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Journal Article Randomized Controlled Trial Ppublish 86 citations

PubMed: 38848477 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.

JAMA Intern Med 184(9):1024-1034

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

Affiliations

  • Department of Medicine, Stanford University School of Medicine, Stanford, California.
  • Kaiser Permanente Northern California Division of Research, Oakland.
  • Department of Biomedical Data Science, Stanford School of Medicine, Stanford, California.
  • Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California.
  • Stanford University, Stanford, California.
  • Pfizer Research and Development, Pfizer Inc, Cambridge, Massachusetts.
  • Clinical Research Collaborations COE, Worldwide Medical and Safety, Pfizer Inc, Groton, Connecticut.
  • Strategic Planning, Worldwide Medical and Safety, Pfizer Inc, New York, New York.
  • Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, California.
  • Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California.

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.

MeSH

Sars-Cov-2, Vaccines, Internal Medicine, Ritonavir, Signs And Symptoms, Covid-19, Fatigue, Therapeutics, Dyspnea, Severe Acute Respiratory Syndrome-Related Coronavirus, Infections

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