Tixagevimab-cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial.
Tixagevimab-cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial.
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DOI：
10.1016/s2213-2600(22)00215-6
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发表时间：
2022-10
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Tixagevimab-cilgavimab是一种中和性单克隆抗体组合，假设可以改善COVID-19住院患者的预后。我们的目的是比较接受瑞德西韦和其他标准治疗的患者的替沙吉维单抗-西gavimab和安慰剂。在一项随机、双盲、3期安慰剂对照试验中，在美国、欧洲、乌干达和新加坡的81个地点，因COVID-19住院并出现症状长达12天的成年人按1:1的比例随机分配，除瑞德西韦和其他标准治疗外，还接受静脉注射替沙吉维单抗300毫克-西加维单抗300毫克或安慰剂。排除急性器官衰竭患者，包括接受有创机械通气、体外膜氧合、血管加压治疗、机械循环支持或新的肾脏替代治疗。研究药物是由一名未蒙面的药剂师配制的；研究参与者、现场研究人员、调查人员和临床提供者对研究分配不知情。主要终点是持续恢复至第90天的时间，定义为出院后连续在家14天，并对整个队列和基线时抗体阴性的参与者进行联合主要分析。疗效和安全性分析是在修改意向治疗人群中进行的，定义为接受完全或部分输注替沙吉维单抗-西gavimab或安慰剂的参与者。该研究已在ClinicalTrials.gov注册，编号NCT04501978，参与者的随访正在进行中。从2021年2月10日至9月30日，1455名患者被随机分配，其中1417名患者在主要修改意向治疗人群中输注了替沙吉维单抗-西gavimab （n=710）或安慰剂（n=707）。在全队列中，第90天，替沙吉维单-西gavimab组的持续恢复累积发生率估计为89%，安慰剂组的持续恢复累积发生率为86%（回收率比[RRR] 1.08 [95% CI 0.97 - 1.20]; p= 0.21）。血清阴性亚组结果相似（RRR为1.14 [0.97 ~ 1.34];p= 0.13）。替沙韦玛-西gavimab组的死亡率（61例[9%]）低于安慰剂组（86例[12%]；风险比[HR] 0.70 [95% CI 0.50 - 0.97]; p= 0.032）。复合安全性结局发生在178名（25%）替沙吉维单抗-西gavimab组和212名（30%）安慰剂组（HR = 0.83 [0.68 - 1.01]; p= 0.059）。在替沙吉维单抗-西gavimab组中有34名（5%）参与者发生了严重不良事件，在安慰剂组中有38名（5%）参与者发生了严重不良事件。在接受瑞德西韦和其他标准治疗的COVID-19住院患者中，替沙吉韦单抗-西加维单抗并未改善持续恢复时间的主要结局，但安全且死亡率较低。美国国立卫生研究院（NIH）和翘曲速度操作。
Tixagevimab–cilgavimab is a neutralising monoclonal antibody combination hypothesised to improve outcomes for patients hospitalised with COVID-19. We aimed to compare tixagevimab–cilgavimab versus placebo, in patients receiving remdesivir and other standard care. In a randomised, double-blind, phase 3, placebo-controlled trial, adults with symptoms for up to 12 days and hospitalised for COVID-19 at 81 sites in the USA, Europe, Uganda, and Singapore were randomly assigned in a 1:1 ratio to receive intravenous tixagevimab 300 mg–cilgavimab 300 mg or placebo, in addition to remdesivir and other standard care. Patients were excluded if they had acute organ failure including receipt of invasive mechanical ventilation, extracorporeal membrane oxygenation, vasopressor therapy, mechanical circulatory support, or new renal replacement therapy. The study drug was prepared by an unmasked pharmacist; study participants, site study staff, investigators, and clinical providers were masked to study assignment. The primary outcome was time to sustained recovery up to day 90, defined as 14 consecutive days at home after hospital discharge, with co-primary analyses for the full cohort and for participants who were neutralising antibody-negative at baseline. Efficacy and safety analyses were done in the modified intention-to-treat population, defined as participants who received a complete or partial infusion of tixagevimab–cilgavimab or placebo. This study is registered with ClinicalTrials.gov, NCT04501978 and the participant follow-up is ongoing. From Feb 10 to Sept 30, 2021, 1455 patients were randomly assigned and 1417 in the primary modified intention-to-treat population were infused with tixagevimab–cilgavimab (n=710) or placebo (n=707). The estimated cumulative incidence of sustained recovery was 89% for tixagevimab–cilgavimab and 86% for placebo group participants at day 90 in the full cohort (recovery rate ratio [RRR] 1·08 [95% CI 0·97–1·20]; p=0·21). Results were similar in the seronegative subgroup (RRR 1·14 [0·97–1·34]; p=0·13). Mortality was lower in the tixagevimab–cilgavimab group (61 [9%]) versus placebo group (86 [12%]; hazard ratio [HR] 0·70 [95% CI 0·50–0·97]; p=0·032). The composite safety outcome occurred in 178 (25%) tixagevimab–cilgavimab and 212 (30%) placebo group participants (HR 0·83 [0·68–1·01]; p=0·059). Serious adverse events occurred in 34 (5%) participants in the tixagevimab–cilgavimab group and 38 (5%) in the placebo group. Among patients hospitalised with COVID-19 receiving remdesivir and other standard care, tixagevimab–cilgavimab did not improve the primary outcome of time to sustained recovery but was safe and mortality was lower. US National Institutes of Health (NIH) and Operation Warp Speed.