Nirmatrelvir–ritonavir targeting viral persistence in post-COVID-19 condition (long COVID) in the USA (RECOVER-VITAL): a randomised, double-blind, placebo-controlled, phase 2 trial
Year: 2026
Type: article
Study designs: Randomized Controlled Trial, Clinical Trial
Abstract: BACKGROUND: Post-acute sequelae of SARS-CoV-2 infection, more commonly known as long COVID, has emerged as a major health problem. The pathogenesis of long COVID is unknown, but among the leading hypotheses is viral persistence. We aimed to investigate whether the use of the SARS-CoV-2 antiviral nirmatrelvir-ritonavir improved long COVID symptoms. METHODS: We conducted a double-blind, placebo-controlled, randomised trial involving adults who had developed persistent symptoms (≥12 weeks) associated with three major symptom phenotypes (cognitive, autonomic, or exercise) after acute SARS-CoV-2 infection at 69 US sites. Participants were eligible if they were 18 years or older and had a previous suspected, probable, or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization. Eligible participants were also required to have either at least two moderate symptoms from the same phenotype or one severe phenotype-associated symptom, as identified with the Cluster Targeted COVID-19 Symptom Questions. Participants were randomly allocated in a double-blind manner in a 1:1:1 ratio using permuted blocks of size 30 to receive either 15 days of active intervention followed by 10 days of placebo (300 mg nirmatrelvir-100 mg ritonavir twice daily, then 100 mg ritonavir-placebo); 25 days of active intervention (300 mg nirmatrelvir-100 mg ritonavir twice daily); or 25 days of placebo-ritonavir (100 mg ritonavir-placebo). A clinically significant change in patient-reported outcomes at day 90 comprised the primary endpoint: Patient-Reported Outcomes Measurement Information System Cognitive Function Short Form 8a, Orthostatic Hypotension Questionnaire question 1, and a modified version of the DePaul Symptom Questionnaire Post-Exertional Malaise short form. Secondary outcomes were phenotype-specific performance measures. The study was registered at ClinicalTrials.gov (NCT05595369) and is complete. FINDINGS: Between July 27, 2023, and Sept 6, 2024, 1207 individuals were screened. Of these, 964 were randomly allocated and 959 participants, excluding four participants who were later found ineligible and one who did not initiate treatment, were enrolled in the three phenotypes: 332 to cognitive, 334 to autonomic, and 332 to exercise. In the 959 participants in the mITT population, 643 (67%) self-reported as female, 314 (33%) were male, and two participants had a sex of unknown or undifferentiated; 750 (78%) were White; and 108 (11%) were Hispanic, Latino, or Spanish. The median age was 49 years (IQR 38-59). No statistically significant benefits were observed for any phenotype for primary endpoints. For the cognitive phenotype, adjusted differences compared to placebo were 3·2% (95% CI -10·4 to 16·8, p=0·65) for the 25-day regimen and -2·2% (-15·5 to 11·1, p=0·74) for the 15-day regimen. For the autonomic phenotype, adjusted differences were -6·4% (-18·5 to 5·7, p=0·30) for the 25-day regimen compared to placebo and -0·1% (-12·5 to 12·3, p=0·99) for the 15-day regimen compared to placebo. For exercise, adjusted differences were -7·8% (-19·5 to 3·8, p=0·19) for the 25-day regimen compared to placebo and 0·9% (-11·4 to 13·2, p=0·88) for the 15-day regimen compared to placebo. There were no differences in secondary endpoints, and no safety signals were observed; there were no deaths, and 52 serious adverse events occurred in 42 (4%) of 963 participants over the course of the study. INTERPRETATION: Nirmatrelvir-ritonavir for 15 days or 25 days showed no evidence of benefit in long COVID in any of the three phenotypes studied. These findings suggest additional approaches to measuring the symptom burden and treating Long COVID are needed. FUNDING: National Institutes of Health.
