Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial.
Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial.
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DOI：
10.1016/s0140-6736(22)02078-5
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发表时间：
2022-11-26
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STREAM study collaborators
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作者：
Goodall RL;Meredith SK;Nunn AJ;Bayissa A;Bhatnagar AK;Bronson G;Chiang CY;Conradie F;Gurumurthy M;Kirenga B;Kiria N;Meressa D;Moodliar R;Narendran G;Ngubane N;Rassool M;Sanders K;Solanki R;Squire SB;Torrea G;Tsogt B;Tudor E;Van Deun A;Rusen ID;STREAM study collaborators
STREAM 1期试验表明，治疗耐利福平结核病的9个月方案不逊于2011年世卫组织推荐的20个月方案。在STREAM 2期，我们的目的是比较两种含贝达喹啉的方案与9个月的STREAM 1期方案。我们在7个国家的13家医院诊所进行了一项随机的3期非劣效性试验，患者年龄在15岁或以上，患有利福平耐药结核病，但不耐氟喹诺酮或氨基糖苷。参与者以1:2:2的比例随机分配到2011年WHO方案（提前终止）、9个月的对照方案、9个月的口服贝达喹啉方案（初步比较）或6个月的贝达喹啉和8周的二线注射剂方案。随机分组按地点、HIV状态和CD4计数进行分层。参与者和临床医生知道治疗组的分配，但实验室工作人员被掩盖。76周时，主要结果为有利状态（结核分枝杆菌培养阴性，之前无不利结果）；任何死亡、细菌学失败或复发以及重大治疗改变都被认为是不良结局。所有的比较都使用随机分配的参与者组。要显示非劣效性，在改良意向治疗（mITT）和方案分析中，95% CI的上边界应小于10%，如果显示非劣效性，则进行预先指定的优势测试。本试验注册号为ISRCTN， ISRCTN18148631。在2016年3月28日至2020年1月28日期间，筛选了1436名参与者，随机分配了588名参与者。在mITT人群的517名参与者中，187名对照方案中的133名（71%）和196名口服方案中的162名（83%）有良好的结果：经HIV状态和随机化方案调整后，差异为11.0% (95% CI 2.9 - 19.0)（非劣效性p< 0.0001）。到76周时，202名对照组中的108名（53%）和211名口服组中的106名（50%）出现了3级或4级不良事件；对照组5人（2%）和口服组7人（3%）死亡。对照组患者听力损失（Brock 3级或4级）发生率高于口服组（18例[9%]vs 4例[2%]，p= 0.0015）。在134名被分配到6个月方案的mITT人群中，122名（91%）的结果良好，而同时被随机分配到对照方案的127名参与者中有87名（69%）的结果良好（调整差22.2%,95% CI 13.1 - 31.2）；在为期6个月的治疗方案中，143名参与者中有6名（4%）患有3级或4级听力损失。两种含贝达喹啉的方案，9个月的口服方案和6个月的二线8周注射方案，与含9个月的注射方案相比，疗效更佳，听力损失病例更少。美国国际开发署和杨森研发公司。
The STREAM stage 1 trial showed that a 9-month regimen for the treatment of rifampicin-resistant tuberculosis was non-inferior to the 20-month 2011 WHO-recommended regimen. In STREAM stage 2, we aimed to compare two bedaquiline-containing regimens with the 9-month STREAM stage 1 regimen. We did a randomised, phase 3, non-inferiority trial in 13 hospital clinics in seven countries, in individuals aged 15 years or older with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance. Participants were randomly assigned 1:2:2:2 to the 2011 WHO regimen (terminated early), a 9-month control regimen, a 9-month oral regimen with bedaquiline (primary comparison), or a 6-month regimen with bedaquiline and 8 weeks of second-line injectable. Randomisations were stratified by site, HIV status, and CD4 count. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome) at 76 weeks; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable outcomes. All comparisons used groups of participants randomly assigned concurrently. For non-inferiority to be shown, the upper boundary of the 95% CI should be less than 10% in both modified intention-to-treat (mITT) and per-protocol analyses, with prespecified tests for superiority done if non-inferiority was shown. This trial is registered with ISRCTN, ISRCTN18148631. Between March 28, 2016, and Jan 28, 2020, 1436 participants were screened and 588 were randomly assigned. Of 517 participants in the mITT population, 133 (71%) of 187 on the control regimen and 162 (83%) of 196 on the oral regimen had a favourable outcome: a difference of 11·0% (95% CI 2·9–19·0), adjusted for HIV status and randomisation protocol (p<0·0001 for non-inferiority). By 76 weeks, 108 (53%) of 202 participants on the control regimen and 106 (50%) of 211 allocated to the oral regimen had an adverse event of grade 3 or 4; five (2%) participants on the control regimen and seven (3%) on the oral regimen had died. Hearing loss (Brock grade 3 or 4) was more frequent in participants on the control regimen than in those on the oral regimen (18 [9%] vs four [2%], p=0·0015). Of 134 participants in the mITT population who were allocated to the 6-month regimen, 122 (91%) had a favourable outcome compared with 87 (69%) of 127 participants randomly assigned concurrently to the control regimen (adjusted difference 22·2%, 95% CI 13·1–31·2); six (4%) of 143 participants on the 6-month regimen had grade 3 or 4 hearing loss. Both bedaquiline-containing regimens, a 9-month oral regimen and a 6-month regimen with 8 weeks of second-line injectable, had superior efficacy compared with a 9-month injectable-containing regimen, with fewer cases of hearing loss. USAID and Janssen Research & Development.