Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial
Efficacy and safety of delamanid in combination with an optimised background regimen for treatment of multidrug-resistant tuberculosis: a multicentre, randomised, double-blind, placebo-controlled, parallel group phase 3 trial
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DOI：
10.1016/s2213-2600(18)30426-0
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发表时间：
2019-03-01
影响因子：
76.2
通讯作者：
Gupta, Rajesh
中科院分区：
文献类型：
--
作者：
von Groote-Bidlingmaier, Florian;Patientia, Ramonde;Gupta, Rajesh
背景：地拉曼是最近被批准用于治疗耐多药结核病的两种药物之一。方法在7个国家(爱沙尼亚、拉脱维亚、立陶宛、摩尔多瓦、秘鲁、菲律宾和南非)的17个地点进行了这项随机、双盲、安慰剂对照的3期试验。我们招募了符合条件的成人(>；18岁)，接受根据世卫组织和国家指南制定的优化背景方案的联合治疗，既可以口服地拉曼德(每天两次，100毫克)2个月，然后每天200毫克，连续4个月，或者服用安慰剂(相同方案)。患者被集中随机(2：1)，并根据延迟痰培养转换的风险类别进行分层。主要结果是6个月以上的痰培养转换时间和两组之间6个月以上痰培养转换时间的分布差异，这是在改良的意向治疗人群中评估的。该试验在ClinicalTrials.gov上注册，编号NCT01424670。在2011年9月2日至2013年11月27日期间，我们筛选了714名患者，其中511人被随机分配(341人接受delamanid加优化背景方案[delamanid组]，170人接受安慰剂+优化背景方案[安慰剂组])，并形成安全性分析人群。在基线时，327名耐多药结核病培养阳性患者组成了疗效分析人群(delamanid组226人，安慰剂组101人)。痰培养转阴的中位时间在两组间无差异(p=0.0562；改良Peto-Peto法)，Delamanid组51天(IQR29-98)，安慰剂组57天(43-85)，风险比为1.17(95%CI0.91-1.51，p=0.2157)。在511例患者中，501例(98.0%)至少有一次治疗--紧急不良事件。在511名患者中，136名(26.6%)至少有一次严重的紧急治疗不良事件；治疗组之间的发生率相似(德拉马尼组341名患者中89名(26.1%)，安慰剂组170名患者中47名[27.6%])。与紧急不良事件有关的死亡率在两组间相似(服用地拉马尼组341例，死亡15例[4.4%]；安慰剂组170例，死亡6例[3.5%])。没有死亡被认为与Delamanid有关。初步分析中，痰培养转换的中位时间在6个月以上的减少并不显著。Delamanid耐受性良好，具有高度特征性的安全特性。需要对delamanid进行进一步评估，以确定其在快速发展的护理标准中的作用。版权所有(C)2019爱思唯尔有限公司。保留所有权利。
Background Delamanid is one of two recently approved drugs for the treatment of multidrug-resistant tuberculosis. We aimed to evaluate the safety and efficacy of delamanid in the first 6 months of treatment.Methods This randomised, double-blind, placebo-controlled, phase 3 trial was done at 17 sites in seven countries (Estonia, Latvia, Lithuania, Moldova, Peru, the Philippines, and South Africa). We enrolled eligible adults (>18 years) with pulmonary multidrug-resistant tuberculosis to receive, in combination with an optimised background regimen developed according to WHO and national guidelines, either oral delamanid (100 mg twice daily) for 2 months followed by 200 mg once daily for 4 months or placebo (same regimen). Patients were centrally randomised (2:1) and stratified by risk category for delayed sputum culture conversion. Primary outcomes were the time to sputum culture conversion over 6 months and the difference in the distribution of time to sputum culture conversion over 6 months between the two groups, as assessed in the modified intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424670.Findings Between Sept 2, 2011, and Nov 27, 2013, we screened 714 patients, of whom 511 were randomly assigned (341 to delamanid plus optimised background regimen [delamanid group] and 170 to placebo plus optimised background regimen [placebo group]) and formed the safety analysis population. 327 patients were culture-positive for multidrug-resistant tuberculosis at baseline and comprised the efficacy analysis population (226 in the delamanid group and 101 in the placebo group). Median time to sputum culture conversion did not differ between the two groups (p=0.0562; modified Peto-Peto), with 51 days (IQR 29-98) in the delamanid group and 57 days (43-85) in the placebo group; the hazard ratio was 1.17 (95% CI 0.91-1.51, p=0.2157). 501 (98.0%) of 511 patients had at least one treatment-emergent adverse event. 136 (26.6%) of 511 patients had at least one serious treatment-emergent adverse event; the incidence was similar between treatment groups (89 [26.1%] of 341 patients for delamanid and 47 [27.6%] of 170 for placebo). Deaths related to treatment-emergent adverse events were similar between groups (15 [4.4%] of 341 for delamanid and six [3.5%] of 170 for placebo). No deaths were considered to be related to delamanid.Interpretation The reduction in median time to sputum culture conversion over 6 months was not significant in the primary analysis. Delamanid was well tolerated with a highly characterised safety profile. Further evaluation of delamanid is needed to determine its role in a rapidly evolving standard of care. Copyright (C) 2019 Elsevier Ltd. All rights reserved.