Source: The Lancet Infectious Diseases
Authors: Lindsey R Baden, Nirav S Shah, Sean T H Liu, Jonathan Cohen, James Moy, Andre Kumar, Grace A McComsey, Peter Chen, Michelle Floris-Moore, Nora G Singer, Inti Fernandez, Alex J Slandzicki, Zanthia Wiley, Alexandra Kadl, David A Kaminsky, Harvey Hsu, Tiffany A Walker, Aluko A Hope, Luis Ostrosky-Zeichner, Jason D Goldman, Michael J Peluso, Thomas F Patterson, Sairam Parthasarathy, Janet M Mullington, Paul Bolin, Sarah E Jolley, Jerry A Krishnan, Mario Castro, Sally L Hodder, Priscilla Pemu, Helen Y Chu, Michael G Risbano, Maya R Jerath, Eleftherios Mylonakis, Ryan T Hurt, Radica Alicic, Nabila S Azad, Marc A Sala, Michelle S Harkins, Jeffrey Parsonnet, Neil Stafford, Philip Robinson, Sabiha Hussain, Xian Qiao, Sophie Two Hawk, Michael Lillestol, Nathan Erdmann, Kelly A Gebo, Praveen Sudhindra, Joseph Sassine, Gailen D Marshall, Tulika Chatterjee, Caryn G Morse, Eyal Kedar, William W Stringer, Jennifer A Frontera, Michael Jordan, Caitlin Blaskewicz, Jorge L Santana, Rachel A Foot, Cherry Wongtrakool, Matthew William McCarthy, Alem Mehari, Arch Amon, Alison K Cohen, Nita Jain, Christine Maughan, Doug Lindsay, Rachel Olson, Samuel Broderick, Pearl Rowe, Sean M O’Brien, David R Walt, Bruce D Levy, Leonard A Jason, Phillip A Low, Cyndya A Shibao, Barry Make, Lucinda Bateman, Susan Redline, David Knopman, Adrian F Hernandez, Tracy L Nolen, Craig Reist, Lisa Berdan, Richard Whitley, Kanecia O Zimmerman, Khaled Mohammed Abdel-Hamid, Judith Aberg, Dushmanthi Adhikaram, Radica Alicic, Majd Alsoubani, Arch Amon, Jordan Anderson, Maria Antonelli, Arundhati Arjun, Mirna Ayache, Laura Aylward, Nabila Azad, Alba Azola, Lindsey Baden, James Bardes, Julie Biller, Caitlin Blaskewicz, Paul Bolin, Sherilyn Brinkley, Tarashon Broomes, Jamie Brown, Amanda Casto, Mario Castro, Ashley Cattran, Arista Chand, Tulika Chatterjee, Peter Chen, Helen Chu, Jonathan Cohen, Sushma Cribbs, Ivana Croghan, Matthew Culp, Thomas Decato, Julien Dedier, Joshua Detelich, Omar Elsayed-Ali, Karissa Emerson, Cecilia Engelson, Nathaniel Erdmann, Kristine Erlandson, Inti Fernandez, Michelle Floris-Moore, Rachel Foot, Jennifer Frontera, Kimberly Gaffney, Kelly Gebo, Maher Ghauloush, Jamie Gibson, Lee Gilman, Alison Gimbel, Paul Goepfert, Jason Goldman, Jon Gothing, Jenny Han, Elizabeth Haney, Michelle Harkins, Kimberly Hartwig, Timothy Hatlen, Sally Hodder, Aluko Hope, James Horrocks, Harvey Hsu, Sarah Humphreys, Ryan Hurt, Sabiha Hussain, Homam Ibrahim, Priscilla Igho-Pemu, Carmen Isache, Maya Jerath, Sarah Jolley, Michael Jordan, Joy Juskowich, Alexandra Kadl, David Kaminsky, Jeremy Katcher, Andrew Kau, Eyal Kedar, Christina Kim, Ryan Knodle, Stanley Koch, Jerry Krishnan, Andre Kumar, Alicia Layton, Michael Lillestol, Michael Lillestol, Matthew Lin, Sean Liu, Grace Lozinski, McKailey Lyndaker, Maureen Lyons, Nayna Maini, Shahdi Malakooti, Tarisa Mantia, Jai Marathe, Vincent Marconi, Gailen Marshall, Matthew McCarthy, Grace McComsey, Ahem Mehari, Sarah Mehta, Katherine Menson, Sondra Middleton, Casi Miller, Jennifer Monroy, Juhi Moon, Caryn Morse, Talal Moukabary, James Moy, Janet Mullington, Eleftherios Mylonakis, Rahul Nanchal, Robert Neuman, Anna Nordvig, Luis Ostrosky-Zeichner, Charity Owusu-Asare, Ann Parker, Jeffrey Parsonnet, Sairam Parthasarathy, Bela Patel, Thomas Patterson, Michael Peluso, Xian Qiao, Rebecca Reece, Michael Risbano, Franz Rischard, Philip Robinson, Marc Sala, John Salomone, Jorge Santana, Armen Sanosyan, Farjad Sarafian, Arif Sarwari, Joseph Sassine, Frank Sciurba, Abraham Sender, Mehr Zahra Shah, Nirav Shah, Elyce Sheehan, Amy Sherman, Kamal Shouman, Christopher Simmons, Wolfgang Singer, Nora Singer, Kristina Skinner, Alex Slandzicki, Catherine Small, Tanya Smullin, Neil Stafford, Janice Stout, William Stringer, Praveen Sudhindra, Fatima Sukhera, Sophie Two Hawk, Tim Vanwagoner, Wyatt Verplaetse, Tiffany Walker, Stephen Walsh, H. James Wedner, Elisheva Weinberger, Sidney Whiteheart, Aimee Wilkin, Zanthia Wiley, Cherry Wongtrakool, Siddhant Yadav, Manajyoti Yadav, Nathan Yee, George Yendewa
