Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial.
Lenzilumab in hospitalised patients with COVID-19 pneumonia (LIVE-AIR): a phase 3, randomised, placebo-controlled trial.
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DOI：
10.1016/s2213-2600(21)00494-x
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发表时间：
2022-03
期刊：
影响因子：
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通讯作者：
LIVE-AIR Study Group
中科院分区：
文献类型：
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作者：
Temesgen Z;Burger CD;Baker J;Polk C;Libertin CR;Kelley CF;Marconi VC;Orenstein R;Catterson VM;Aronstein WS;Durrant C;Chappell D;Ahmed O;Chappell G;Badley AD;LIVE-AIR Study Group
COVID-19的病理生理学包括免疫介导的过度炎症，这可能导致呼吸衰竭和死亡。粒细胞-巨噬细胞集落刺激因子（GM-CSF）是促成炎症过程的细胞因子之一。Lenzilumab是一种GM-CSF中和单克隆抗体，在LIVE-AIR试验中进行了研究，以评估其在现有治疗方法之外治疗COVID-19的有效性和安全性。LIVE-AIR是一项3期随机、双盲、安慰剂对照试验，从美国和巴西的29个地点招募了不需要有创机械通气的COVID-19肺炎住院成年患者，并随机分配（1:1）接受三次静脉注射剂量的lenzilumab（每剂600 mg）或间隔8小时给药的安慰剂。所有患者均接受标准的支持性治疗，包括使用瑞德西韦和皮质类固醇。患者按年龄和疾病严重程度随机分层。主要终点是在修改意向治疗人群（mITT）中无创机械通气存活至第28天，包括所有在主要研究者或副研究者的书面监督下接受至少一剂研究药物的随机受试者。对所有接受至少一剂研究药物的患者进行不良事件评估。该试验已在ClinicalTrials.gov注册，编号NCT04351152，并已完成。患者入组时间为2020年5月5日至2021年1月27日。528名患者接受了筛查，其中520人被随机分配并纳入意向治疗人群。其中479例患者（lenzilumab组236例，安慰剂组243例）被纳入主要结局的mITT分析。各组之间的基线人口统计数据相似。311名（65%）参与者为男性，基线时平均年龄61岁（SD 14），中位c反应蛋白浓度为79 (IQR 41-137) mg/L。449例（94%）患者接受类固醇治疗，347例（72%）患者接受瑞德西韦治疗；331例（69%）患者同时接受两种治疗。lenzilumab组198名（84%;95% CI 79-89）患者和安慰剂组190名（78%;72-83）患者无创机械通气存活至第28天，lenzilumab组生存的可能性大于安慰剂组（风险比1.54;95% CI 1.02 - 2 - 32; p= 0.040）。lenzilumab组的255名患者中有68名（27%）和安慰剂组的257名患者中有84名（33%）经历了至少一次不良事件，根据CTCAE标准，严重程度至少为3级。最常见的治疗中出现的3级或以上不良事件与呼吸系统疾病（26%）和心脏疾病（6%）有关，没有导致死亡。Lenzilumab显著提高了住院COVID-19患者无创机械通气的生存率，其安全性与安慰剂相似。lenzilumab比用于治疗COVID-19的其他免疫调节剂和类固醇的附加价值尚不清楚。Humanigen。
The pathophysiology of COVID-19 includes immune-mediated hyperinflammation, which could potentially lead to respiratory failure and death. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is among cytokines that contribute to the inflammatory processes. Lenzilumab, a GM-CSF neutralising monoclonal antibody, was investigated in the LIVE-AIR trial to assess its efficacy and safety in treating COVID-19 beyond available treatments. In LIVE-AIR, a phase 3, randomised, double-blind, placebo-controlled trial, hospitalised adult patients with COVID-19 pneumonia not requiring invasive mechanical ventilation were recruited from 29 sites in the USA and Brazil and were randomly assigned (1:1) to receive three intravenous doses of lenzilumab (600 mg per dose) or placebo delivered 8 h apart. All patients received standard supportive care, including the use of remdesivir and corticosteroids. Patients were stratified at randomisation by age and disease severity. The primary endpoint was survival without invasive mechanical ventilation to day 28 in the modified intention-to-treat population (mITT), comprising all randomised participants who received at least one dose of study drug under the documented supervision of the principal investigator or sub-investigator. Adverse events were assessed in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT04351152, and is completed. Patients were enrolled from May 5, 2020, until Jan 27, 2021. 528 patients were screened, of whom 520 were randomly assigned and included in the intention-to-treat population. 479 of these patients (n=236, lenzilumab; n=243, placebo) were included in the mITT analysis for the primary outcome. Baseline demographics were similar between groups. 311 (65%) participants were males, mean age was 61 (SD 14) years at baseline, and median C-reactive protein concentration was 79 (IQR 41–137) mg/L. Steroids were administered to 449 (94%) patients and remdesivir to 347 (72%) patients; 331 (69%) patients received both treatments. Survival without invasive mechanical ventilation to day 28 was achieved in 198 (84%; 95% CI 79–89) participants in the lenzilumab group and in 190 (78%; 72–83) patients in the placebo group, and the likelihood of survival was greater with lenzilumab than placebo (hazard ratio 1·54; 95% CI 1·02–2·32; p=0·040). 68 (27%) of 255 patients in the lenzilumab group and 84 (33%) of 257 patients in the placebo group experienced at least one adverse event that was at least grade 3 in severity based on CTCAE criteria. The most common treatment-emergent adverse events of grade 3 or higher were related to respiratory disorders (26%) and cardiac disorders (6%) and none led to death. Lenzilumab significantly improved survival without invasive mechanical ventilation in hospitalised patients with COVID-19, with a safety profile similar to that of placebo. The added value of lenzilumab beyond other immunomodulators used to treat COVID-19 alongside steroids remains unknown. Humanigen.