The current tuberculosis (TB) drug development pipeline is being re-populated with candidates, including nitroimidazoles such as pretomanid, that exhibit a potential to shorten TB therapy by exerting a bactericidal effect on non-replicating bacilli. Based on results from preclinical and early clinical studies, a four-drug combination of bedaquiline, pretomanid, moxifloxacin, and pyrazinamide (BPaMZ) regimen was identified with treatment-shortening potential for both drug-susceptible (DS) and drug-resistant (DR) TB. This trial aimed to determine the safety and efficacy of BPaMZ. We compared 4 months of BPaMZ to the standard 6 months of isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) in DS-TB. 6 months of BPaMZ was assessed in DR-TB. SimpliciTB was a partially randomised, phase 2c, open-label, clinical trial, recruiting participants at 26 sites in eight countries. Participants aged 18 years or older with pulmonary TB who were sputum smear positive for acid-fast bacilli were eligible for enrolment. Participants with DS-TB had with sensitivity to rifampicin and isoniazid. Participants with DR-TB had with resistance to rifampicin, isoniazid, or both. Participants with DS-TB were randomly allocated in a 1:1 ratio, stratified by HIV status and cavitation on chest radiograph, using balanced block randomisation with a fixed block size of four. The primary efficacy endpoint was time to sputum culture-negative status by 8 weeks; the key secondary endpoint was unfavourable outcome at week 52. A non-inferiority margin of 12% was chosen for the key secondary outcome. Safety and tolerability outcomes are presented as descriptive analyses. The efficacy analysis population contained patients who received at least one dose of medication and who had efficacy data available and had no major protocol violations. The safety population contained patients who received at least one dose of medication. This study is registered with () and is completed. Between July 30, 2018, and March 2, 2020, 455 participants were enrolled and received at least one dose of study treatment. 324 (71%) participants were male and 131 (29%) participants were female. 303 participants with DS-TB were randomly assigned to 4 months of BPaMZ (n=150) or HRZE (n=153). In a modified intention-to-treat (mITT) analysis, by week 8, 122 (84%) of 145 and 70 (47%) of 148 participants were culture-negative on 4 months of BPaMZ and HRZE, respectively, with a hazard ratio for earlier negative status of 2·93 (95% CI 2·17–3·96; p<0·0001). Median time to negative culture (TTN) was 6 weeks (IQR 4–8) on 4 months of BPaMZ and 11 weeks (6–12) on HRZE. 86% of participants with DR-TB receiving 6 months of BPaMZ (n=152) reached culture-negative status by week 8, with a median TTN of 5 weeks (IQR 3–7). At week 52, 120 (83%) of 144, 134 (93%) of 144, and 111 (83%) of 133 on 4 months of BPaMZ, HRZE, and 6 months of BPaMZ had favourable outcomes, respectively. Despite bacteriological efficacy, 4 months of BPaMZ did not meet the non-inferiority margin for the key secondary endpoint in the pre-defined mITT population due to higher withdrawal rates for adverse hepatic events. Non-inferiority was demonstrated in the per-protocol population confirming the effect of withdrawals with 4 months of BPaMZ. At least one liver-related treatment-emergent adverse effect (TEAE) occurred among 45 (30%) participants on 4 months of BPaMZ, 38 (25%) on HRZE, and 33 (22%) on 6 months of BPaMZ. Serious liver-related TEAEs were reported by 20 participants overall; 11 (7%) among those on 4 months of BPaMZ, one (1%) on HRZE, and eight (5%) on 6 months of BPaMZ. The most common reasons for discontinuation of trial treatment were hepatotoxicity (ten participants [2%]), increased hepatic enzymes (nine participants [2%]), QTcF prolongation (three participants [1%]), and hypersensitivity (two participants [<1%]). For DS-TB, BPaMZ successfully met the primary efficacy endpoint of sputum culture conversion. The regimen did not meet the key secondary efficacy endpoint due to adverse events resulting in treatment withdrawal. Our study demonstrated the potential for treatment-shortening efficacy of the BPaMZ regimen for DS-TB and DR-TB, providing clinical validation of a murine model widely used to identify such regimens. It also highlights that novel, treatment-shortening TB treatment regimens require an acceptable toxicity and tolerability profile with minimal monitoring in low-resource and high-burden settings. The increased risk of unpredictable severe hepatic adverse events with 4 months of BPaMZ would be a considerable obstacle to implementation of this regimen in settings with high burdens of TB with limited infrastructure for close surveillance of liver biochemistry. Future research should focus on improving the preclinical and early clinical detection and mitigation of safety issues together and further efforts to optimise shorter treatments. TB Alliance.

