Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial.
Sarilumab in patients admitted to hospital with severe or critical COVID-19: a randomised, double-blind, placebo-controlled, phase 3 trial.
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DOI：
10.1016/s2213-2600(21)00099-0
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发表时间：
2021-05
期刊：
影响因子：
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通讯作者：
Sarilumab COVID-19 Global Study Group
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作者：
Lescure FX;Honda H;Fowler RA;Lazar JS;Shi G;Wung P;Patel N;Hagino O;Sarilumab COVID-19 Global Study Group
促炎细胞因子升高与COVID-19严重程度升高相关。我们旨在评估sarilumab（一种白细胞介素-6受体抑制剂）在重症（需要通过鼻插管或面罩补充氧气）或危重（需要更多补充氧气、机械通气或体外支持）COVID-19患者中的安全性和有效性。我们在阿根廷、巴西、加拿大、智利、法国、德国、以色列、意大利、日本、俄罗斯和西班牙的45家医院进行了一项为期60天的随机、双盲、安慰剂对照、多国iii期试验。我们纳入了实验室确诊的SARS-CoV-2感染和肺炎住院的成年人（≥18岁），他们需要补充氧气或重症监护。患者被随机分配（2:2:1，排列为5个块）接受静脉注射sarilumab 400mg， sarilumab 200mg或安慰剂。在整个研究过程中，患者、护理提供者、结果评估者和调查人员对指定的干预措施保持缄默。主要终点是在修改意向治疗人群中2分或2分以上的临床改善时间（7分制，从1分[死亡]到7分[出院]）。关键的次要终点是第29天存活的患者比例。安全性结果包括不良事件和实验室评估。本研究已在ClinicalTrials.gov注册，编号NCT04327388；EudraCT, 2020-001162-12;世界卫生组织，U1111-1249-6021。在2020年3月28日至7月3日期间，在筛选的431名患者中，420名患者被随机分配，416名患者接受安慰剂（n=84 [20%]）， sarilumab 200 mg （n=159[38%]）或sarilumab 400 mg （n=173[42%]）。在29天,未见显著差异值之间的两个或两个以上的点时间来改善安慰剂(12·0天[95% CI 9·0到15·0])和sarilumab 200毫克(10·0天(9·0到12·0);风险比[HR] 1·03[95%可信区间0·75 1·40];log-rank p = 0·96)或sarilumab 400毫克(10·0天(9·0 13·0);人力资源1·14[95%可信区间0·84 1·54];log-rank p = 0·34),或在病人活着的比例(77[92%]在安慰剂组84例;143(90%)的159名患者sarilumab 200毫克组;差- 1·7[- 9·3 ~ 5·8]；P = 0.63 vs安慰剂；sarilumab 400mg组173例患者中有159例（92%）；差值0·2[−6·9 ~ 7·4]；P = 0.85 vs安慰剂)。在第29天，对于患有危重疾病的患者，sarilumab 400mg（88%）和安慰剂（79%；差异+ 8.9% [95% CI−7.7至25.5];p= 0.25）之间存在数值上的无显著性生存差异。没有看到意外的安全信号。治疗中出现的不良事件发生率在安慰剂组为65%（84人中55人），在沙律单抗200 mg组为65%（159人中103人），在沙律单抗400 mg组为70%（173人中121人），在导致死亡的不良事件中，安慰剂组为11%（84人中9人），沙律单抗200 mg组为11%（159人中17人），沙律单抗400 mg组为10%（173人中18人）。该试验未显示sarilumab对入院并接受补充氧气的COVID-19患者的疗效。建议在COVID-19危重患者中进行靶向免疫调节疗法的充分有力试验，以评估生存率为主要终点。赛诺菲和Regeneron制药。
Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference −1·7 [−9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [−6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI −7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. Sanofi and Regeneron Pharmaceuticals.