A Randomized Trial of Otilimab in Severe COVID-19 Pneumonia (OSCAR)
A Randomized Trial of Otilimab in Severe COVID-19 Pneumonia (OSCAR)
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DOI：
10.1101/2021.04.14.21255475
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发表时间：
2021-04
期刊：
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通讯作者：
J. Patel;A. Beishuizen;Xavier Bocca Ruiz;H. Boughanmi;A. Cahn;G. Criner;K. Davy;J. de-Miguel-Diez;S. Fernandes;B. François;Anubha Gupta;K. Hanrott;T. Hatlen;D. Inman;J. Isaacs;Emily Jarvis;N. Kostina;J. Lacherade;P. Martínez-Ayala;C. Mcevoy;R. Muñoz-Bermúdez;J. Neisen;G. Plantefeve;L. Schifano;L. Schwab;Zainab Shahid;M. Shirano;Julia E Smith;E. Sprinz;C. Summers;N. Terzi;M. Tidswell;R. Williamson;D. Wyncoll;M. Layton
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文献类型：
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作者：
J. Patel;A. Beishuizen;Xavier Bocca Ruiz;H. Boughanmi;A. Cahn;G. Criner;K. Davy;J. de-Miguel-Diez;S. Fernandes;B. François;Anubha Gupta;K. Hanrott;T. Hatlen;D. Inman;J. Isaacs;Emily Jarvis;N. Kostina;J. Lacherade;P. Martínez-Ayala;C. Mcevoy;R. Muñoz-Bermúdez;J. Neisen;G. Plantefeve;L. Schifano;L. Schwab;Zainab Shahid;M. Shirano;Julia E Smith;E. Sprinz;C. Summers;N. Terzi;M. Tidswell;R. Williamson;D. Wyncoll;M. Layton
背景 年龄增长是 COVID-19 严重程度和死亡率的一个危险因素；新兴科学表明 GM-CSF 和失调的骨髓细胞反应与严重 COVID-19 的病理生理学有关。方法 我们进行了一项大型、全球、双盲、随机、安慰剂对照研究，评估单次输注 90 mg 奥替利单抗（人抗 GM-CSF 单克隆抗体）加标准护理对因严重 COVID-19 呼吸衰竭和全身炎症住院的成人的治疗，按年龄和临床状态分层。主要结局是第 28 天时存活且未出现呼吸衰竭的患者比例；次要终点包括第 60 天的全因死亡率。 结果 总体而言，806 名患者被随机分组（1:1）；接受奥替利单抗治疗的患者中有 71% 在第 28 天存活且未出现呼吸衰竭，而接受安慰剂治疗的患者为 67%，尽管这没有达到统计学显着性（模型调整差异 5.3% [95% CI 0.8, 11.4]；p=0.09）。然而，预先定义的 [≥]70 岁年龄组有获益（模型调整差异 19.1% [95% CI 5.2, 33.1]；名义 p=0.009）；这些患者在第 60 天的模型调整全因死亡率也降低了 14.4%（95% CI 0.9, 27.9%；名义 p=0.04）。奥替利单抗和安慰剂之间的安全性结果相当，并且与严重的 COVID-19 一致。结论 尽管在总体人群中不具有统计学意义，但奥替利单抗对年龄≥70岁的患者显示出显着的益处，这可能反映了在以骨髓细胞失调为主的严重 COVID-19 中，可以从 GM-CSF 治疗阻断中受益的人群。这些发现在本研究第 2 部分的另一组年龄≥70 岁的患者中得到了证实。 （ClinicalTrials.gov 编号：NCT04376684）。
BACKGROUND Increasing age is a risk factor for COVID-19 severity and mortality; emerging science implicates GM-CSF and dysregulated myeloid cell responses in the pathophysiology of severe COVID-19. METHODS We conducted a large, global, double-blind, randomized, placebo-controlled study evaluating a single 90 mg infusion of otilimab (human anti-GM-CSF monoclonal) plus standard of care in adults hospitalized with severe COVID-19 respiratory failure and systemic inflammation, stratified by age and clinical status. Primary outcome was the proportion of patients alive and free of respiratory failure at Day 28; secondary endpoints included all-cause mortality at Day 60. RESULTS Overall, 806 patients were randomized (1:1); 71% of patients receiving otilimab were alive and free of respiratory failure at Day 28 versus 67% receiving placebo, although this did not reach statistical significance (model-adjusted difference 5.3% [95% CI 0.8, 11.4]; p=0.09). However, there was a benefit in the pre-defined [≥]70-year age group (model-adjusted difference 19.1% [95% CI 5.2, 33.1]; nominal p=0.009); these patients also had a reduction of 14.4% (95% CI 0.9, 27.9%; nominal p=0.04) in model-adjusted all-cause mortality at Day 60. Safety findings were comparable between otilimab and placebo, and consistent with severe COVID-19. CONCLUSIONS Although not statistically significant in the overall population, otilimab demonstrated a substantial benefit in patients aged [≥]70, possibly reflecting a population that could benefit from therapeutic blocking of GM-CSF in severe COVID-19 where myeloid cell dysregulation is predominant. These findings are being confirmed in a further cohort of patients aged [≥]70 in Part 2 of this study. (ClinicalTrials.gov number: NCT04376684).