From the Departments of Pulmonary and Critical Care Medicine (B.C., Y.W., L.S., J.X., Chen Wang) and Clinical Research and Data Management (X.G.), Institute of Respiratory Medicine in the Chinese Academy of Medical Sciences, National Clinical Research Center for Respiratory Diseases, National Center for Respiratory Medicine, China-Japan Friendship Hospital, Changping Laboratory (B.C., Chen Wang), the Department of Medicine, Non-oncology, Jiangsu Simcere Pharmaceutical (Y.Y.), Clinical and Research Center of Infectious Diseases Beijing Ditan Hospital, Capital Medical University (R.J.), and Chinese Academy of Medical Sciences and Peking Union Medical College (Chen Wang), Beijing, the Department of Infectious Diseases, Third People's Hospital of Shenzhen, National Clinical Research Center for Infectious Diseases, Shenzhen (H.L., F.W.), Jin Yin-tan Hospital (C.H., F.G.) and Wuhan Institute of Virology, Chinese Academy of Sciences (L.Z.), Wuhan, the Public Health Clinical Center of Chengdu, Chengdu (Z.C.), Tianjin First Central Hospital, Tianjin (Y.L.), the Department of Cardiology, Hainan Third People's Hospital, Sanya (L.L.), the Department of Respiratory Medicine, Guangzhou Eighth People's Hospital, Guangzhou (P.P.), the Department of Clinical Statistics and Data Management, Jiangsu Simcere Pharmaceutical (H.H.), the Department of Infection and Immunity, Shanghai Public Health Clinical Center (Y.S.), and the Department of Infectious Diseases, Zhongshan Hospital (B.H.), Fudan University, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences (J.S., Y.X.), and the Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, and Key Laboratory of Carcinogenesis and Cancer Invasion of the Ministry of Education (J.F.), Shanghai, the Second Hospital of Nanjing (C.C.), Jiangsu Simcere Pharmaceutical (R.T.), and State Key Laboratory of Neurology and Oncology Drug Development (R.T.), Nanjing, the First Affiliated Hospital of Xiamen University, Xiamen (X. Yao), Guizhou Provincial People's Hospital, Guiyang (X. Ye, H.Z.), the Second Department of Infection, Shandong Public Health Clinical Center, Jinan (C.L.), Xuzhou Infectious Diseases Hospital, Xuzhou (Chunying Wang), and Central People's Hospital of Zhanjiang, Zhanjiang (Z.Y.) - all in China.
N Engl J Med. 2024 Jan 18;390(3):230-241. doi: 10.1056/NEJMoa2301425.
Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial.
In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed.
A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate.
Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).
Simnotrelvir 是一种口服 3-糜蛋白酶样蛋白酶抑制剂，已被发现对严重急性呼吸综合征冠状病毒 2（SARS-CoV-2）具有体外活性，并在 1B 期试验中具有潜在疗效。
在这项 2-3 期、双盲、随机、安慰剂对照试验中，我们将发病症状在过去 3 天内的轻度至中度 2019 年冠状病毒病（Covid-19）患者以 1:1 的比例随机分为两组，每日两次接受 750 毫克 Simnotrelvir 和 100 毫克利托那韦或安慰剂治疗 5 天。主要疗效终点是症状持续缓解的时间，定义为连续 2 天没有 11 种与 Covid-19 相关的症状。还评估了安全性和病毒载量的变化。
共有 35 个中国研究点的 1208 名患者入组；603 名患者被分配接受 Simnotrelvir 治疗，605 名患者接受安慰剂治疗。在接受试验药物或安慰剂治疗的首剂量在症状出现后 72 小时内的改良意向治疗人群中，Simnotrelvir 组的症状持续缓解时间明显短于安慰剂组（180.1 小时[95%置信区间{CI}，162.1 至 201.6] vs. 216.0 小时[95%CI，203.4 至 228.1]；中位数差异，-35.8 小时[95%CI，-60.1 至-12.4]；P=0.006 按 Peto-Prentice 检验）。第 5 天，Simnotrelvir 组从基线的病毒载量下降幅度大于安慰剂组（平均差异[±SE]，-1.51±0.14 log 拷贝/毫升；95%CI，-1.79 至-1.24）。治疗期间不良反应的发生率在 Simnotrelvir 组高于安慰剂组（29.0% vs. 21.6%）。大多数不良反应为轻度或中度。
在成年 Covid-19 患者中，早期使用 Simnotrelvir 加利托那韦可缩短症状缓解时间，且无明显安全性担忧。（由江苏先声药业资助；ClinicalTrials.gov 编号，NCT05506176。）
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