Bedaquiline, delamanid, linezolid, and clofazimine for rifampicin-resistant and fluoroquinolone-resistant tuberculosis (endTB-Q): an open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial.

Methods

This open-label, multicentre, stratified, non-inferiority, randomised, controlled, phase 3 trial was conducted in ten hospitals in India, Kazakhstan, Lesotho, Pakistan, Peru, and Viet Nam.

这是一项开放标签、多中心、分层、非劣效性、随机、对照的III期试验，在印度、哈萨克斯坦、莱索托、巴基斯坦、秘鲁和越南的十家医院进行。

Participants aged 15 years or older who had pulmonary tuberculosis with resistance to rifampicin and fluoroquinolones were included.

纳入年龄在15岁或以上的参与者，这些参与者患有对利福平和氟喹诺酮类药物耐药的肺结核。

Participants were randomly assigned (2:1) to the BDLC group (all-oral bedaquiline 400 mg once per day for 2 weeks followed by 200 mg three times per week, delamanid 100 mg twice per day, linezolid 600 mg once per day for 16 weeks and then either 300 mg once per day or 600 mg three times per week, and clofazimine 100 mg once per day) or the control group (individualised WHO-recommended longer standard of care).

参与者被随机分配（2:1）到BDLC组（所有口服的贝达喹啉400毫克每天一次，持续2周后改为每周三次200毫克，每日两次100毫克的德拉马尼，每日一次600毫克的利奈唑胺持续16周，之后改为每日一次300毫克或每周三次600毫克，以及每日一次100毫克的氯法齐明）或对照组（个体化的WHO推荐的更长的标准治疗方案）。

Randomisation was stratified by country and baseline disease extent.

随机分组按国家和基线疾病范围进行分层。

BDLC was administered for 39 weeks (9-month regimen) for extensive disease and 24 weeks (6-month regimen) for limited disease and extended to 9 months for those with a positive culture at 8 weeks or later or a missing 8-week culture result.

BDLC治疗方案对于广泛期疾病患者为39周（9个月方案），对于局限期疾病患者为24周（6个月方案），并且对于8周或之后培养结果为阳性或缺失8周培养结果的患者延长至9个月。

Site staff and participants were not masked, whereas investigators and laboratory staff were masked to treatment assignment.

现场工作人员和参与者未被蒙蔽，而研究者和实验室工作人员对治疗分配进行了蒙蔽。

The primary endpoint was favourable outcome (two consecutive, negative cultures including one between weeks 65 and 73; or favourable bacteriological, radiological, and clinical evolution) at week 73 after randomisation in the modified intention-to-treat(mITT) and per-protocol populations.

主要终点是在随机化后第73周，对修改后的意向治疗(mITT)人群和按方案人群，出现有利结果（连续两次阴性培养，包括在第65周到第73周之间的一次；或有利的细菌学、放射学和临床演变）。

We report the risk differences adjusted for stratification variables, with a non-inferiority margin of -12%.

我们报告了调整了分层变量后的风险差异，非劣效界值为-12%。

This trial is registered with ClinicalTrials.gov, NCT03896685.

该试验已在ClinicalTrials.gov注册，注册号为NCT03896685。

Results

Between April 4, 2020, and March 28, 2023, 1030 individuals were screened and 324 (31%) were randomly assigned (219 to the BDLC group and 105 to the control group). 114 (46%) participants were female and 133 (54%) were male.

2020年4月4日至2023年3月28日期间，对1030名个体进行了筛查，其中324名（31%）被随机分配（219名分配至BDLC组，105名分配至对照组）。114名（46%）参与者为女性，133名（54%）为男性。

Median age was 30·5 years (IQR 21·6-43·0). 157 (64%) participants had extensive disease at baseline.

中位年龄为30.5岁（四分位数间距21.6-43.0）。157名（64%）参与者在基线时患有广泛性疾病。

In the BDLC group, 47 (29%) of 163 were assigned to receive the 6-month regimen and 116 (71%) the 9-month regimen.

在BDLC组中，163名患者中有47名（29%）被分配接受6个月的治疗方案，116名（71%）接受9个月的治疗方案。

The core regimen of BDLC plus one or more other drugs was used for 76 (91%) of 84 participants in the control group.

对照组中有84名参与者，其中76名（91%）使用BDLC加一种或多种其他药物的核心治疗方案。

At week 73, favourable outcome was reached by 141 (87%) participants in the BDLC group versus 75 (89%) in the control group in the mITT population (adjusted risk difference 0·2% [95% CI -9·1 to 9·5]; pnon-inferiority=0·0051) and by 138 (88%) of 157 versus 71 (93%) of 76 in the per-protocol population (adjusted risk difference -3·5% [-12·8 to 5·9]; pnon-inferiority=0·037).

在第73周，BDLC组中有141名（87%）参与者在mITT人群中达到有利结果，对照组为75名（89%）（调整后的风险差异为0.2% [95% 置信区间 -9.1至9.5]；p非劣效性=0.0051），在按方案（per-protocol）人群中，BDLC组138名（88%）中的157名和对照组71名（93%）中的76名达到有利结果（调整后的风险差异为-3.5% [-12.8至5.9]；p非劣效性=0.037）。

Overall non-inferiority was not shown. 145 (68%) of 213 participants in the BDLC group and 77 (73%) of 105 in the control group had at least one grade 3 or higher adverse event, with eight (4%) and two (2%) all-cause deaths by week 73, respectively.

整体上并未显示出非劣效性。BDLC组中有145名（68%）的213名参与者和对照组中有77名（73%）的105名参与者至少出现了一次3级或更高级别的不良事件，到第73周时，两组分别有八名（4%）和两名（2%）的全因死亡。

interpretation

The shortened BDLC strategy was not non-inferior to the control.

缩短的BDLC策略并不优于对照组。

Accumulating evidence suggests that this patient population might require longer, reinforced regimens.

越来越多的证据表明，这一患者群体可能需要更长、加强的治疗方案。

funding

Unitaid, Médecins Sans Frontières, Partners In Health, Interactive Research and Development, Ramón Areces Foundation, the Jung Foundation for Science and Research, Research Foundation-Flanders.

Unitaid、无国界医生组织、健康伙伴组织、互动研究与发展组织、拉蒙·阿塞斯基金会、容基金会科学与研究以及佛兰德斯研究基金会。

translations

For the Hindi, Marathi, Spanish, Vietnamese, Russian, Urdu and French translations of the abstract see Supplementary Materials section.

摘要的印地语、马拉地语、西班牙语、越南语、俄语、乌尔都语和法语翻译，请参见补充材料部分。