Institutions: Brigham and Women's Hospital, Harvard University, Endeavor Health, Icahn School of Medicine at Mount Sinai, Adventist HealthCare, Rush University Medical Center, Rush University, Stanford Medicine, Stanford University, University Hospitals of Cleveland, Case Western Reserve University, Cedars-Sinai Medical Center, University of North Carolina at Chapel Hill, MetroHealth, Emory University, University of Virginia, University of Vermont, Banner - University Medical Center Phoenix, University of Arizona College of Medicine- Phoenix, Oregon Health & Science University, The University of Texas Health Science Center at Houston, University of Washington, San Francisco General Hospital, University of California, San Francisco, The University of Texas at San Antonio Health Science Center, University of Arizona, Beth Israel Deaconess Medical Center, East Carolina University, University of Colorado Anschutz, University of Illinois Chicago, University of Kansas, University of Kansas Medical Center, West Virginia University, Morehouse School of Medicine, University of Pittsburgh, Washington University in St. Louis, Houston Methodist, Mayo Clinic, Inland Northwest Health Services, Boston University, Northwestern University, University of New Mexico, Dartmouth–Hitchcock Medical Center, Duke University, Duke Medical Center, Hoag Memorial Hospital Presbyterian, Rutgers, The State University of New Jersey, Eastern Virginia Medical School, Old Dominion University, University of South Dakota, Avera Health, University of Alabama at Birmingham, George Washington University, University of Oklahoma, University of Mississippi Medical Center, Peoria campus of the University of Illinois System, Wake Forest University Health Sciences, Wake Forest University, University of Potsdam, University of California, Los Angeles, The Lundquist Institute, Harbor–UCLA Medical Center, New York University, Tufts University, Cleveland Clinic, University of Puerto Rico, Medical Sciences Campus, University of Puerto Rico System, University of Cincinnati, Atlanta VA Health Care System, Weill Cornell Medicine, Howard University, Lakeland Regional Medical Center, Duke Clinical Research Institute, Wyss Institute for Biologically Inspired Engineering, Mass General Brigham, DePaul University, Vanderbilt University Medical Center, National Jewish Health, Bateman Horne Center, RTI International, National Institutes of Health, UAB Medicine
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $7,280
Funders: National Science Foundation, U.S. Department of Health and Human Services, U.S. Department of Veterans Affairs, Bill and Melinda Gates Foundation, International AIDS Vaccine Initiative, American Heart Association, American Thoracic Society, Amgen, Pfizer, AstraZeneca, GlaxoSmithKline, Sanofi, Gilead Sciences, Biogen, Patient-Centered Outcomes Research Institute, Teva Pharmaceutical Industries, Emory University, Respiratory Health Association, University of Cincinnati, COPD Foundation, European Respiratory Society, Sleep Research Society, Regeneron Pharmaceuticals, Wellcome Trust, Cidara Therapeutics, Celldex Therapeutics, U.S. General Services Administration, Covis Pharma, Arrowhead Pharmaceuticals, Leidos, Moderna, Cambridge University Hospitals, Shionogi, National Institutes of Health, Agency for Healthcare Research and Quality, Genentech, University of California, San Francisco, Biomedical Advanced Research and Development Authority, National Heart, Lung, and Blood Institute, National Cancer Institute, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, Duke Clinical Research Institute, U.S. Military HIV Research Program
OpenAlex ID: W7204803121