Intravenous ravulizumab in mechanically ventilated patients hospitalised with severe COVID-19: a phase 3, multicentre, open-label, randomised controlled trial.
Intravenous ravulizumab in mechanically ventilated patients hospitalised with severe COVID-19: a phase 3, multicentre, open-label, randomised controlled trial.
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DOI：
10.1016/s2213-2600(23)00082-6
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发表时间：
2023-12
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补体途径是治疗重症COVID-19的潜在靶点。我们评估了ravulizumab（一种终末补体C5抑制剂）在需要有创或无创机械通气的重症COVID-19住院患者中的安全性和有效性。这项3期、多中心、开放标签、随机对照试验（ALXN1210-COV-305）招募了来自法国、日本、西班牙、英国和美国31家医院的成年患者（年龄≥18岁）。符合条件的患者确诊为SARS-CoV-2，需要住院治疗并进行有创或无创机械通气，并伴有CT扫描或x线确诊的严重肺炎、急性肺损伤或急性呼吸窘迫综合征。我们随机分配参与者（2:1）接受静脉注射ravulizumab加最佳支持治疗（BSC）或BSC单独使用基于网络的互动反应系统。随机分组为6组，按插管状态分层。在第1、5、10和15天给予基于体重的静脉注射剂量的ravulizumab。主要疗效终点是在意向治疗（ITT）人群中基于第29天全因死亡率的生存。对所有随机分配的接受了至少一剂ravulizumab的ravulizumab + BSC组患者和所有随机分配的BSC组患者的安全性终点进行了分析。该试验已在ClinicalTrials.gov注册，注册号为NCT04369469，并在中期分析时因无效而终止。在2020年5月10日至2021年1月13日期间，202名患者入组研究，并随机分配到ravulizumab + BSC或BSC组。201名患者被纳入ITT人群（ravulizumab + BSC组135名，BSC组66名）。ravulizumab + BSC组包括96名男性（71%）和39名女性（29%），平均年龄为66.2岁（SD 13.23）；BSC组包括43名（65%）男性和23名（35%）女性，平均年龄为63.5岁（12.40岁）。大多数患者（ravulizumab + BSC组135例中113例[84%]，BSC组66例中53例[80%]）在基线时使用有创机械通气。接受ravulizumab联合BSC的患者基于多重归算的总生存率估计为58%，接受BSC的患者为60% （manel - haenszel分析：风险差异- 0.0205;95% CI - 0.1703至0.1293；单侧p= 0.61）。在安全人群中，ravulizumab + BSC组127例患者中有113例（89%），BSC组67例患者中有56例（84%）出现治疗后出现的不良事件。在这些事件中，感染和感染（73例[57%]vs 24例[36%]）和血管疾病（39例[31%]vs 12例[18%]）在ravulizumab联合BSC组比BSC组更频繁地观察到。5例患者有严重不良事件，被认为与ravulizumab有关。这些事件为菌血症、血小板减少症、食管出血、隐球菌性肺炎和发热（各1例）。在BSC中加入ravulizumab并没有改善生存或其他次要结果。安全性研究结果与ravulizumab在其批准适应症中的已知安全性一致。尽管缺乏疗效，但该研究表明，C5抑制可以在重症患者中完成，为未来对危重疾病补体疗法的研究增加了价值。阿斯利康罕见病。
The complement pathway is a potential target for the treatment of severe COVID-19. We evaluated the safety and efficacy of ravulizumab, a terminal complement C5 inhibitor, in patients hospitalised with severe COVID-19 requiring invasive or non-invasive mechanical ventilation. This phase 3, multicentre, open-label, randomised controlled trial (ALXN1210-COV-305) enrolled adult patients (aged ≥18 years) from 31 hospitals in France, Japan, Spain, the UK, and the USA. Eligible patients had a confirmed diagnosis of SARS-CoV-2 that required hospitalisation and either invasive or non-invasive mechanical ventilation, with severe pneumonia, acute lung injury, or acute respiratory distress syndrome confirmed by CT scan or x-ray. We randomly assigned participants (2:1) to receive intravenous ravulizumab plus best supportive care (BSC) or BSC alone using a web-based interactive response system. Randomisation was in permuted blocks of six with stratification by intubation status. Bodyweight-based intravenous doses of ravulizumab were administered on days 1, 5, 10, and 15. The primary efficacy endpoint was survival based on all-cause mortality at day 29 in the intention-to-treat (ITT) population. Safety endpoints were analysed in all randomly assigned patients in the ravulizumab plus BSC group who received at least one dose of ravulizumab, and in all randomly assigned patients in the BSC group. The trial is registered with ClinicalTrials.gov, NCT04369469, and was terminated at interim analysis due to futility. Between May 10, 2020, and Jan 13, 2021, 202 patients were enrolled in the study and randomly assigned to ravulizumab plus BSC or BSC. 201 patients were included in the ITT population (135 in the ravulizumab plus BSC group and 66 in the BSC group). The ravulizumab plus BSC group comprised 96 (71%) men and 39 (29%) women with a mean age of 63·2 years (SD 13·23); the BSC group comprised 43 (65%) men and 23 (35%) women with a mean age of 63·5 years (12·40). Most patients (113 [84%] of 135 in the ravulizumab plus BSC group and 53 [80%] of 66 in the BSC group) were on invasive mechanical ventilation at baseline. Overall survival estimates based on multiple imputation were 58% for patients receiving ravulizumab plus BSC and 60% for patients receiving BSC (Mantel-Haenszel analysis: risk difference –0·0205; 95% CI –0·1703 to 0·1293; one-sided p=0·61). In the safety population, 113 (89%) of 127 patients in the ravulizumab plus BSC group and 56 (84%) of 67 in the BSC group had a treatment-emergent adverse event. Of these events, infections and infestations (73 [57%] vs 24 [36%] patients) and vascular disorders (39 [31%] vs 12 [18%]) were observed more frequently in the ravulizumab plus BSC group than in the BSC group. Five patients had serious adverse events considered to be related to ravulizumab. These events were bacteraemia, thrombocytopenia, oesophageal haemorrhage, cryptococcal pneumonia, and pyrexia (in one patient each). Addition of ravulizumab to BSC did not improve survival or other secondary outcomes. Safety findings were consistent with the known safety profile of ravulizumab in its approved indications. Despite the lack of efficacy, the study adds value for future research into complement therapeutics in critical illnesses by showing that C5 inhibition can be accomplished in severely ill patients. Alexion, AstraZeneca Rare Disease.