Long-term efficacy and safety of two short standardised regimens for the treatment of rifampicin-resistant tuberculosis (STREAM stage 2): extended follow-up of an open-label, multicentre, randomised, non-inferiority trial

IF 38.7 1区医学 Q1 CRITICAL CARE MEDICINE

Lancet Respiratory Medicine Pub Date : 2024-10-01 DOI:10.1016/s2213-2600(24)00186-3

Ruth L Goodall, Andrew J Nunn, Sarah K Meredith, Adamu Bayissa, Anuj K Bhatnagar, Chen-Yuan Chiang, Francesca Conradie, Narendran Gopalan, Meera Gurumurthy, Bruce Kirenga, Nana Kiria, Daniel Meressa, Ronelle Moodliar, Nosipho Ngubane, Mohammed Rassool, Karen Sanders, Rajesh Solanki, S Bertel Squire, Mekonnen Teferi, Gabriela Torrea, Eve Worrall

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引用次数: 0

Abstract

Background

STREAM stage 2 showed that two bedaquiline-containing regimens (a 9-month all-oral regimen and a 6-month regimen with 8 weeks of aminoglycoside) had superior efficacy to a 9-month injectable-containing regimen for rifampicin-resistant tuberculosis up to 76 weeks after randomisation. Our objective in this follow-up analysis was to assess the durability of efficacy and safety, including mortality, at 132 weeks.

Methods

We report the long-term outcomes from STREAM stage 2, a randomised, phase 3 non-inferiority (10% margin) trial in participants (aged ≥15 years) with rifampicin-resistant tuberculosis without fluoroquinolone or aminoglycoside resistance at 13 clinical sites in seven countries (Ethiopia, Georgia, India, Moldova, Mongolia, South Africa, and Uganda). Participants were randomly assigned 1:2:2:2 (via permuted blocks and stratified by site and HIV status plus CD4 cell count) to the 2011 WHO long 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 an injectable antituberculous drug. Participants and clinicians were aware of treatment-group assignments, but laboratory staff were masked. The primary outcome, reported previously, was favourable status (negative cultures for Mycobacterium tuberculosis without a preceding unfavourable outcome; any death, bacteriological failure or recurrence, and major treatment change were considered unfavourable) at week 76. Here we report efficacy outcomes at week 132, analysed in the modified intention-to-treat (mITT) population. Safety assessments continued to 132 weeks and were in all participants who received at least one dose of the study regimen. All comparisons used concurrently randomised participants. This trial is registered on ISRCTN (ISRCTN18148631) and is now completed.

Findings

Between March 28, 2016, and Jan 28, 2020, 588 participants were randomly assigned to the long (n=32), control (n=202), oral (n=211), or 6-month (n=143) treatment regimens; 352 (60%) were male and 236 (40%) were female. Of the 556 participants on the three shorter regimens, 517 were included in the mITT population (187 in control group, 196 in oral group, and 134 in 6-month group) and 465 in the per-protocol analyses. Six additional participants had an unfavourable outcome that occurred between week 76 and the end of efficacy follow-up (one in control group, four in oral group, one in 6-month group). In the mITT population, the proportion of patients with an unfavourable outcome at the end of follow-up was 19·6% (95% CI 14·3 to 24·9) in the oral group and 29·3% (23·3 to 36·5) in the control group (–9·7 percentage points difference [95% CI –18·7 to –1·8]; p_superiority=0·024). An estimated 9·8% (95% CI 4·6 to 14·9) of participants on the 6-month regimen had an unfavourable outcome, which was significantly lower than for those concurrently on the control regimen (32·5% [23·7 to 40·2]; p_superiority<0·0001) or the oral regimen (23·8% [16·9 to 31·1]; p_superiority=0·013). Few serious or severe adverse events were reported after week 76, with no indication of a difference between the regimens. At week 132, treatment-emergent hearing loss was recorded in significantly fewer participants on the oral regimen (7/205; 3%) than the control regimen (16/198; 8%; p=0.041); there was no significant difference in severe hearing loss between the oral regimen (6/139; 4%) and the 6-month regimen (5/143; 4%; p=0·72). Death rates were low: 1·01 (95% CI 0·48 to 2·12) per 100 person-years in participants allocated to bedaquiline (ie, oral and 6-month regimen, n=287) compared with 1·52 (0·63 to 3·66) in participants on the control regimen (n=140; p=0·49).

Interpretation

Both of the bedaquiline-containing regimens maintained superiority to the control regimen, without evidence of increased mortality, providing two additional evidence-based treatment options for patients; previous mortality concerns for bedaquiline were not substantiated.

Funding

US Agency for International Development and Janssen Research & Development.

