Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.
Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19.
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DOI：
10.1056/nejmoa2118542
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发表时间：
2022-04-14
期刊：
影响因子：
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通讯作者：
EPIC-HR Investigators
中科院分区：
文献类型：
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作者：
Hammond J;Leister-Tebbe H;Gardner A;Abreu P;Bao W;Wisemandle W;Baniecki M;Hendrick VM;Damle B;Simón-Campos A;Pypstra R;Rusnak JM;EPIC-HR Investigators
Nirmatrelvir是一种口服给药的严重急性呼吸综合征冠状病毒2主要蛋白酶（Mpro）抑制剂，在体外具有有效的泛人类冠状病毒活性。我们进行了一项2-3期双盲、随机、对照试验，在该试验中，有症状、未接种疫苗、未住院、有进展为2019年严重冠状病毒病（Covid-19）高风险的成年人以1：1的比例被分配接受300 mg Nirmatrelvir +100 mg利托那韦（一种药代动力学增强剂）或安慰剂，每12小时一次，持续5天。评估了截至第28天的Covid-19相关住院或任何原因的死亡、病毒载量和安全性。共有2246名患者接受随机分组; 1120名患者接受Nirmatrelvir+利托那韦（Nirmatrelvir组），1126名患者接受安慰剂（安慰剂组）。在症状发作后3天内接受治疗的患者的计划中期分析中（修改的意向治疗人群，包括全分析人群中1361例患者中的774例），截至第28天，Nirmatrelvir组的Covid-19相关住院或死亡发生率比安慰剂组低6.32个百分点（95%置信区间[CI]，-9.04至-3.59; P<0.001;相对风险降低，89.1%）; Nirmatrelvir组的发生率为0.77%（389例患者中的3例），0例死亡，而安慰剂组为7.01%（385例患者中的27例），7例死亡。在最终分析中，1379例患者在改良的意向治疗人群中维持了疗效，差异为-5.81个百分点（95%CI，-7.78至-3.84; P<0.001;相对风险降低，88.9%）。所有13例死亡均发生在安慰剂组。在治疗第5天，Nirmaltrelvir+利托那韦的病毒载量低于安慰剂组，当在症状发作后3天内开始治疗时，校正的平均差异为-0.868 log 10拷贝/毫升。两组治疗期间出现的不良事件发生率相似（任何不良事件，Nirmatrelvir+利托那韦组为22.6%，安慰剂组为23.9%;严重不良事件，1.6% vs. 6.6%;导致停药或安慰剂的不良事件，2.1% vs. 4.2%）。与安慰剂组相比，Nirmatrelvir+利托那韦组味觉障碍（5.6% vs. 0.3%）和腹泻（3.1% vs. 1.6%）的发生率更高。用Nirmatrelvir加利托那韦治疗症状性Covid-19导致进展为严重Covid-19的风险比安慰剂低89%，没有明显的安全性问题。（由辉瑞公司支持; ClinicalTrials.gov编号，NCT 04960202。）
Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan–human-coronavirus activity in vitro. We conducted a phase 2–3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19–related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19–related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], −9.04 to −3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of −5.81 percentage points (95% CI, −7.78 to −3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of −0.868 log10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.)