Goodall Ruth L, Nunn Andrew J, Meredith Sarah K, Bayissa Adamu, Bhatnagar Anuj K, Chiang Chen-Yuan, Conradie Francesca, Gopalan Narendran, Gurumurthy Meera, Kirenga Bruce, Kiria Nana, Meressa Daniel, Moodliar Ronelle, Ngubane Nosipho, Rassool Mohammed, Sanders Karen, Solanki Rajesh, Squire S Bertel, Teferi Mekonnen, Torrea Gabriela, Tsogt Bazarragchaa, Tudor Elena, Van Deun Armand, Rusen I D
MRC Clinical Trials Unit at UCL, University College London, London, UK.
MRC Clinical Trials Unit at UCL, University College London, London, UK.
Lancet Respir Med. 2024 Dec;12(12):975-987. doi: 10.1016/S2213-2600(24)00186-3. Epub 2024 Oct 1.
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.
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.
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=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<0·0001) or the oral regimen (23·8% [16·9 to 31·1]; p=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).
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.
US Agency for International Development and Janssen Research & Development.
STREAM 研究的第二阶段表明，两种含贝达喹啉的治疗方案（一种 9 个月的全口服方案和一种含 8 周氨基糖苷类药物的 6 个月方案）在随机分组后长达 76 周的时间里，对耐利福平结核病的疗效优于一种 9 个月的含注射剂方案。我们此次随访分析的目的是评估 132 周时疗效和安全性（包括死亡率）的持续性。
我们报告了 STREAM 研究第二阶段的长期结果，这是一项在七个国家（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 个临床地点开展的随机、3 期非劣效性（10%界值）试验，参与者为年龄≥15 岁、耐利福平结核病且对氟喹诺酮或氨基糖苷类药物无耐药性的患者。参与者按 1:2:2:2 的比例（通过置换区组并按地点、HIV 状态加 CD4 细胞计数分层）随机分配至 2011 年世界卫生组织长期方案（提前终止）、一种 9 个月的对照方案、一种含贝达喹啉的 9 个月口服方案（主要比较组）或一种含贝达喹啉及 8 周注射用抗结核药物的 6 个月方案。参与者和临床医生知晓治疗组分配情况，但实验室工作人员对分组情况不知情。先前报告的主要结局是第 76 周时的良好状态（结核分枝杆菌培养阴性且无先前不良结局；任何死亡、细菌学失败或复发以及重大治疗变更均视为不良结局）。在此，我们报告在改良意向性治疗（mITT）人群中第 132 周时的疗效结局。安全性评估持续至 132 周，纳入所有接受至少一剂研究方案的参与者。所有比较均使用同期随机分组的参与者。该试验已在国际标准随机对照试验编号注册库（ISRCTN18148631）注册，现已完成。
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至长期方案组（n = 32）、对照组（n = 202）、口服方案组（n = 211）或 6 个月方案组（n = 143）；352 名（60%）为男性，236 名（40%）为女性。在接受三种较短方案治疗的 556 名参与者中，517 名被纳入 mITT 人群（对照组 187 名、口服方案组 196 名、6 个月方案组 134 名），465 名纳入符合方案分析。另外 6 名参与者在第 76 周与疗效随访结束之间出现了不良结局（对照组 1 名、口服方案组 4 名、6 个月方案组 1 名）。在 mITT 人群中，随访结束时口服方案组不良结局患者的比例为 19.6%（95%CI 14.3 至 24.9），对照组为 29.3%（23.3 至 36.5）（差异为 -9.7 个百分点[95%CI -18.7 至 -1.8]；p = 0.024）。估计 6 个月方案组中有 9.8%（95%CI 4.6 至 14.9）的参与者出现不良结局，这显著低于同期接受对照方案（32.5%[23.7 至 40.2]；p < 0.0001）或口服方案（23.8%[16.9 至 31.1]；p = 0.013）的参与者。第 76 周后报告的严重或重度不良事件很少，各方案之间无差异迹象。在第 132 周时，口服方案组出现治疗引发听力损失的参与者明显少于对照方案组（7/205；3%）与对照方案组（16/198；8%；p = 0.041）；口服方案组（6/139；4%）与 6 个月方案组（5/143；4%；p = 0.72）之间在重度听力损失方面无显著差异。死亡率较低：分配至含贝达喹啉方案（即口服方案组和 6 个月方案组，n = 287）的参与者每 100 人年的死亡率为 1.01（95%CI 0.48 至 2.12），而对照方案组（n = 140）为 1.52（0.63 至 3.66）（p = 0.49）。
两种含贝达喹啉的方案均维持了优于对照方案的效果，且无死亡率增加的证据，为患者提供了另外两种基于证据的治疗选择；先前对贝达喹啉死亡率的担忧未得到证实。
美国国际开发署和杨森研发公司。
