RECOVER-VITAL: Platform Protocol to Measure the Effects of Antiviral Therapies on Long COVID Symptoms (RECOVER-VITAL)

RECOVER-VITAL: A Platform Protocol for Evaluation of Interventions for Viral Persistence, Viral Reactivation, and Immune Dysregulation in Post-Acute Sequelae of SARS-CoV-2 Infection (PASC)

This study is a platform protocol designed to be flexible so that it is suitable for a wide range of settings within health care systems and in community settings where it can be integrated into COVID-19 programs and subsequent treatment plans. This protocol is a prospective, multi-center, multi-arm, double-blind, randomized, controlled platform trial with different interventions organized as appendices to the protocol. Each appendix (or sub-study) evaluates potential mechanisms of action, efficacy, and safety of antivirals and other therapeutics in individuals with PASC, according to the platform protocol objectives. The hypothesis is that persistent viral infection, viral reactivation, and/or overactive/chronic immune response and inflammation are underlying contributors to PASC and that antiviral and other applicable therapies may result in viral clearance or decreased inflammation and improvement in PASC symptoms.

Study Overview

• Status: Completed
• Conditions: Long COVID; Long Covid19
• Intervention / Treatment: Drug: Experimental: Paxlovid 25 day dosing; Drug: Experimental: Paxlovid 15 day dosing; Drug: Placebo Comparator: Control

Detailed Description

Participants will be randomized to study interventions or placebo/controls based on the arms that are actively enrolling at the time of randomization. Study interventions may be added or removed according to adaptive design and/or emerging evidence. When there are multiple study interventions available, randomization will occur based on appropriateness of each intervention for the participant as determined by the study protocol.

• Study Type: Interventional
• Enrollment (Actual): 963
• Phase: Phase 2

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00935
    • Hispanic Alliance for Clinical and Translational Research, Univ of Puerto Rico
• United States
  • Alabama
    • Birmingham, Alabama, United States, 35205
      • University of Alabama at Birmingham
  • Arizona
    • Phoenix, Arizona, United States, 85006
      • University of Arizona/Banner University Medical Center Phoenix
    • Tucson, Arizona, United States, 85719
      • University of Arizona Banner Medical Center
  • California
    • Los Angeles, California, United States, 90048
      • Cedars Sinai Medical Center
    • Newport Beach, California, United States, 92663
      • Hoag Memorial Hospital
    • San Francisco, California, United States, 94110
      • University of California San Francisco General Hospital
    • Stanford, California, United States, 94305
      • Stanford University
    • Torrance, California, United States, 90502
      • Los Angeles Biomedical Institute at Harbor-UCLA Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • University of Colorado
  • District of Columbia
    • Washington D.C., District of Columbia, United States, 20060
      • Howard University Hospital
  • Florida
    • Jacksonville, Florida, United States, 32206
      • University of Florida College of Medicine Jacksonville
    • Lakeland, Florida, United States, 33805
      • Lakeland Regional Medical Center
    • Miami, Florida, United States, 33165
      • Valencia Medical and Research Center
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Grady Memorial Hospital
    • Atlanta, Georgia, United States, 30310
      • Morehouse School of Medicine
    • Atlanta, Georgia, United States, 45267
      • Atlanta VA Medical Center
    • Atlanta, Georgia, United States, 30305
      • Kaiser Permanente Southwood
    • Decatur, Georgia, United States, 30030
      • Emory Health Care
  • Illinois
    • Chicago, Illinois, United States, 60612
      • University of Illinois at Chicago
    • Chicago, Illinois, United States, 60612
      • Rush University Medical Center
    • Chicago, Illinois, United States, 60611
      • Northwestern Memorial Hospital
    • Evanston, Illinois, United States, 60201
      • North Shore University Health System
    • Morton, Illinois, United States, 61550
      • Koch Family Medicine
    • Peoria, Illinois, United States, 61603
      • Methodist Medical Center of Illinois
    • Peoria, Illinois, United States, 61637
      • Saint Francis Medical Center
  • Kansas
    • Kansas City, Kansas, United States, 66160
      • University of Kansas Medical Center
  • Kentucky
    • Lexington, Kentucky, United States, 40536
      • University of Kentucky Chandler Medical Center
  • Maryland
    • Baltimore, Maryland, United States, 21287
      • Johns Hopkins Hospital
    • Silver Spring, Maryland, United States, 20904
      • Jadestone Clinical Research, LLC
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02111
      • Tufts Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
    • Boston, Massachusetts, United States, 02115
      • Brigham and Womens Hospital
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic
  • Mississippi
    • Jackson, Mississippi, United States, 39216
      • University of Mississippi Medical Center
  • Missouri
    • St Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New Hampshire
    • Lebanon, New Hampshire, United States, 03756
      • Dartmouth Hitchcock Medical Center
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Rutgers University-Robert Wood Johnson Medical School
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • University of New Mexico Health Science Center
  • New York
    • Brooklyn, New York, United States, 11220
      • NYU Langone Health/Brooklyn Hospital
    • Canton, New York, United States, 13676
      • St. Lawrence Health Medical Campus
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
    • New York, New York, United States, 10065
      • Weil Cornell Medicine
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • University of North Carolina
    • Greenville, North Carolina, United States, 27834
      • East Carolina University
    • Kannapolis, North Carolina, United States, 28081
      • Duke Clinical and Translational Science Institute
    • Winston-Salem, North Carolina, United States, 27103
      • Wake Forest University
  • North Dakota
    • Fargo, North Dakota, United States, 58104
      • Lillestol Research, LLC
  • Ohio
    • Cincinnati, Ohio, United States, 45267
      • University of Cincinnati Medical Center
    • Cleveland, Ohio, United States, 44195
      • Cleveland Clinic
    • Cleveland, Ohio, United States, 44106
      • University Hospitals Cleveland Medical Center
    • Cleveland, Ohio, United States, 44109
      • MetroHealth System
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Oklahoma Clinical and Translational Science Institute
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • UPMC Presbyterian Shadyside
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57108
      • Avera McKennan Hospital & University Health Center
  • Tennessee
    • Franklin, Tennessee, United States, 37067
      • Clinical Trials Center of Middle Tennessee
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital
    • Houston, Texas, United States, 77030
      • University of Texas Health Science Center at Houston
    • San Antonio, Texas, United States, 78229
      • University of Texas Health Science Center at San Antonio
  • Vermont
    • Colchester, Vermont, United States, 05446
      • Vermont Lung Center, University of Vermont
  • Virginia
    • Charlottesville, Virginia, United States, 22903
      • University of Virginia
    • Norfolk, Virginia, United States, 23507
      • Sentara Norfolk General Hospital
  • Washington
    • Seattle, Washington, United States, 98109
      • University of Washington
    • Seattle, Washington, United States, 98104
      • Swedish Health Services
    • Spokane, Washington, United States, 99204
      • Providence Medical Research Center
  • West Virginia
    • Morgantown, West Virginia, United States, 26506
      • West Virginia Clinical and Translational Science Institute
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert Hospital-Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. ≥ 18 years of age at the time of enrollment

