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.

中文翻译：

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两种短期标准化方案治疗利福平耐药结核病的长期​​疗效和安全性（STREAM 2 期）：开放标签、多中心、随机、非劣效性试验的长期随访

 背景

STREAM 2 期表明，两种含贝达喹啉的方案（9 个月的全口服方案和 6 个月的氨基糖苷类方案，8 周的氨基糖苷类方案）对于利福平耐药结核病的疗效优于 9 个月的注射方案。随机分组后 76 周。我们此次随访分析的目的是评估 132 周时疗效和安全性的持久性，包括死亡率。

 方法

我们报告了 STREAM 2 期的长期结果，这是一项随机、3 期非劣效性（10% 边际）试验，受试者为利福平耐药结核病患者（年龄≥15 岁），且不具有氟喹诺酮类或氨基糖苷类耐药性，在 7 个临床中心的 13 个临床中心进行国家（埃塞俄比亚、格鲁吉亚、印度、摩尔多瓦、蒙古、南非和乌干达）。参与者被随机分配至 2011 年 WHO 长期方案（提前终止）、9 个月对照方案、9 个月口服方案（通过排列组并按部位和 HIV 状态加 CD4 细胞计数分层）。贝达喹啉治疗方案（主要比较），或贝达喹啉 6 个月治疗方案加 8 周注射抗结核药物。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。先前报告的主要结局为第 76 周时的有利状态（结核分枝杆菌培养物阴性，且之前没有不利结果；任何死亡、细菌学失败或复发以及重大治疗改变均被认为是不利的）。在此，我们报告第 132 周时的疗效结果，在改良意向治疗 (mITT) 人群中进行分析。安全性评估持续至 132 周，评估对象为所有接受至少一剂研究方案的参与者。所有比较均使用同时随机化的参与者。该试验已在 ISRCTN (ISRCTN18148631) 上注册，现已完成。

 发现

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接受长期治疗（n=32）、对照组（n=202）、口服治疗（n=211）或6个月治疗（n=143）治疗方案； 352 名（60%）为男性，236 名（40%）为女性。在接受三种较短疗程的 556 名参与者中，517 名被纳入 mITT 人群（对照组 187 名，口服组 196 名，6 个月组 134 名），465 名参加符合方案分析。另外 6 名参与者在第 76 周至疗效随访结束期间出现不良结果（对照组 1 名，口服组 4 名，6 个月组 1 名）。在 mITT 人群中，随访结束时出现不良结果的患者比例，口服组为 19·6%（95% CI 14·3 至 24·9），29·3%（23·3至 36·5）（–9·7 个百分点差异 [95% CI –18·7 至 –1·8]；p_优效性= 0·024）。估计 9·8%（95% CI 4·6 至 14·9）接受 6 个月治疗方案的参与者出现不良结果，明显低于同时接受对照方案的参与者（32·5% [23 ·7 至 40·2]；p_优势<0·0001) 或口服方案（23·8% [16·9 至 31·1]；p_优势=0·013）。 76 周后几乎没有报告严重或严重的不良事件，没有迹象表明治疗方案之间存在差异。在第 132 周，口服治疗方案的参与者 (7/205; 3%) 中出现治疗突发性听力损失的人数显着少于对照组 (16/198; 8%; p=0.041)。口服治疗方案（6/139；4%）和6个月治疗方案（5/143；4%；p=0·72）之间的严重听力损失没有显着差异。 死亡率较低：分配至贝达奎林（即口服 6 个月治疗方案，n=287）的参与者每 100 人年有 1·01 例（95% CI 0·48 至 2·12），而分配至贝达喹啉组的参与者为 1·52（95% CI 0·48 至 2·12）。 0·63 至 3·66）在对照方案的参与者中（n = 140；p = 0·49）。

 解释

两种含贝达喹啉的方案均保持优于对照方案，且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；先前对贝达喹啉死亡率的担忧并未得到证实。

 资金

美国国际开发署和杨森研究与开发公司。