β-1b 干扰素联合洛匹那韦利托那韦治疗中东呼吸综合征
Interferon Beta-1b and Lopinavir-Ritonavir for Middle East Respiratory Syndrome.
机构信息
From the Intensive Care Department (Y.M.A., A.A.-D.) and the Departments of Infection Prevention and Control (H.H.B.), Pathology and Laboratory Medicine (S.A.J.), Pharmaceutical Care (S.A.H.), and Medicine (A.A.), King Abdulaziz Medical City, Ministry of National Guard Health Affairs, the College of Medicine (Y.M.A., S.A.J., A.A.-D., A.A.) and the College of Pharmacy (M.A.J., S.A.H.), King Saud bin Abdulaziz University for Health Sciences, Prince Mohammed bin Abdulaziz Hospital (A.Y.A., Z.A.M., S.G., S.A.F.), Infection Prevention and Control, Preventive Health (A.M.A.), and Deputyship for Public Health (H.A.A.J.), Ministry of Health, Clinical Trials Services (M.A.J., A.M.D., B.M.A.) and the Departments of Biostatistics and Informatics (J.J., M.A.H.) and Infectious Disease Research (N.K.A.), King Abdullah International Medical Research Center, the Military Medical Services, Ministry of Defense (Y.M.), the Department of Intensive Care Services (G.A.A.M.), and the Infectious Diseases Division (N.M.S., F.E.E.), Prince Sultan Military Medical City, and the College of Medicine, Alfaisal University (Z.A.M.), Riyadh, the Department of Critical Care Medicine, King Khalid University, Aseer Central Hospital, Abha (A.A.B.), Medical Services (M.H.A.A.) and the Department of Critical Care Medicine (M.A.), King Abdullah Medical Complex, the Health Directorate, Ministry of Health (M.H.A.A.), and the Internal Medicine Department, King Fahad General Hospital, Ministry of Health (W.B.), the Intensive Care Department (F.A.-H.) and the Department of Infection Prevention and Control (A.A.S.), Ministry of National Guard Health Affairs, and the College of Medicine and King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center (F.A.-H., A.A.S.), Jeddah, and the Intensive Care Department, King Khalid Hospital, Najran (A.M.B.E.) - all in Saudi Arabia; the World Health Organization, Geneva (H.H.B.); the Hubert Department of Global Health, Rollins School of Public Health, Emory University, Atlanta (Z.A.M.); the Departments of Critical Care Medicine and Medicine, Sunnybrook Hospital, and the Institute of Health Policy Management and Evaluation, University of Toronto, Toronto (R.A.F.); and the Division of Infectious Diseases and International Health, Department of Medicine, University of Virginia School of Medicine, Charlottesville (F.G.H.).
出版信息
N Engl J Med. 2020 Oct 22;383(17):1645-1656. doi: 10.1056/NEJMoa2015294. Epub 2020 Oct 7.
BACKGROUND
Whether combined treatment with recombinant interferon beta-1b and lopinavir-ritonavir reduces mortality among patients hospitalized with Middle East respiratory syndrome (MERS) is unclear.
METHODS
We conducted a randomized, adaptive, double-blind, placebo-controlled trial that enrolled patients at nine sites in Saudi Arabia. Hospitalized adults with laboratory-confirmed MERS were randomly assigned to receive recombinant interferon beta-1b plus lopinavir-ritonavir (intervention) or placebo for 14 days. The primary outcome was 90-day all-cause mortality, with a one-sided P-value threshold of 0.025. Prespecified subgroup analyses and safety analyses were conducted. Because of the pandemic of coronavirus disease 2019, the data and safety monitoring board requested an unplanned interim analysis and subsequently recommended the termination of enrollment and the reporting of the results.
RESULTS
A total of 95 patients were enrolled; 43 patients were assigned to the intervention group and 52 to the placebo group. A total of 12 patients (28%) in the intervention group and 23 (44%) in the placebo group died by day 90. The analysis of the primary outcome, with accounting for the adaptive design, yielded a risk difference of -19 percentage points (upper boundary of the 97.5% confidence interval [CI], -3; one-sided P = 0.024). In a prespecified subgroup analysis, treatment within 7 days after symptom onset led to lower 90-day mortality than use of placebo (relative risk, 0.19; 95% CI, 0.05 to 0.75), whereas later treatment did not. Serious adverse events occurred in 4 patients (9%) in the intervention group and in 10 (19%) in the placebo group.
CONCLUSIONS
A combination of recombinant interferon beta-1b and lopinavir-ritonavir led to lower mortality than placebo among patients who had been hospitalized with laboratory-confirmed MERS. The effect was greatest when treatment was started within 7 days after symptom onset. (Funded by the King Abdullah International Medical Research Center; MIRACLE ClinicalTrials.gov number, NCT02845843.).
背景
在因中东呼吸综合征（MERS）住院的患者中，联合使用重组干扰素 β-1b 和洛匹那韦/利托那韦是否能降低死亡率尚不清楚。
方法
我们开展了一项随机、适应性、双盲、安慰剂对照试验，在沙特阿拉伯的 9 个地点招募了患者。入院时实验室确诊为中东呼吸综合征的成年患者被随机分配接受重组干扰素 β-1b 加洛匹那韦/利托那韦（干预组）或安慰剂治疗 14 天。主要结局是 90 天全因死亡率，单侧 P 值阈值为 0.025。进行了预设的亚组分析和安全性分析。由于 2019 年冠状病毒病大流行，数据和安全监测委员会要求进行计划外中期分析，随后建议停止入组并报告结果。
结果
共纳入 95 例患者，其中 43 例患者被分配到干预组，52 例患者被分配到安慰剂组。干预组有 12 例（28%）患者和安慰剂组有 23 例（44%）患者在第 90 天死亡。对主要结局进行分析，考虑到适应性设计，风险差异为-19 个百分点（97.5%置信区间的上限[-3]；单侧 P=0.024）。在一项预设的亚组分析中，症状出现后 7 天内进行治疗比使用安慰剂的 90 天死亡率更低（相对风险，0.19；95%置信区间，0.05 至 0.75），而后期治疗则没有。干预组有 4 例（9%）患者和安慰剂组有 10 例（19%）患者发生严重不良事件。
结论
在因实验室确诊的 MERS 住院的患者中，重组干扰素 β-1b 与洛匹那韦/利托那韦联合使用的死亡率低于安慰剂。当治疗在症状出现后 7 天内开始时，效果最大。（由阿卜杜拉国王国际医学研究中心资助；MIRACLE ClinicalTrials.gov 编号，NCT02845843。）
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