Infectious Disease Translational Research Programme, National University of Singapore, Singapore; Department of Medicine, National University Health Systems, Singapore.
Department of Medicine, National University Health Systems, Singapore.
Lancet Infect Dis. 2023 Jul;23(7):847-855. doi: 10.1016/S1473-3099(23)00067-1. Epub 2023 Mar 23.
Shorter treatments are needed for drug-susceptible tuberculosis. Adjunctive statins increase bactericidal activity in preclinical tuberculosis models. We investigated the safety and efficacy of adjunctive rosuvastatin in people with tuberculosis. We tested the hypothesis that adjunctive rosuvastatin accelerates sputum culture conversion within the first 8 weeks of treatment of rifampicin-susceptible tuberculosis.
This phase 2b, randomised, open-label, multicentre trial conducted in five hospitals or clinics in three countries with high tuberculosis burden (ie, the Philippines, Viet Nam, and Uganda) enrolled adult participants aged 18-75 years with sputum smear or Xpert MTB/RIF positive, rifampicin-susceptible tuberculosis who had received less than 7 days of previous tuberculosis treatment. Participants were randomly assigned via a web-based system to receive either 10 mg rosuvastatin once per day for 8 weeks plus standard tuberculosis therapy (rifampicin, isoniazid, pyrazinamide, and ethambutol; rosuvastatin group) or standard tuberculosis therapy alone (control group). Randomisation was stratified by trial site, history of diabetes, and HIV co-infection. Laboratory staff and central investigators involved in data cleaning and analysis were masked to treatment allocation, but study participants and site investigators were not. Both groups continued standard treatment to week 24. Sputum samples were collected once per week for the first 8 weeks after randomisation, and then at weeks 10, 12, and 24. The primary efficacy outcome was time to culture conversion (TTCC; days) in liquid culture by week 8, assessed in randomised participants who had microbiological confirmation of tuberculosis, took at least one dose of rosuvastatin, and who did not show resistance to rifampicin (modified intention-to-treat population), for which groups were compared with the Cox proportional hazards model. The main safety outcome was grade 3-5 adverse events by week 24, assessed in the intention-to-treat population, for which groups were compared with Fisher's exact test. All participants completed 24 weeks of follow-up. This trial is registered with ClinicalTrials.gov (NCT04504851).
Between Sept 2, 2020, and Jan 14, 2021, 174 participants were screened and 137 were randomly assigned to the rosuvastatin group (70 participants) or control group (67 participants). In the modified intention-to-treat population of 135 participants, 102 (76%) were men and 33 (24%) were women. Median TTCC in liquid media was 42 days (95% CI 35-49) in the rosuvastatin group (68 participants) and 42 days (36-53) in the control group (67 participants; hazard ratio 1·30 [0·88-1·91], p=0·19). Grade 3-5 adverse events occurred in six (9%) of 70 in the rosuvastatin group (none were considered related to rosuvastatin) and four (6%) of 67 in the control group (p=0·75). There were no serious adverse events that were considered to be related to rosuvastatin.
Adjunctive rosuvastatin at 10 mg once per day was safe but did not produce substantive benefits on culture conversion in the overall study population. Future trials could explore the safety and efficacy of higher doses of adjunctive rosuvastatin.
National Medical Research Council, Singapore.
对于耐多药结核病，需要更短的治疗时间。辅助性他汀类药物可提高临床前结核病模型中的杀菌活性。我们研究了辅助性瑞舒伐他汀在结核病患者中的安全性和疗效。我们检验了辅助性瑞舒伐他汀可加速利福平敏感结核病治疗的前 8 周内痰培养转阴的假设。
这项在三个结核病负担高的国家（菲律宾、越南和乌干达）的五家医院或诊所进行的 2b 期、随机、开放标签、多中心试验纳入了年龄在 18-75 岁之间、痰涂片或 Xpert MTB/RIF 阳性、利福平敏感的结核病患者，他们在接受研究药物治疗之前接受了不到 7 天的结核病治疗。参与者通过一个基于网络的系统被随机分配接受瑞舒伐他汀 10mg 每天一次治疗 8 周加标准结核病治疗（利福平、异烟肼、吡嗪酰胺和乙胺丁醇；瑞舒伐他汀组）或单独接受标准结核病治疗（对照组）。随机分组按试验地点、糖尿病史和 HIV 合并感染进行分层。参与数据清理和分析的实验室工作人员和中心调查人员对治疗分配进行了盲法，但研究参与者和现场调查人员没有。两组均继续接受标准治疗至第 24 周。在随机分组后的前 8 周内每周采集一次痰样，然后在第 10、12 和 24 周采集。主要疗效终点是第 8 周时液体培养的培养转换时间（TTCC；天），在有结核病微生物学确认、至少服用一剂瑞舒伐他汀且未显示利福平耐药的随机参与者中评估（改良意向治疗人群），组间采用 Cox 比例风险模型进行比较。主要安全性终点是第 24 周时的 3-5 级不良事件，在意向治疗人群中评估，组间采用 Fisher 精确检验进行比较。所有参与者均完成了 24 周的随访。该试验在 ClinicalTrials.gov 注册（NCT04504851）。
在 2020 年 9 月 2 日至 2021 年 1 月 14 日期间，有 174 名参与者接受了筛查，其中 137 名被随机分配到瑞舒伐他汀组（70 名参与者）或对照组（67 名参与者）。在改良意向治疗人群的 135 名参与者中，102 名（76%）为男性，33 名（24%）为女性。液体培养中 TTCC 的中位数在瑞舒伐他汀组为 42 天（95%CI 35-49）（68 名参与者），在对照组为 42 天（36-53）（67 名参与者；危险比 1.30[0.88-1.91]，p=0.19）。瑞舒伐他汀组有 6 名（9%）参与者出现 3-5 级不良事件（无不良事件被认为与瑞舒伐他汀有关），对照组有 4 名（6%）参与者出现 3-5 级不良事件（p=0.75）。无被认为与瑞舒伐他汀有关的严重不良事件。
每天一次服用 10mg 的辅助性瑞舒伐他汀是安全的，但在整个研究人群中对培养转换没有产生实质性益处。未来的试验可以探索辅助性瑞舒伐他汀更高剂量的安全性和疗效。
新加坡国家医学研究理事会。
