Department of Medicine, Stanford University School of Medicine, Stanford, California.
Kaiser Permanente Northern California Division of Research, Oakland.
JAMA Intern Med. 2024 Sep 1;184(9):1024-1034. doi: 10.1001/jamainternmed.2024.2007.
There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC).
To assess the efficacy of a 15-day course of nirmatrelvir-ritonavir in reducing the severity of select PASC symptoms.
DESIGN, SETTING, AND PARTICIPANTS: This was a 15-week blinded, placebo-controlled, randomized clinical trial conducted from November 2022 to September 2023 at Stanford University (California). The participants were adults with moderate to severe PASC symptoms of 3 months or longer duration.
Participants were randomized 2:1 to treatment with oral nirmatrelvir-ritonavir (NMV/r, 300 mg and 100 mg) or with placebo-ritonavir (PBO/r) twice daily for 15 days.
Primary outcome was a pooled severity of 6 PASC symptoms (fatigue, brain fog, shortness of breath, body aches, gastrointestinal symptoms, and cardiovascular symptoms) based on a Likert scale score at 10 weeks. Secondary outcomes included symptom severity at different time points, symptom burden and relief, patient global measures, Patient-Reported Outcomes Measurement Information System (PROMIS) measures, orthostatic vital signs, and sit-to-stand test change from baseline.
Of the 155 participants (median [IQR] age, 43 [34-54] years; 92 [59%] females), 102 were randomized to the NMV/r group and 53 to the PBO/r group. Nearly all participants (n = 153) had received the primary series for COVID-19 vaccination. Mean (SD) time between index SARS-CoV-2 infection and randomization was 17.5 (9.1) months. There was no statistically significant difference in the model-derived severity outcome pooled across the 6 core symptoms at 10 weeks between the NMV/r and PBO/r groups. No statistically significant between-group differences were found at 10 weeks in the Patient Global Impression of Severity or Patient Global Impression of Change scores, summative symptom scores, and change from baseline to 10 weeks in PROMIS fatigue, dyspnea, cognitive function, and physical function measures. Adverse event rates were similar in NMV/r and PBO/r groups and mostly of low grade.
The results of this randomized clinical trial showed that a 15-day course of NMV/r in a population of patients with PASC was generally safe but did not demonstrate a significant benefit for improving select PASC symptoms in a mostly vaccinated cohort with protracted symptom duration. Further studies are needed to determine the role of antivirals in the treatment of PASC.
ClinicalTrials.gov Identifier: NCT05576662.
迫切需要确定针对 SARS-CoV-2 感染后（PASC）的治疗方法。
评估奈玛特韦-利托那韦 15 天疗程对减轻部分 PASC 症状严重程度的效果。
设计、地点和参与者：这是一项在斯坦福大学（加利福尼亚州）进行的为期 15 周的双盲、安慰剂对照、随机临床试验。参与者为患有持续 3 个月或更长时间的中度至重度 PASC 症状的成年人。
参与者以 2:1 的比例随机分配接受口服奈玛特韦-利托那韦（NMV/r，300 mg 和 100 mg）或安慰剂-利托那韦（PBO/r）每日两次，持续 15 天。
主要结局是在 10 周时根据 Likert 量表评分综合 6 种 PASC 症状（疲劳、头脑模糊、呼吸急促、肌肉疼痛、胃肠道症状和心血管症状）的严重程度。次要结局包括不同时间点的症状严重程度、症状负担和缓解、患者整体测量、患者报告的结果测量信息系统（PROMIS）测量、直立生命体征和从基线到坐位站立测试的变化。
在 155 名参与者（中位数[IQR]年龄，43[34-54]岁；92[59%]为女性）中，102 名随机分配到 NMV/r 组，53 名随机分配到 PBO/r 组。几乎所有参与者（n=153）均已接受过 COVID-19 疫苗的主要系列接种。从指数 SARS-CoV-2 感染到随机分组的平均（SD）时间为 17.5（9.1）个月。在 10 周时，NMV/r 组和 PBO/r 组之间，6 种核心症状的综合严重程度结果在模型推导中没有统计学上的显著差异。在 10 周时，患者整体严重程度和患者整体变化评分、总结症状评分以及从基线到 10 周时 PROMIS 疲劳、呼吸困难、认知功能和身体功能测量的变化，NMV/r 组和 PBO/r 组之间没有统计学上的显著差异。NMV/r 组和 PBO/r 组的不良事件发生率相似，且大多为低级别。
这项随机临床试验的结果表明，在 PASC 患者人群中使用 NMV/r 治疗 15 天通常是安全的，但在持续时间较长的大多数已接种疫苗且症状持续时间较长的患者队列中，并没有显著改善某些 PASC 症状。需要进一步的研究来确定抗病毒药物在 PASC 治疗中的作用。
ClinicalTrials.gov 标识符：NCT05576662。
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