背景:Pretomanid是一种新的硝基咪唑,在耐药结核病中具有公认的缩短治疗效果。Pretomanid-利福霉素-吡嗪酰胺组合对小鼠有效,但尚未进行临床测试。利福平,但不是Rifabutin,减少Pretomanid暴露。
目的:在药物敏感型肺结核患者中评价含前托马尼特-利福霉素-吡嗪酰胺方案的安全性和有效性。
方法:异烟肼2期12周开放标签随机试验,吡嗪酰胺,加(a)pretomanid和利福平(第1组);(b)pretomanid和利福布汀(第2组)或(c)利福平和乙胺丁醇(护理标准,Arm3).在第1、2、3、4、6、8、10、12周收集安全实验室和痰培养物。在液体培养基上培养转化的时间是主要结果。
结果:在157名参与者中,125(80%)患有空洞疾病。改良意向治疗(mITT)人群(n=150)的液体培养阴性时间中位数为41(第1组),28(第2臂),55天(第3组)(p=0.01)(调整后的危险比为1.41(0.93-2.12,p=0.10),手臂1vs.第3臂)和1.89(1.24-2.87,p=0.003,第2臂与Arm3)).八周液体培养转化率为79%,89%,69%,分别。3/56(5%)发生了3级以上的不良事件,5/53(9%),和2/56(4%)的参与者。六名参与者因转氨酶升高而退出(第2组5人,第1组1人)。有3例严重不良事件(第2组),无死亡。
结论:Pretomanid增强了含有利福霉素-吡嗪酰胺的方案的微生物活性。使用含Pretomanid和利福布汀的方案,疗效和肝脏不良事件最高。这是否是由于较高的prectomanid浓度值得探索。临床试验注册可在www.
结果:政府,ID:NCT02256696。
Rationale: Pretomanid is a new nitroimidazole with proven treatment-shortening efficacy in drug-resistant tuberculosis. Pretomanid-rifamycin-pyrazinamide combinations are potent in mice but have not been tested clinically. Rifampicin, but not rifabutin, reduces pretomanid exposures. Objectives: To evaluate the safety and efficacy of regimens containing pretomanid-rifamycin-pyrazinamide among participants with drug-sensitive pulmonary tuberculosis. Methods: A phase 2, 12-week, open-label randomized
trial was conducted of isoniazid and pyrazinamide plus 1) pretomanid and rifampicin (arm 1), 2) pretomanid and rifabutin (arm 2), or 3) rifampicin and ethambutol (standard of care; arm 3). Laboratory values of safety and sputum cultures were collected at Weeks 1, 2, 3, 4, 6, 8, 10, and 12. Time to culture conversion on liquid medium was the primary outcome. Measurements and Main Results: Among 157 participants, 125 (80%) had cavitary disease. Median time to liquid culture negativity in the modified intention-to-treat population (n = 150) was 42 (arm 1), 28 (arm 2), and 56 (arm 3) days (P = 0.01) (adjusted hazard ratio for arm 1 vs. arm 3, 1.41 [95% confidence interval (CI), 0.93-2.12; P = 0.10]; adjusted hazard ratio for arm 2 vs. arm 3, 1.89 [95% CI, 1.24-2.87; P = 0.003]). Eight-week liquid culture conversion was 79%, 89%, and 69%, respectively. Grade ≥3 adverse events occurred in 3 of 56 (5%), 5 of 53 (9%), and 2 of 56 (4%) participants. Six participants were withdrawn because of elevated transaminase concentrations (five in arm 2, one in arm 1). There were three serious adverse events (arm 2) and no deaths. Conclusions: Pretomanid enhanced the microbiologic activity of regimens containing a rifamycin and pyrazinamide. Efficacy and hepatic adverse events appeared highest with the pretomanid and rifabutin-containing regimen. Whether this is due to higher pretomanid concentrations merits exploration. Clinical
trial registered with www.clinicaltrials.gov (NCT02256696).