Tuberculosis preventive treatment (TPT) is a key component of tuberculosis elimination. To improve completion and reduce the burden for people and health systems, short, safe, and effective TPT regimens are needed. We aimed to compare safety and treatment completion of various doses and durations of rifampicin in people who were recommended to receive TPT. This partially blinded, parallel-arm, non-inferiority, randomised, controlled, phase 2b trial was done at seven university-affiliated clinics in Canada, Indonesia, and Viet Nam. Participants aged 10 years or older were included if they had an indication for TPT according to WHO guidelines for Indonesia and Viet Nam, or Canadian guidelines for Canadian sites, and a positive tuberculin skin test or interferon-γ release assay. Participants were randomly assigned (1:1:1) to receive oral rifampicin at 10 mg/kg once daily for 4 months (standard-dose group), 20 mg/kg daily for 2 months (20 mg/kg group), or 30 mg/kg daily for 2 months (30 mg/kg group). The randomisation sequence was computer generated with blocks of variable size (three, six, and nine) and stratified by country for Indonesia and Viet Nam, and by city within Canada. Participants and investigators were masked to dose in high-dose groups, but unmasked to duration in all groups. The two co-primary outcomes were safety (in the safety population, in which participants received at least one dose of the study drug) and treatment completion (in the modified intention-to-treat [mITT] population, excluding those ineligible after randomisation). Protocol-defined adverse events were defined as grade 3 or worse, or rash or allergy of any grade, judged by an independent and masked panel as possibly or probably related to the study. A margin of 4% was used to assess non-inferiority. This study is registered with , (active). Between Sept 1, 2019, and Sept 30, 2022, 1692 people were assessed for eligibility, 1376 were randomly assigned, and eight were excluded after randomisation. 1368 participants were included in the mITT population (454 in the standard group, 461 in the 20 mg/kg group, and 453 in the 30 mg/kg group). 589 (43%) participants were male and 779 (57%) were female. 372 (82%) in the standard-dose group, 329 (71%) in the 20 mg/kg group, and 293 (65%) in the 30 mg/kg group completed treatment. No participants in the standard-dose group, one (<1%) of 441 participants in the 20 mg/kg group, and four (1%) of 423 in the 30 mg/kg group developed grade 3 hepatotoxicity. Risk of protocol-defined adverse events was higher in the 30 mg/kg group than in the standard-dose group (adjusted risk difference 4·6% [95% CI 1·8 to 7·4]) or the 20 mg/kg group (5·1% [2·3 to 7·8]). There was no difference in the risk of adverse events between the 20 mg/kg and standard-dose groups (–0·5% [95% CI –2·4 to 1·5]; non-inferiority met). Completion was lower in the 20 mg/kg group (–7·8% [95% CI –13·6 to –2·0]) and the 30 mg/kg group (–15·4% [–21·4 to –9·4]) than in the standard-dose group. In this trial, 2 months of 30 mg/kg daily rifampicin had significantly worse safety and completion than 4 months of 10 mg/kg daily and 2 months of 20 mg/kg daily (the latter, a fully blinded comparison); we do not consider 30 mg/kg to be a good option for TPT. Rifampicin at 20 mg/kg daily for 2 months was as safe as standard treatment, but with lower completion. This difference remains unexplained. Canadian Institutes of Health Research.

中文翻译：

---

高剂量、短持续时间与标准利福平用于结核病预防治疗的比较：部分盲法、三组、非劣效性、随机对照试验


结核病预防治疗（TPT）是消除结核病的关键组成部分。为了提高完成率并减轻人民和卫生系统的负担，需要短期、安全和有效的 TPT 方案。我们的目的是比较推荐接受 TPT 的患者使用不同剂量和持续时间的利福平的安全性和治疗完成情况。这项部分盲法、平行臂、非劣效性、随机、对照 2b 期试验在加拿大、印度尼西亚和越南的七家大学附属诊所进行。年龄在 10 岁或以上的参与者，如果根据世界卫生组织针对印度尼西亚和越南的指南或加拿大针对加拿大地点的指南有 TPT 指征，并且结核菌素皮试或干扰素-γ 释放测定呈阳性，则将其纳入研究范围。参与者被随机分配（1:1:1）接受口服利福平，每日一次 10 mg/kg，持续 4 个月（标准剂量组），每天 20 mg/kg，持续 2 个月（20 mg/kg 组），或 30每日毫克/公斤，持续 2 个月（30 毫克/公斤组）。随机序列是由计算机生成的，具有可变大小的块（三个、六个和九个），并按印度尼西亚和越南的国家以及加拿大的城市进行分层。参与者和研究人员在高剂量组中隐藏了剂量，但在所有组中都隐藏了持续时间。两个共同主要结局是安全性（在安全人群中，其中参与者接受至少一剂研究药物）和治疗完成（在修改后的意向治疗 [mITT] 人群中，不包括随机分组后不符合资格的人群） 。方案定义的不良事件被定义为 3 级或更严重，或任何级别的皮疹或过敏，由独立且不公开的小组判断可能或可能与研究相关。 使用 4% 的裕度来评估非劣效性。这项研究已在 ,（有效）注册。 2019年9月1日至2022年9月30日期间，对1692人进行了资格评估，其中1376人被随机分配，8人在随机分配后被排除。 mITT 人群中包括 1368 名参与者（标准组 454 名，20 mg/kg 组 461 名，30 mg/kg 组 453 名）。 589 名 (43%) 参与者为男性，779 名 (57%) 为女性。标准剂量组有 372 例（82%）完成治疗，20 mg/kg 组有 329 例（71%）完成治疗，30 mg/kg 组有 293 例（65%）完成治疗。标准剂量组中没有参与者、20 mg/kg 组 441 名参与者中的 1 名参与者（<1%）和 30 mg/kg 组 423 名参与者中的 4 名参与者（1%）出现 3 级肝毒性。 30 mg/kg 组发生方案定义的不良事件的风险高于标准剂量组（调整后风险差异 4·6% [95% CI 1·8 至 7·4]）或 20 mg/kg 组组（5·1% [2·3 至 7·8]）。 20 mg/kg 组和标准剂量组之间的不良事件风险没有差异（–0·5% [95% CI –2·4 至 1·5]；满足非劣效性）。 20 mg/kg 组（–7·8% [95% CI –13·6 至 –2·0]）和 30 mg/kg 组（–15·4% [–21·4 至 –21·0]）的完成率较低。 –9·4]）高于标准剂量组。在该试验中，2个月每日30mg/kg利福平的安全性和完成度明显比4个月每日10mg/kg和2个月每日20mg/kg（后者为全盲比较）差；我们认为 30 mg/kg 不是 TPT 的一个好的选择。利福平每日 20 mg/kg，持续 2 个月与标准治疗一样安全，但完成率较低。这种差异仍然无法解释。加拿大健康研究所。