Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial,The Lancet

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Evaluation of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): an open-label, multicentre, randomised, non-inferiority trial
The Lancet ( IF 98.4 ) Pub Date : 2022-11-08 , DOI: 10.1016/s0140-6736(22)02078-5
Ruth L Goodall , Sarah K Meredith , Andrew J Nunn , Adamu Bayissa , Anuj K Bhatnagar , Gay Bronson , Chen-Yuan Chiang , Francesca Conradie , Meera Gurumurthy , Bruce Kirenga , Nana Kiria , Daniel Meressa , Ronelle Moodliar , Gopalan Narendran , Nosipho Ngubane , Mohammed Rassool , Karen Sanders , Rajesh Solanki , S Bertel Squire , Gabriela Torrea , Bazarragchaa Tsogt , Elena Tudor , Armand Van Deun , I D Rusen , Oyunchimeg Adilaa , Sofia Alexandru , Katharine Bellenger , Jaclyn Bennet , Deborah Bennet , Priyanka Bindroo , Ghanshyam Borisagar , Claire Cook , Doljinsuren Dalai , Andrew Davis , Bouke de Jong , Wendy Dodds , Lynette Duckworth , Nonhlanhla Gahima , Belay Gebreegziabher , Anne Goldfeld , Mahmud Hanifa , Gareth Hughes , Ivan Kimuli , Jan Komrska , Nino Lomtadze , Brendan Murphy , Thando Mwelase , Joanitah Nalunjogi , Leena Patel , Irina Pirlog , Ishmael Qawiy , Mary Rauchenberger , Leen Rigouts , Carol Roach , Laura Rosu , Ezio Santos-Filho , Thirumaran Senguttuvan , Million Sisay , Rathinam Sridhar , Vignes Srinivasulu , Mekonnen Teferi , Helen Teklu , Narangarav Tsegeen , Odette van Amsterdam , Lisa White , Johanna Whitney , Chuluunbaatar Zagd

Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

USAID and Janssen Research & Development.

中文翻译：

评估治疗利福平耐药结核病的两种短期标准化方案（STREAM 2 期）：一项开放标签、多中心、随机、非劣效性试验

背景

STREAM 1 期试验表明，治疗利福平耐药结核病的 9 个月治疗方案并不劣于 2011 年 WHO 推荐的 20 个月治疗方案。在 STREAM 2 期中，我们的目的是将两种含贝达喹啉的方案与 9 个月的 STREAM 1 期方案进行比较。

方法

我们在 7 个国家的 13 家医院诊所进行了一项随机、3 期非劣效性试验，受试者为 15 岁或以上、患有利福平耐药结核病但不具有氟喹诺酮类或氨基糖苷类耐药性的个体。参与者按 1:2:2:2 随机分配至 2011 年 WHO 方案（提前终止）、9 个月对照方案、9 个月贝达奎林口服方案（主要比较）或 6 个月贝达奎林和二线注射8周。随机分组按地点、HIV 状况和 CD4 计数进行分层。参与者和临床医生都知道治疗组的分配，但实验室工作人员却被蒙蔽了。主要结果是第 76 周时的良好状态（结核分枝杆菌培养物阴性，且之前没有不良结果）；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利的结果。所有比较均使用同时随机分配的参与者组。为了显示非劣效性，在改良意向治疗 (mITT) 和符合方案分析中，95% CI 的上限应小于 10%，如果非劣效性达到，则进行预先指定的优效性测试。显示。该试验已在 ISRCTN 注册，ISRCTN18148631。

发现

2016年3月28日至2020年1月28日期间，筛选了1436名参与者，并随机分配了588名参与者。在 mITT 人群的 517 名参与者中，187 名参与者中的 133 名 (71%) 接受对照方案，196 名口服方案的 162 名参与者 (83%) 获得了良好的结果：差异为 11·0% (95% CI 2·9 –19·0)，根据 HIV 状态和随机方案进行调整（p<0·0001 表示非劣效性）。到第 76 周时，接受对照方案的 202 名参与者中有 108 名（53%）和分配至口服方案的 211 名参与者中有 106 名（50%）出现了 3 级或 4 级不良事件；五名（2%）接受对照方案的参与者和七名（3%）接受口服方案的参与者死亡。接受对照方案的参与者比接受口服方案的参与者更容易出现听力损失（布罗克 3 级或 4 级）（18 名 [9%]比4 名 [2%]，p=0·0015）。在 mITT 人群中，被分配到 6 个月治疗方案的 134 名参与者中，有 122 名 (91%) 获得了良好的结果，而同时随机分配到对照方案的 127 名参与者中有 87 名 (69%) 获得了良好的结果（调整后的差异 22·2%） , 95% CI 13·1–31·2); 接受 6 个月治疗的 143 名参与者中有 6 名（4%）患有 3 级或 4 级听力损失。