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Randomized Controlled Trial
. 2024 Sep 1;184(9):1024-1034.
doi: 10.1001/jamainternmed.2024.2007.

Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection: The STOP-PASC Randomized Clinical Trial

Linda N Geng  1 , Hector Bonilla  1 , Haley Hedlin  1 , Karen B Jacobson  1   2 , Lu Tian  3 , Prasanna Jagannathan  1 , Phillip C Yang  1 , Aruna K Subramanian  1 , Jane W Liang  1 , Sa Shen  1 , Yaowei Deng  1 , Blake J Shaw  1 , Bren Botzheim  1 , Manisha Desai  1 , Divya Pathak  1 , Yasmin Jazayeri  1 , Daniel Thai  1 , Andrew O'Donnell  1 , Sukanya Mohaptra  1 , Zenita Leang  1 , Gabriella Z M Reynolds  1 , Erin F Brooks  1 , Ami S Bhatt  1 , Robert W Shafer  1 , Mitchell G Miglis  4 , Tom Quach  5 , Anushri Tiwari  5 , Anindita Banerjee  6 , Rene N Lopez  7 , Magdia De Jesus  8 , Lawrence R Charnas  7 , Paul J Utz  1   9 , Upinder Singh  1   10
Affiliations
Randomized Controlled Trial

Nirmatrelvir-Ritonavir and Symptoms in Adults With Postacute Sequelae of SARS-CoV-2 Infection: The STOP-PASC Randomized Clinical Trial

Linda N Geng et al. JAMA Intern Med. .

Erratum in

  • Errors in Figure 2.
    [No authors listed] [No authors listed] JAMA Intern Med. 2024 Sep 1;184(9):1137. doi: 10.1001/jamainternmed.2024.3735. JAMA Intern Med. 2024. PMID: 39037781 Free PMC article. No abstract available.

Abstract

Importance: There is an urgent need to identify treatments for postacute sequelae of SARS-CoV-2 infection (PASC).

Objective: 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.

Interventions: 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.

Main outcomes and measures: 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.

Results: 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.

Conclusions and relevance: 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.

Trial registration: ClinicalTrials.gov Identifier: NCT05576662.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Geng reported grants from Pfizer during the conduct of the study; personal fees from UnitedHealth Group; and grants from the US National Institutes of Health (NIH), and the Agency for Healthcare Research and Quality (AHRQ) outside the submitted work. Dr Bonilla reported grants from Pfizer during the conduct of the study and consulting fees from Resverlogix outside the submitted work. Dr Hedlin reported financial support by Pfizer during the conduct of the study and grants from the NIH outside the submitted work. Dr Jacobson reported grants from the National Institute of Allergy and Infectious Diseases outside the submitted work. Dr Jagannathan reported grants from Pfizer for an industry-sponsored trial during the conduct of the study. Dr Subramanian reported grants from Moderna outside the submitted work. Dr Botzheim reported grants from Pfizer during the conduct of the study. Dr Desai reported grants from the NIH outside the submitted work. Dr Bhatt reported grants and honorarium from the NIH; grants from Emerson Collective, Stand Up 2 Cancer, Stanford University, and the Paul Allen Foundation; consulting and advisory board membership for Stylus Medicine, Caribou Biosciences, and BiomX outside the submitted work. Dr Shafer reported Speaking honorarium from Gilead, ViiV Healthcare, and advisory fees from GlaxoSmithKline outside the submitted work. Dr Miglis reported consulting/advisory fees from 2nd MD, Alight Health, Jazz Pharmaceuticals, and Pfizer; grants from Dysautonomia International, NIH, Embr Wave, Argenx; and royalty fees from Elsevier outside the submitted work. Dr Banerjee reported equity in Pfizer during the conduct of the study. Dr Utz reported funding including partial salary and financial support of laboratory during the conduct of the study. Dr Singh reported grants from Pfizer during the conduct of the study; grants from the NIH and AHRQ, advisory fees from Gilead and Regeneron for COVID-19 studies outside the submitted work. No other disclosures were reported.

Figures

Figure 1.
Figure 1.. CONSORT Diagram
Eligibility exclusion reasons are not mutually exclusive. DSMB, indicates data and safety monitoring board; ITT, intent-to-treat, and mITT, modified intent-to-treat.
Figure 2.
Figure 2.. Distribution of Core Symptom Severity Scores Over Time in Adults With Postacute Sequelae of SARS-CoV-2 Infection
Dashed line on the left marks the end of the 15-day treatment period, and on the right, it marks the 10-week primary end point. NMV/r indicates nirmatrelvir-ritonavir, and PBO/r, placebo-ritonavir.
Figure 3.
Figure 3.. Patient Global Impression Scores Over Time in Adults With Postacute Sequelae of SARS-CoV-2 Infection
Likert plots depict the distribution of PGIS (A) and PGIC (B) scores at each week, by treatment group. NMV/r indicates nirmatrelvir-ritonavir; PBO/r, placebo-ritonavir; PGIC, Patient Global Impression of Change; and PGIS, Patient Global Impression of Severity.
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References

    1. Wulf Hanson S, Abbafati C, Aerts JG, et al. ; Global Burden of Disease Long COVID Collaborators . Estimated global proportions of individuals with persistent fatigue, cognitive, and respiratory symptom clusters following symptomatic COVID-19 in 2020 and 2021. JAMA. 2022;328(16):1604-1615. doi:10.1001/jama.2022.18931 - DOI - PMC - PubMed
    1. O’Mahoney LL, Routen A, Gillies C, et al. . The prevalence and long-term health effects of long COVID among hospitalised and non-hospitalised populations: a systematic review and meta-analysis. EClinicalMedicine. 2022;55:101762. doi:10.1016/j.eclinm.2022.101762 - DOI - PMC - PubMed
    1. US Centers for Disease Control and Prevention . Long COVID-19—Household Pulse Survey—COVID-19. Published October 11, 2023. Accessed October 18, 2023. https://www.cdc.gov/nchs/covid19/pulse/long-covid.htm
    1. Malesevic S, Sievi NA, Baumgartner P, et al. . Impaired health-related quality of life in long-COVID syndrome after mild to moderate COVID-19. Sci Rep. 2023;13(1):7717. doi:10.1038/s41598-023-34678-8 - DOI - PMC - PubMed
    1. Davis HE, Assaf GS, McCorkell L, et al. . Characterizing long COVID in an international cohort: 7 months of symptoms and their impact. EClinicalMedicine. 2021;38:101019. doi:10.1016/j.eclinm.2021.101019 - DOI - PMC - PubMed

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