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治疗耐利福平结核病的两种短期标准化方案的长期疗效和安全性（STREAM 第 2 阶段）：一项开放标签、多中心、随机、非劣效试验的延长随访期

背景STREAM第2阶段显示，在随机分组后76周内，两种含贝达喹啉的治疗方案（9个月的全口服治疗方案和6个月的含8周氨基糖苷的治疗方案）治疗耐利福平结核病的疗效优于9个月的含注射剂的治疗方案。我们报告了 STREAM 第 2 阶段的长期疗效，这是一项随机、3 期非劣效性（10% 差值）试验，在 7 个国家（埃塞俄比亚、格鲁吉亚、印度、摩尔多瓦、蒙古、南非和乌干达）的 13 个临床研究机构进行，受试者（年龄≥15 岁）患有耐利福平结核病，但对氟喹诺酮类药物或氨基糖苷类药物无耐药性。参与者按1:2:2:2的比例被随机分配到2011年世卫组织长疗程方案（提前终止）、9个月对照方案、9个月贝达喹啉口服方案（主要对比方案）或6个月贝达喹啉和8周注射抗结核药物方案（主要对比方案）。参与者和临床医生都知道治疗组的分配，但实验室工作人员被蒙蔽。先前报告的主要疗效是第 76 周时的良好疗效（结核分枝杆菌培养阴性，且之前未出现不良疗效；任何死亡、细菌学失败或复发以及重大治疗改变均被视为不良疗效）。我们在此报告的是第132周的疗效结果，分析对象为改良意向治疗（mITT）人群。安全性评估一直持续到第132周，评估对象是所有接受了至少一个剂量研究方案的参与者。所有比较均采用同时随机化的参与者。研究结果在2016年3月28日至2020年1月28日期间，588名参与者被随机分配到长效治疗方案（32人）、对照组（202人）、口服治疗方案（211人）或6个月治疗方案（143人）；其中352人（60%）为男性，236人（40%）为女性。在接受三种较短疗程治疗的 556 名参与者中，517 人被纳入 mITT 群体（对照组 187 人、口服组 196 人、6 个月组 134 人），465 人被纳入按方案分析。另有6名参与者在第76周至疗效随访结束期间出现了不利结果（对照组1人、口服组4人、6个月组1人）。在mITT人群中，随访结束时出现不利结果的患者比例为：口服组19-6%（95% CI 14-3至24-9），对照组29-3%（23-3至36-5）（差异为-9-7个百分点[95% CI -18-7至-1-8]；Ps优于=0-024）。估计有9-8%（95% CI 4-6至14-9）的6个月疗程参与者出现不利结果，明显低于同时接受对照疗程（32-5% [23-7至40-2]；ps优效性<0-0001）或口服疗程（23-8% [16-9至31-1]；ps优效性=0-013）的参与者。第 76 周后报告的严重或严重不良事件很少，没有迹象表明两种方案之间存在差异。在第132周时，口服方案（7/205；3%）中出现治疗引起的听力损失的人数明显少于对照方案（16/198；8%；P=0.041）；口服方案（6/139；4%）和6个月方案（5/143；4%；P=0-72）中出现严重听力损失的人数没有明显差异。死亡率较低：接受贝达喹啉治疗的参与者（即口服方案和6个月方案，n=287）每100人年的死亡率为1-01（95% CI为0-48至2-12），而接受对照方案的参与者（n=140；p=0-49）每100人年的死亡率为1-52（0-63至3-66）。解释两种含有贝达喹啉的治疗方案均保持了优于对照方案的效果，没有证据表明死亡率增加，为患者提供了两种额外的循证治疗选择；之前对贝达喹啉死亡率的担忧没有得到证实。

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来源期刊

Lancet Respiratory Medicine RESPIRATORY SYSTEM-RESPIRATORY SYSTEM

CiteScore

87.10

自引率

0.70%

发文量

572

期刊介绍： The Lancet Respiratory Medicine is a renowned journal specializing in respiratory medicine and critical care. Our publication features original research that aims to advocate for change or shed light on clinical practices in the field. Additionally, we provide informative reviews on various topics related to respiratory medicine and critical care, ensuring a comprehensive coverage of the subject. The journal covers a wide range of topics including but not limited to asthma, acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), tobacco control, intensive care medicine, lung cancer, cystic fibrosis, pneumonia, sarcoidosis, sepsis, mesothelioma, sleep medicine, thoracic and reconstructive surgery, tuberculosis, palliative medicine, influenza, pulmonary hypertension, pulmonary vascular disease, and respiratory infections. By encompassing such a broad spectrum of subjects, we strive to address the diverse needs and interests of our readership.