西尼莫司单抗对 COVID-19 住院患者器官支持生存的影响：一项随机对照试验。
Effect of the P-Selectin Inhibitor Crizanlizumab on Survival Free of Organ Support in Patients Hospitalized for COVID-19: A Randomized Controlled Trial.
机构信息
Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.D.S., A.S.B., A.P., A.B.).
Johns Hopkins School of Medicine, Baltimore, MD (C.J.L.).
出版信息
Circulation. 2023 Aug;148(5):381-390. doi: 10.1161/CIRCULATIONAHA.123.065190. Epub 2023 Jun 25.
BACKGROUND
COVID-19 has been associated with endothelial injury, resultant microvascular inflammation and thrombosis. Activated endothelial cells release and express P-selectin and von Willebrand factor, both of which are elevated in severe COVID-19 and may be implicated in the disease pathophysiology. We hypothesized that crizanlizumab, a humanized monoclonal antibody to P-selectin, would reduce morbidity and death in patients hospitalized for COVID-19.
METHODS
An international, adaptive, randomized controlled platform trial, funded by the National Heart, Lung, and Blood Institute, randomly assigned 422 patients hospitalized with COVID-19 with moderate or severe illness to receive either a single infusion of the P-selectin inhibitor crizanlizumab (at a dose of 5 mg/kg) plus standard of care or standard of care alone in an open-label 1:1 ratio. The primary outcome was organ support-free days, evaluated on an ordinal scale consisting of the number of days alive free of organ support through the first 21 days after trial entry.
RESULTS
The study was stopped for futility by the data safety monitoring committee. Among 421 randomized patients with known 21-day outcomes, 163 patients (77%) randomized to the crizanlizumab plus standard-of-care arm did not require any respiratory or cardiovascular organ support compared with 169 (80%) in the standard-of-care-alone arm. The adjusted odds ratio for the effect of crizanlizumab on organ support-free days was 0.70 (95% CI, 0.43-1.16), where an odds ratio >1 indicates treatment benefit, yielding a posterior probability of futility (odds ratio <1.2) of 98% and a posterior probability of inferiority (odds ratio <1.0) of 91%. Overall, there were 37 deaths (17.5%) in the crizanlizumab arm and 27 deaths (12.8%) in the standard-of-care arm (hazard ratio, 1.33 [95% CrI, 0.85-2.21]; [probability of hazard ratio>1] = 0.879).
CONCLUSIONS
Crizanlizumab, a P-selectin inhibitor, did not result in improvement in organ support-free days in patients hospitalized with COVID-19.
REGISTRATION
URL: https://www.
CLINICALTRIALS
gov; Unique identifier: NCT04505774.
背景
COVID-19 与内皮细胞损伤、微血管炎症和血栓形成有关。活化的内皮细胞释放和表达 P 选择素和血管性血友病因子，这两种物质在严重的 COVID-19 中升高，可能与疾病的病理生理学有关。我们假设，P 选择素的人源化单克隆抗体 crizanlizumab 可降低因 COVID-19 住院的患者的发病率和死亡率。
方法
这是一项由美国国立心肺血液研究所资助的国际性、适应性、随机对照平台试验，纳入了 422 例因 COVID-19 住院且病情为中重度的患者，将其以 1:1 的比例随机分为两组，分别接受单次输注 P 选择素抑制剂 crizanlizumab（剂量为 5mg/kg）加标准治疗或单纯标准治疗，两组均为开放标签。主要结局是器官支持零天，通过试验入组后前 21 天内的无器官支持天数的等级量表进行评估。
结果
数据安全监测委员会因无效性而提前终止了研究。在已知 21 天结局的 421 例随机患者中，与标准治疗组相比，163 例（77%）接受 crizanlizumab 加标准治疗的患者无需任何呼吸或心血管器官支持，而标准治疗组为 169 例（80%）。crizanlizumab 对器官支持零天的影响的调整后优势比为 0.70（95%CI，0.43-1.16），优势比>1 表明治疗有益，这产生了无效（优势比<1.2）的后验概率为 98%，劣势（优势比<1.0）的后验概率为 91%。总的来说，crizanlizumab 组有 37 例（17.5%）死亡，标准治疗组有 27 例（12.8%）死亡（风险比，1.33[95%CrI，0.85-2.21]；[风险比>1 的概率] = 0.879）。
结论
P 选择素抑制剂 crizanlizumab 并未改善 COVID-19 住院患者的器官支持零天。
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