2. Previous suspected, probably or confirmed SARS-CoV-2 infection, as defined by the Pan American Health Organization*

   *Suspected and probable cases will only be allowed if it occurred before May 1, 2021, and will be limited to 10% of the study population. Otherwise, confirmed cases are required.

   Suspected case of SARS-CoV-2 infection - Three options, A through C:

   A. A person who meets the clinical OR epidemiological criteria. Clinical criteria: Acute onset of fever AND cough (influenza-like illness) OR Acute onset of ANY THREE OR MORE of the following signs or symptoms: fever, cough, general, weakness/fatigue, headache, myalgia, sore throat, coryza, dyspnea, nausea, diarrhea, anorexia. Epidemiological criteria: Contact of a probable or confirmed case or linked to a COVID-19 cluster; or

   B. Acute respiratory infection with history of fever or measured fever of ≥ 38°C; and cough; with onset within the last 10 days; and who requires hospitalization); or

   C. With no clinical signs or symptoms, NOR meeting epidemiologic criteria with a positive professional use or self-test SARS-CoV-2 antigen-Rapid Diagnostic Test.

   Probable case of SARS-CoV-2 infection:

   A. A patient who meets clinical criteria above AND is a contact of a probable or confirmed case or is linked to a COVID-19 cluster.

   Confirmed case of SARS-CoV-2 infection - Two options, A through B:

   A. A person with a positive nucleic acid amplification test, regardless of clinical criteria OR epidemiological criteria; or

   B. Meeting clinical criteria AND/OR epidemiological criteria (See suspect case A). With a positive professional use or self-test SARS-CoV-2 Antigen-Rapid Diagnostic Test.

3. At least two moderate symptoms from the same symptom cluster or one severe cluster-associated symptom identified via the Cluster Targeted COVID-19 Symptom Questions (CTCSQ), with participant identifying new symptoms since COVID-19 illness and having persisted for at least 12 weeks
4. Meeting PRO Symptom Cluster criteria for at least one Symptom Cluster
5. Willing and able to provide informed consent, complete the surveys, clinical assessments, and return for all of the necessary follow-up visits

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study. Refer to appendices for additional appendix-level criteria:

1. Known active acute SARS-CoV-2 infection ≤ 4 weeks from consent
2. Known severe anemia, defined as < 8 g/dL

3. Meeting the following symptom cluster exclusion for all eligible clusters*:

   a. Cognitive dysfunction: known stroke that resulted in cognitive impairment within 3 months of enrollment b. Autonomic dysfunction: atrial fibrillation or significant cardiac arrhythmia, more than moderate alcohol consumption**, pre-existing sustained severe hypertension (BP> 180/110 mmHg in the sitting position) c. Exercise intolerance: i. any of the following within 4 weeks of consent - an acute myocardial infarction or unstable angina, uncontrolled arrhythmias causing symptoms or hemodynamic compromise, acute myocarditis or pericarditis, uncontrolled acutely decompensated heart failure (acute pulmonary edema), acute pulmonary embolism, suspected dissecting aneurysm, severe hypoxemia at rest, any acute or chronic disorder that may affect exercise performance ii. if the participant is aggravated by exercise (e.g., infection, thyrotoxicosis, unable to cooperate)

   *Participants who are eligible for > 1 cluster must meet all inclusion and no exclusion criteria for an individual symptom cluster. If not, the participant will be excluded from that individual symptom cluster.

