmia) were reported. No phenotypic resistance developed to any of the drugs in the regimen.Interpretation The combination of moxifloxacin, pretomanid, and pyrazinamide, was safe, well tolerated, and showed superior bactericidal activity in drug-susceptible tuberculosis during 8 weeks of treatment. Results were consistent between drug-susceptible and MDR tuberculosis. This new regimen is ready to enter phase 3 trials in patients with drug-susceptible tuberculosis and MDR-tuberculosis, with the goal of shortening and simplifying treatment.