24 周全口服方案治疗利福平耐药结核病。

A 24-Week, All-Oral Regimen for Rifampin-Resistant Tuberculosis.

机构信息

From the Public Health Department, Operational Center Amsterdam (OCA), Médecins sans Frontières, Amsterdam (B.-T.N., K.R.); the Public Health Department, OCA, Médecins sans Frontières (C.B., E.K., I.M.), the London School of Hygiene and Tropical Medicine (B.-T.N., M.D., D.A.J.M., K.F.), and University College London (T.D.M.) - all in London; the Republican Specialized Scientific and Practical Medical Center of Phthisiology and Pulmonology, Tashkent (N.P., I.L.), and the Republican Phthisiological Hospital No. 2, Nukus (Z.T.) - both in Uzbekistan; the Republican Scientific and Practical Center for Pulmonology and Tuberculosis, Minsk, Belarus (V.S.); THINK TB and HIV Investigative Network, Durban (R.M.), and Wits Health Consortium, Johannesburg (N.N., M.R.) - both in South Africa; the Global Alliance for TB Drug Development, New York (M.S.); and the Burnet Institute, Melbourne, VIC, Australia (P.C.).

出版信息

N Engl J Med. 2022 Dec 22;387(25):2331-2343. doi: 10.1056/NEJMoa2117166.

DOI:10.1056/NEJMoa2117166

PMID:36546625

Abstract

BACKGROUND

In patients with rifampin-resistant tuberculosis, all-oral treatment regimens that are more effective, shorter, and have a more acceptable side-effect profile than current regimens are needed.

METHODS

We conducted an open-label, phase 2-3, multicenter, randomized, controlled, noninferiority trial to evaluate the efficacy and safety of three 24-week, all-oral regimens for the treatment of rifampin-resistant tuberculosis. Patients in Belarus, South Africa, and Uzbekistan who were 15 years of age or older and had rifampin-resistant pulmonary tuberculosis were enrolled. In stage 2 of the trial, a 24-week regimen of bedaquiline, pretomanid, linezolid, and moxifloxacin (BPaLM) was compared with a 9-to-20-month standard-care regimen. The primary outcome was an unfavorable status (a composite of death, treatment failure, treatment discontinuation, loss to follow-up, or recurrence of tuberculosis) at 72 weeks after randomization. The noninferiority margin was 12 percentage points.

RESULTS

Recruitment was terminated early. Of 301 patients in stage 2 of the trial, 145, 128, and 90 patients were evaluable in the intention-to-treat, modified intention-to-treat, and per-protocol populations, respectively. In the modified intention-to-treat analysis, 11% of the patients in the BPaLM group and 48% of those in the standard-care group had a primary-outcome event (risk difference, -37 percentage points; 96.6% confidence interval [CI], -53 to -22). In the per-protocol analysis, 4% of the patients in the BPaLM group and 12% of those in the standard-care group had a primary-outcome event (risk difference, -9 percentage points; 96.6% CI, -22 to 4). In the as-treated population, the incidence of adverse events of grade 3 or higher or serious adverse events was lower in the BPaLM group than in the standard-care group (19% vs. 59%).

CONCLUSIONS

In patients with rifampin-resistant pulmonary tuberculosis, a 24-week, all-oral regimen was noninferior to the accepted standard-care treatment, and it had a better safety profile. (Funded by Médecins sans Frontières; TB-PRACTECAL ClinicalTrials.gov number, NCT02589782.).

摘要

背景

在耐利福平的结核病患者中，需要有比目前方案更有效、更短、副作用谱更易接受的全口服治疗方案。

方法

我们进行了一项开放性、2 期-3 期、多中心、随机、对照、非劣效性试验，以评估三种 24 周全口服方案治疗耐利福平的肺结核的疗效和安全性。来自白俄罗斯、南非和乌兹别克斯坦的 15 岁及以上患有耐利福平的肺结核患者参加了这项试验。在试验的第 2 阶段，24 周的贝达喹啉、普托马尼德、利奈唑胺和莫西沙星（BPaLM）方案与 9 至 20 个月的标准护理方案进行了比较。主要终点是随机分组后 72 周时不良结局（死亡、治疗失败、治疗中止、失访或结核病复发的综合指标）。非劣效性边界为 12 个百分点。

结果

入组提前终止。在第 2 阶段的 301 名患者中，分别有 145、128 和 90 名患者在意向治疗、改良意向治疗和方案人群中进行了评估。在改良意向治疗分析中，BPaLM 组的 11%患者和标准护理组的 48%患者发生了主要结局事件（风险差异，-37 个百分点；96.6%置信区间[CI]，-53 至-22）。在按方案分析中，BPaLM 组的 4%患者和标准护理组的 12%患者发生了主要结局事件（风险差异，-9 个百分点；96.6%CI，-22 至 4）。在治疗人群中，BPaLM 组的 3 级或更高级别的不良事件和严重不良事件发生率低于标准护理组（19%比 59%）。