Objective: To evaluate safety and efficacy of Itolizumab in hospitalized COVID-19 patients with PaO₂/FiO₂ ratio (PFR) ≤200 requiring oxygen therapy. Design: A multicentre, single-arm, Phase-4 study with a treatment period of 30-Days and an extended follow-up period of 90-Days. Methods: Hospitalized adult patients (n=300) with SARS-CoV-2 infection, with PFR ≤200, oxygen saturation ≤94% and ≥1 elevated inflammatory markers were included from 17 COVID-19 specific tertiary hospitals in India. Patients received Itolizumab infusion 1.6 mg/kg and were assessed for 1-month and then followed up to Day-90. Results: Day-30 post-treatment safety/efficacy results and Day-90 mortality results are presented. Primary outcome measures: incidence of severe acute infusion-related reactions (IRRs) (≥Grade-3) was 1.3% and mortality rate at 1-month was 6.7% (n=20/300). Key secondary analyses: Mortality rate at Day-90 was 8.0% (24/300). 91.7% patients came off the oxygen therapy within Day-30 of treatment. By Day-7, most patients had stable/improved SpO₂ without increasing FiO₂. Mean PFR improved by 50% by Day-7 (p<0.001) and the trend remained consistent till Day-30. Median time of recovery was 8 days. Cumulatively, at Day-30, 260(86.7%), 256(85.3%), 132(44.0%), 113(37.6%) and 32(10.7%) patients showed >1-point, >2-point, >3-point, >4-point and 5-point improvement on the modified COVID-19 8-point ordinal scale and worsening of symptoms by >1 point, >2 points and 3-points was seen in 26(8.7%), 20(6.7%) and 6(2.0%) patients, respectively. CRP, D-dimer, LDH and serum ferritin levels significantly decreased (p≤0.01) compared with baseline. IL-6 and TNFα levels also decreased 48-hours post-infusion. Overall, 123 treatment-emergent adverse events (TEAEs) were reported in 63 patients, most being Grades 1-3. Most common TEAEs were IRRs and lymphopenia; most common serious TEAEs were septic shock, worsening of ARDS and respiratory failure. No deaths were attributable to Itolizumab. Conclusion: Itolizumab shows no new safety concerns and suggests a mortality and recovery benefit at 1-month in hospitalized COVID-19 patients requiring oxygen therapy.

中文翻译：

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COVID-19 所致中度至重度急性呼吸窘迫综合征 (ARDS) 患者的康复和生存：一项多中心、单臂、IV 期 Itolizumab 试验：RESURRECT

目的：评估 Itolizumab 在住院 COVID-19 患者中 PaO ₂ /FiO ₂比值（PFR）≤200 需要氧疗的安全性和有效性。 设计：一项多中心、单臂、4 期研究，治疗期为 30 天，随访期为 90 天。方法：从印度 17 家 COVID-19 特定三级医院纳入患有 SARS-CoV-2 感染、PFR ≤200、氧饱和度≤94% 和≥1 个炎症标志物升高的住院成年患者（n=300）。患者接受了 1.6 mg/kg 的 Itolizumab 输注，并接受了 1 个月的评估，然后随访至第 90 天。 结果：显示第 30 天治疗后安全性/有效性结果和第 90 天死亡率结果。主要结局指标：严重急性输液相关反应 (IRR)（≥3 级）的发生率为 1.3%，1 个月时的死亡率为 6.7%（n=20/300）。关键次要分析：第 90 天的死亡率为 8.0% (24/300)。91.7% 的患者在治疗的第 30 天内停止了氧疗。由日- 7，大多数患者具有稳定/提高血氧饱和度₂而不增加氧合指数₂. 到第 7 天，平均 PFR 提高了 50%（p<0.001），并且趋势一直保持到第 30 天。中位恢复时间为 8 天。累计，在第 30 天，260（86.7%）、256（85.3%）、132（44.0%）、113（37.6%）和 32（10.7%）名患者表现出>1 分、>2 分、>3 26(8.7%)、20(8.7%)、改进的 COVID-19 8 分顺序量表的 - 分、> 4 分和 5 分改善以及症状恶化 > 1 分、> 2 分和 3 分( 6.7%) 和 6 (2.0%) 名患者。与基线相比，CRP、D-二聚体、LDH 和血清铁蛋白水平显着降低（p≤0.01）。IL-6 和 TNFα 水平也在输注后 48 小时下降。总体而言，63 名患者报告了 123 次治疗出现的不良事件 (TEAE)，大多数为 1-3 级。最常见的 TEAE 是 IRR 和淋巴细胞减少；最常见的严重 TEAE 是感染性休克，ARDS 恶化和呼吸衰竭。没有死亡可归因于伊托珠单抗。 结论：Itolizumab 没有显示出新的安全问题，并表明需要氧疗的住院 COVID-19 患者在 1 个月时的死亡率和恢复获益。