Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial
Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial
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DOI：
10.1016/s1473-3099(19)30574-2
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发表时间：
2020-03-01
影响因子：
56.3
通讯作者：
Chastre, Jean
中科院分区：
文献类型：
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作者：
Niederman, Michael S.;Alder, Jeff;Chastre, Jean
背景：即使患者按照既定的指南进行治疗，通气性肺炎的治疗通常也不成功。因此，我们的目的是调查联合药物装置阿米卡星吸入剂作为静脉标准护理抗生素治疗气管插管和机械通气患者中革兰氏阴性病原体引起的肺炎的辅助治疗的有效性。III期研究包括在25个国家的153家医院重症监护室进行的两项试验（INHALE 1和INHALE 2）。符合条件的患者年龄≥ 18岁;患有肺炎，经胸部X线摄影诊断，并记录为由革兰氏阴性、多重耐药病原体引起或显示两种风险因素;插管和机械通气;筛选前48小时内氧合受损;改良临床肺部感染评分至少为6。患者按地区和疾病严重程度分层（根据其急性生理学和慢性健康评估[APACHE] II评分），并通过交互式语音识别系统随机分配（1：1）接受400 mg阿米卡星（阿米卡星吸入）或生理盐水安慰剂，两者均雾化，通过相同的同步吸入系统每12小时给药一次，持续10天，并与标准护理静脉注射抗生素一起给药。所有患者和参与器械给药和监测结局的所有工作人员均对治疗分配设盲。在接受至少一剂研究药物、感染革兰氏阴性病原体且诊断时APACHE II评分至少为10分的所有患者中分析主要终点（第28-32天的生存率）。在接受至少一剂研究药物的所有患者中进行安全性分析。该研究在ClinicalTrials.gov上注册，编号为NCT 01799993和NCT 00805168。结果在2013年4月13日至2017年4月7日期间，对807名患者进行了资格评估，725名患者被随机分配至阿米卡星吸入剂（362名患者）或雾化安慰剂（363名患者）。712例患者接受了至少一剂研究药物（阿米卡星吸入组354例，安慰剂组358例），尽管分配至阿米卡星吸入组的1例患者错误接受了安慰剂，并被纳入安慰剂组进行安全性分析。对508例患者（阿米卡星吸入组255例，安慰剂组253例）进行了主要终点评估。我们没有发现组间生存差异：阿米卡星吸入组191例（75%）患者与安慰剂组196例（77%）患者存活至第28-32天（比值比0.841，95%CI 0.554-1-277; p=0.43）。两个治疗组中发生治疗后出现的不良事件的患者比例相似（阿米卡星吸入组353例患者中295例[84%] vs安慰剂组359例患者中303例[84%]）或严重治疗后出现的不良事件（101例[29%]患者vs 97例[27%]患者）。解释我们的研究结果不支持在革兰氏阴性肺炎机械通气患者中使用吸入性阿米卡星替代标准护理静脉内治疗。版权所有（C）2019 Elsevier Ltd.保留所有权利。
Background Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients.Methods INHALE was a prospective, double-blind, randomised, placebo-controlled, phase 3 study comprising two trials (INHALE 1 and INHALE 2) done in 153 hospital intensive-care units in 25 countries. Eligible patients were aged 18 years or older; had pneumonia that had been diagnosed by chest radiography and that was documented as being caused by or showing two risk factors for a Gram-negative, multidrug-resistant pathogen; were intubated and mechanically ventilated; had impaired oxygenation within 48 h before screening; and had a modified Clinical Pulmonary Infection Score of at least 6. Patients were stratified by region and disease severity (according to their Acute Physiology and Chronic Health Evaluation [APACHE] II score) and randomly assigned (1:1) via an interactive voice-recognition system to receive 400 mg amikacin (Amikacin Inhale) or saline placebo, both of which were aerosolised, administered every 12 h for 10 days via the same synchronised inhalation system, and given alongside standard-of-care intravenous antibiotics. All patients and all staff involved in administering devices and monitoring outcomes were masked to treatment assignment. The primary endpoint, survival at days 28-32, was analysed in all patients who received at least one dose of study drug, were infected with a Gram-negative pathogen, and had an APACHE II score of at least 10 at diagnosis. Safety analyses were done in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, numbers NCT01799993 and NCT00805168.Findings Between April 13, 2013, and April 7, 2017, 807 patients were assessed for eligibility and 725 were randomly assigned to Amikacin Inhale (362 patients) or aerosolised placebo (363 patients). 712 patients received at least one dose of study drug (354 in the Amikacin Inhale group and 358 in the placebo group), although one patient assigned to Amikacin Inhale received placebo in error and was included in the placebo group for safety analyses. 508 patients (255 in the Amikacin Inhale group and 253 in the placebo group) were assessed for the primary endpoint. We found no between-group difference in survival: 191 (75%) patients in the Amikacin Inhale group versus 196 (77%) patients in the placebo group survived until days 28-32 (odds ratio 0.841, 95% CI 0.554-1-277; p=0.43). Similar proportions of patients in the two treatment groups had a treatment-emergent adverse event (295 [84%] of 353 patients in the Amikacin Inhale group vs 303 [84%] of 359 patients in the placebo group) or a serious treatment-emergent adverse event (101 [29%] patients vs 97 [27%] patients).Interpretation Our findings do not support use of inhaled amikacin adjunctive to standard-of-care intravenous therapy in mechanically ventilated patients with Gram-negative pneumonia. Copyright (C) 2019 Elsevier Ltd. All rights reserved.