Background

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.

Methods

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.

Findings

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.

Interpretation

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.

Funding

US National Institutes of Health (NIH) and Operation Warp Speed.

中文翻译：

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Tixagevimab–cilgavimab 用于治疗 COVID-19 住院患者：一项随机、双盲、3 期试验

背景

Tixagevimab–cilgavimab 是一种中和性单克隆抗体组合，据推测可改善 COVID-19 住院患者的预后。我们的目的是在接受瑞德西韦和其他标准治疗的患者中比较 tixagevimab-cilgavimab 与安慰剂。

方法

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 个地点有症状长达 12 天并因 COVID-19 住院的成年人被随机分配到 1： 1 比例接受静脉注射 tixagevimab 300 mg–cilgavimab 300 mg 或安慰剂，以及瑞德西韦和其他标准治疗。如果患者患有急性器官衰竭，包括接受有创机械通气、体外膜氧合、血管升压药治疗、机械循环支持或新的肾脏替代治疗，则患者被排除在外。研究药物由一名未戴口罩的药剂师配制；研究参与者、现场研究人员、研究人员和临床提供者对研究分配不知情。主要结果是持续恢复到第 90 天的时间，定义为出院后连续 14 天在家，对整个队列和基线时中和抗体阴性的参与者进行共同主要分析。在改良意向治疗人群中进行了疗效和安全性分析，该人群定义为接受完全或部分输注 tixagevimab-cilgavimab 或安慰剂的参与者。本研究已在 ClinicalTrials.gov 注册，NCT04501978，参与者的随访正在进行中。

发现

从 2021 年 2 月 10 日到 9 月 30 日，1455 名患者被随机分配，主要改良意向性治疗人群中的 1417 名患者接受了 tixagevimab-cilgavimab (n=710) 或安慰剂 (n=707) 输注。在第 90 天，整个队列中 tixagevimab-cilgavimab 的持续恢复估计累积发生率为 89%，安慰剂组参与者为 86%（恢复率比 [RRR] 1·08 [95% CI 0·97–1·20] ；p=0·21）。结果在血清阴性亚组中相似（RRR 1·14 [0·97–1·34]；p=0·13）。与安慰剂组（86 [12%]；风险比 [HR] 0·70 [95% CI 0·50–0·97]；p=0 ·032). 复合安全性结果发生在 178 名 (25%) tixagevimab–cilgavimab 和 212 名 (30%) 安慰剂组参与者中（HR 0·83 [0·68–1·01]；p=0·059）。

解释

在接受瑞德西韦和其他标准治疗的 COVID-19 住院患者中，tixagevimab-cilgavimab 并未改善持续康复时间的主要结局，但安全且死亡率较低。

资金

美国国立卫生研究院 (NIH) 和曲速行动。