托珠单抗、沙瑞鲁单抗和阿那白滞素用于新冠肺炎危重症患者：一项随机、对照、开放标签、适应性平台试验。
Tocilizumab, sarilumab and anakinra in critically ill patients with COVID-19: a randomised, controlled, open-label, adaptive platform trial.
作者信息
Derde Lennie, Gordon Anthony C, Mouncey Paul R, Al-Beidh Farah, Rowan Kathryn M, Nichol Alistair D, Arabi Yaseen M, Annane Djillali, Beane Abigail, Beasley Richard, Bonten Marc J M, Bradbury Charlotte A, Brunkhorst Frank M, Buzgau Adrian, Buxton Meredith, Cheng Allen C, Cooper Nicola, Cove Matthew, Cremer Olaf L, Detry Michelle A, Duffy Eamon J, Estcourt Lise J, Fitzgerald Mark, Galea James, Goossens Herman, Haniffa Rashan, Hills Thomas E, Huang David T, Ichihara Nao, King Andrew, Lamontagne François, Lawler Patrick R, Leavis Helen L, Lewis Roger J, Litton Edward, Marshall John C, Mayr Florian B, McAuley Daniel F, McGlothlin Anna, McGuinness Shay P, McVerry Bryan J, Morpeth Susan C, Murthy Srinivas, Netea Mihai G, Ogungbenro Kayode, Orr Katrina, Parke Rachael L, Parker Jane C, Patanwala Asad E, Pettila Ville, Reyes Luis Felipe, Saito Hiroki, Santos Marlene S, Saunders Christina T, Seymour Christopher W, Shankar-Hari Manu, Sligl Wendy I, Turgeon Alexis F, Turner Anne M, Tong Steven Y C, Vaara Suvi, Youngstein Taryn, Zarychanski Ryan, Green Cameron, Higgins Alisa M, McArthur Colin J, Berry Lindsay R, Lorenzi Elizabeth, Berry Scott, Webb Steve A, Angus Derek C, van de Veerdonk Frank L
机构信息
Intensive Care Center, University Medical Centre, Utrecht, Netherlands.
Imperial College London, London, UK.
出版信息
Thorax. 2025 May 13. doi: 10.1136/thorax-2024-222488.
INTRODUCTION
Tocilizumab improves outcomes in critically ill patients with COVID-19. Whether other immune-modulator strategies are equally effective or better is unknown.
METHODS
We investigated treatment with tocilizumab, sarilumab, anakinra and no immune modulator in these patients. In this ongoing, adaptive platform trial in 133 sites in 9 countries, we randomly assigned patients with allocation ratios dependent on the number of interventions available at each site. The primary outcome was an ordinal scale combining in-hospital mortality (assigned -1) and days free of organ support to day 21 in survivors. The trial used a Bayesian statistical model with predefined triggers for superiority, inferiority, efficacy, equivalence or futility.
RESULTS
Of 2274 critically ill participants enrolled between 25 March 2020 and 10 April 2021, 972 were assigned to tocilizumab, 485 to sarilumab, 378 to anakinra and 418 to control. Median organ support-free days were 7 (IQR -1, 16), 9 (IQR -1, 17), 0 (IQR -1, 15) and 0 (IQR -1, 15) for tocilizumab, sarilumab, anakinra and control, respectively. Median adjusted ORs were 1.46 (95% credible intervals (CrI) 1.13, 1.87), 1.50 (95% CrI 1.13, 2.00) and 0.99 (95% CrI 0.74, 1.35) for tocilizumab, sarilumab and anakinra relative to control, yielding 99.8%, 99.8% and 46.6% posterior probabilities of superiority, respectively, compared with control. All treatments appeared safe.
CONCLUSIONS
In critically ill patients with COVID-19, tocilizumab and sarilumab have equivalent effectiveness at reducing duration of organ support and death. Anakinra is not effective in this population.
TRIAL REGISTRATION NUMBER
NCT02735707.
简介
托珠单抗可改善危重症 COVID-19 患者的预后。其他免疫调节策略是否同样有效或更优尚不清楚。
方法
我们研究了在这些患者中使用托珠单抗、萨瑞鲁单抗、阿那白滞素以及不使用免疫调节剂进行治疗的情况。在这项正在进行的、在 9 个国家 133 个地点开展的适应性平台试验中，我们根据每个地点可用干预措施的数量按分配比例随机分配患者。主要结局是一个序贯量表，综合了住院死亡率（赋值为 -1）以及幸存者至第 21 天无器官支持的天数。该试验使用了贝叶斯统计模型，具有预先定义的优效性、劣效性、有效性、等效性或无效性触发条件。
结果
在 2020 年 3 月 25 日至 2021 年 4 月 10 日期间入组的 2274 例危重症参与者中，972 例被分配接受托珠单抗治疗，485 例接受萨瑞鲁单抗治疗，3七十二例接受阿那白滞素治疗，418 例接受对照治疗。托珠单抗、萨瑞鲁单抗、阿那白滞素和对照组的无器官支持天数中位数分别为 7（四分位间距 -1，16）、9（四分位间距 -1，17）、0（四分位间距 -1，15）和 0（四分位间距 -1，15）。相对于对照组，托珠单抗、萨瑞鲁单抗和阿那白滞素的调整后中位数 OR 分别为 1.46（95% 可信区间（CrI）1.13，1.87）、1.50（95% CrI 1.13，2.00）和 0.99（95% CrI 0.74，1.35），与对照组相比，优效性的后验概率分别为 99.8%、99.8% 和 46.6%。所有治疗似乎都是安全的。
结论
在危重症 COVID-19 患者中，托珠单抗和萨瑞鲁单抗在缩短器官支持时间和降低死亡率方面具有等效疗效。阿那白滞素在该人群中无效。
试验注册号
NCT02735707。
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