中文翻译：

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贝达喹啉-pretomanid-莫西沙星-吡嗪酰胺治疗药物敏感和耐药肺结核：2c期、开放标签、多中心、部分随机对照试验


目前的结核病 (TB) 药物开发管道正在重新填充候选药物，包括硝基咪唑类药物，如 pretomanid，它们通过对非复制杆菌发挥杀菌作用，具有缩短结核病治疗时间的潜力。根据临床前和早期临床研究的结果，贝达奎林、普托马尼、莫西沙星和吡嗪酰胺 (BPaMZ) 的四种药物组合方案被认为具有缩短药物敏感 (DS) 和耐药 (DR) 治疗时间的潜力结核病。该试验旨在确定 BPaMZ 的安全性和有效性。我们将 4 个月的 BPaMZ 治疗与标准的 6 个月的异烟肼、利福平、吡嗪酰胺和乙胺丁醇 (HRZE) 治疗 DS-TB 进行了比较。在 DR-TB 中评估了 6 个月的 BPaMZ。 SimpliciTB 是一项部分随机、2c 期、开放标签临床试验，在 8 个国家的 26 个地点招募参与者。年龄 18 岁或以上患有肺结核且痰涂片抗酸杆菌呈阳性的参与者有资格参加。患有 DS-TB 的参与者对利福平和异烟肼敏感。患有耐药结核病的参与者对利福平、异烟肼或两者都具有耐药性。患有 DS-TB 的参与者以 1:1 的比例随机分配，根据 HIV 状态和胸片上的空洞情况进行分层，使用固定块大小为 4 的平衡块随机化。主要疗效终点是 8 周时痰培养呈阴性状态的时间；关键次要终点是第 52 周时的不利结果。关键次要终点选择 12% 的非劣效性界限。安全性和耐受性结果以描述性分析的形式呈现。 疗效分析人群包含至少接受一剂药物、有可用疗效数据且没有重大方案违规的患者。安全人群包含至少接受一剂药物的患者。本研究已在（）处注册并已完成。 2018年7月30日至2020年3月2日期间，共有455名参与者入组并接受了至少一剂研究治疗。 324 名（71%）参与者为男性，131 名（29%）参与者为女性。 303 名 DS-TB 参与者被随机分配接受 4 个月的 BPaMZ (n=150) 或 HRZE (n=153)。在修改后的意向治疗 (mITT) 分析中，到第 8 周时，145 名参与者中的 122 名 (84%) 和 148 名参与者中的 70 名 (47%) 在 4 个月的 BPaMZ 和 HRZE 中分别呈培养阴性，存在风险早期阴性状态的比率为 2·93 (95% CI 2·17–3·96；p<0·0001)。在 4 个月的 BPaMZ 中，培养阴性的中位时间 (TTN) 为 6 周 (IQR 4-8)，在 HRZE 中为 11 周 (6-12)。接受 6 个月 BPaMZ 治疗的 DR-TB 参与者 (n=152) 中 86% 在第 8 周达到培养阴性状态，中位 TTN 为 5 周 (IQR 3-7)。在第 52 周，接受 4 个月 BPaMZ、HRZE 和 6 个月 BPaMZ 治疗的 144 例患者中，有 120 例（83%）、144 例中 134 例（93%）、133 例中 111 例（83%）获得了良好的结果。尽管具有细菌学功效，但由于不良肝脏事件的停药率较高，4 个月的 BPaMZ 并未达到预先定义的 mITT 人群中关键次要终点的非劣效性界限。在符合方案的人群中证明了非劣效性，证实了 4 个月 BPaMZ 戒断的效果。 在 BPaMZ 治疗 4 个月期间，有 45 名（30%）参与者发生了至少一种与肝脏相关的治疗相关不良反应（TEAE），在 HRZE 治疗中，有 38 名（25%）参与者，在 BPaMZ 6 个月治疗中，有 33 名（22%）参与者发生了至少一种与肝脏相关的治疗相关不良反应 (TEAE)。总共 20 名参与者报告了严重的肝脏相关 TEAE；接受 4 个月 BPaMZ 治疗的患者中有 11 名 (7%)，接受 HRZE 治疗的患者有 1 名 (1%)，接受 6 个月 BPaMZ 治疗的患者有 8 名 (5%)。停止试验治疗的最常见原因是肝毒性（10 名受试者 [2%]）、肝酶升高（9 名受试者 [2%]）、QTcF 延长（3 名受试者 [1%]）和过敏（2 名受试者 [< 1%]）。对于 DS-TB，BPaMZ 成功达到了痰培养转化的主要疗效终点。由于不良事件导致治疗退出，该方案未达到关键的次要疗效终点。我们的研究证明了 BPaMZ 方案对于 DS-TB 和 DR-TB 具有缩短治疗时间的潜力，为广泛用于识别此类方案的小鼠模型提供了临床验证。它还强调，新颖的、可缩短治疗时间的结核病治疗方案需要具有可接受的毒性和耐受性，并在资源匮乏和高负担的环境中进行最少的监测。 4 个月的 BPaMZ 导致不可预测的严重肝脏不良事件的风险增加，这将成为在结核病高负担且肝脏生化密切监测基础设施有限的环境中实施该方案的一个相当大的障碍。未来的研究应集中于改善临床前和早期临床检测，共同缓解安全问题，并进一步努力优化较短的治疗。结核病联盟。