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Tixagevimab–cilgavimab for treatment of patients hospitalised with COVID-19: a randomised, double-blind, phase 3 trial
The Lancet Respiratory Medicine ( IF 38.7 ) Pub Date : 2022-07-08 , DOI: 10.1016/s2213-2600(22)00215-6
Thomas L. Holland , Adit A. Ginde , Roger Paredes , Thomas A. Murray , Nicole Engen , Greg Grandits , Andrew Vekstein , Noel Ivey , Ahmad Mourad , Uriel Sandkovsky , Robert L. Gottlieb , Mezgebe Berhe , Mamta K. Jain , Rubria Marines-Price , Barbine Tchamba Agbor Agbor , Lourdes Mateu , Sergio España-Cueto , Gemma Lladós , Eleftherios Mylonakis , Ralph Rogers , Fadi Shehadeh , Michael R. Filbin , Kathryn A. Hibbert , Kami Kim , Thanh Tran , Peter E. Morris , Evan P. Cassity , Barbara Trautner , Lavannya M. Pandit , Kirk U. Knowlton , Lindsay Leither , Michael A. Matthay , Angela J. Rogers , Wonder Drake , Beatrice Jones , Garyfallia Poulakou , Konstantinos N. Syrigos , Eduardo Fernández-Cruz , Marisa Di Natale , Eyad Almasri , Leire Balerdi-Sarasola , Sanjay R. Bhagani , Katherine L. Boyle , Jonathan D. Casey , Peter Chen , David J. Douin , D. Clark Files , Huldrych F. Günthard , R. Duncan Hite , Robert C. Hyzy , Akram Khan , Moses Kibirige , Robert Kidega , Ivan Kimuli , Francis Kiweewa , Jens-Ulrik Jensen , Bradley G. Leshnower , Joseph K. Lutaakome , Prasad Manian , Vidya Menon , Jose Luis Morales-Rull , D. Shane O'Mahony , J. Scott Overcash , Srikant Ramachandruni , Jay S. Steingrub , Hassan S. Taha , Michael Waters , Barnaby E. Young , Andrew N. Phillips , Daniel D. Murray , Tomas O. Jensen , Maria L. Padilla , David Sahner , Katy Shaw-Saliba , Robin L. Dewar , Marc Teitelbaum , Ven Natarajan , M. Tauseef Rehman , Sarah Pett , Fleur Hudson , Giota Touloumi , Samuel M. Brown , Wesley H. Self , Christina C. Chang , Adriana Sánchez , Amy C. Weintrob , Timothy Hatlen , Birgit Grund , Shweta Sharma , Cavan S. Reilly , Pedro Garbes , Mark T. Esser , Alison Templeton , Abdel G. Babiker , Victoria J. Davey , Annetine C. Gelijns , Elizabeth S. Higgs , Virginia Kan , Gail Matthews , B. Taylor Thompson , James D. Neaton , H. Clifford Lane , Jens D. Lundgren

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:


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


 背景


Tixagevimab-cilgavimab 是一种中和单克隆抗体组合,假设可以改善因 COVID-19 住院的患者的预后。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 个地点出现症状长达 12 天并因 COVID-19 住院的成年人被随机分配到 1 组: 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、血管加压治疗、机械循环支持或新的肾脏替代治疗,则被排除在外。研究药物是由一位未蒙面的药剂师配制的;研究参与者、现场研究人员、研究人员和临床提供者对研究任务不知情。主要结局是持续恢复至第 90 天的时间,定义为出院后连续在家 14 天,对整个队列和基线时中和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改良的意向治疗人群中进行的,定义为接受完全或部分输注 tixagevimab-cilgavimab 或安慰剂的参与者。这项研究已在 ClinicalTrials.gov 注册,NCT04501978,参与者的随访正在进行中。

 发现


从2021年2月10日至9月30日,1455名患者被随机分配,其中1417名主要改良意向治疗人群接受了替克维玛-西加维玛(n=710)或安慰剂(n=707)输注。在整个队列中,第 90 天时,tixagevimab-cilgavimab 持续恢复的估计累计发生率为 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)。血清阴性亚组的结果相似(RRR 1·14 [0·97–1·34];p=0·13)。与安慰剂组(86 [12%])相比,替克维玛-西加维玛组的死亡率较低(61 [9%]);风险比 [HR] 0·70 [95% CI 0·50–0·97];p=0 ·032)。 178 名 (25%) 替克维玛-西加维玛和 212 名 (30%) 安慰剂组参与者出现了复合安全性结果(HR 0·83 [0·68–1·01];p=0·059)。 tixagevimab-cilgavimab 组有 34 名(5%)参与者发生严重不良事件,安慰剂组有 38 名(5%)参与者发生严重不良事件。

 解释


在接受瑞德西韦和其他标准护理的 COVID-19 住院患者中,替克格维玛-西加维玛并没有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。

更新日期:2022-07-08
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