   ** Defined as greater than 2 drinks a day for men and 1 drink a day for women. A drink is equivalent to 12 ounces of beer (5% alcohol content), 8 ounces of malt liquor (7% alcohol content), 5 ounces of wine (12% alcohol content), 1.5 ounces or a "shot" of 80-proof (40% alcohol content) distilled spirits or liquor (e.g., gin, rum, vodka, whiskey). 21

4. Known diagnosis of chronic Lyme disease with persistent symptoms, sequelae, or related therapy
5. Any non-marijuana illicit drug use within 30 days of informed consent
6. Current or recent use (within the last 14 days) of study intervention*
7. Known allergy/sensitivity or any hypersensitivity to components of the study intervention (s) or control*
8. Known contraindication(s) to study intervention(s),
9. Inability to discontinue symptomatic medications for the identified time periods
10. Moderate or severe immunocompromised patients, such as those described in the NIH COVID-19 Treatment Guidelines (https://www.covid19treatmentguidelines.nih.gov/ special populations/immunocompromised/)

11. Currently enrolled in another clinical trial outside this platform protocol or another study intervention appendix in this platform protocol***

    ***Participants may re-enroll in the trial for a different study intervention appendix if the participant has completed an appropriate washout period and efficacy has been determined for the appendix in which the participant was previously enrolled.

12. Any condition that would make the participant, in the opinion of the investigator, unsuitable for the study

    • If only one study intervention appendix is open at the time of enrollment. If multiple study intervention appendices are open, a participant may be excluded from any study intervention appendix based on contraindications listed in the study intervention appendix, current use of study intervention, or known allergy/sensitivity/hypersensitivity and still remain eligible for the remaining study intervention appendices.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Experimental: Paxlovid 25 day dosing; Drug: Paxlovid 25 day dosing Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 25 days See NCT05965726 (Paxlovid Sub-study)	Drug: Experimental: Paxlovid 25 day dosing; Drug: Paxlovid 25 day dosing Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 25 days See NCT05965726 (Paxlovid Sub-study)
Experimental: Experimental: Paxlovid 15 day dosing; Drug: Paxlovid 15 day Dosing Paxlovid (nirmatrelvir 300mg and ritonavir 100mg) bid x 15 days then ritonavir 100mg bid plus nirmatrelvir matching placebo bid x 10 days See NCT05965726 (Paxlovid Sub-study)	Drug: Experimental: Paxlovid 15 day dosing; Drug: Paxlovid 15 day Dosing Paxlovid (nirmatrelvir 300mg and ritonavir 100mg) bid x 15 days then ritonavir 100mg bid plus nirmatrelvir matching placebo bid x 10 days See NCT05965726 (Paxlovid Sub-study)
Placebo Comparator: Placebo Comparator: Control; Drug: Control ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid bid x 25 days See NCT05965726 (Paxlovid Sub-study)	Drug: Placebo Comparator: Control; Drug: Control ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid bid x 25 days See NCT05965726 (Paxlovid Sub-study)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Total Number of Participants Enrolled in Each Appendix	Appendix-specific outcome measure data will be reported under the associated NCT ID.	90 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Occurrence of individual SAEs		Baseline to Day 90
Occurrence of AEs and SAEs leading to discontinuation		Baseline to Day 90
Occurrence of Events of Special Interest (ESIs)		Baseline to Day 90
Duration of ESIs		Baseline to Day 90
Adherence in intervention versus control groups as measured by number of missed doses		Baseline to Day 90
Change in Cognitive dysfunction symptom cluster, as measured by a neurocognitive battery	The neurocognitive battery outcome is a binary indicator of whether the participant has evidence of deficits (at least one standard deviation below the mean on at least one test within the battery).	Baseline to Day 90
Change in Autonomic dysfunction symptom cluster, as measured by the Active stand test	The active stand test outcome is a binary indicator of whether the follow-up active stand test result was abnormal or normal.	Baseline to Day 90
Change in Exercise intolerance symptom cluster, as measured by the endurance shuttle walk test (ESWT)	The ESWT [Endurance shuttle walk test (performance measure)] consists of timed walking on a 10m course.The ESWT will primarily be analyzed as a binary endpoint defined as an increase of at least 3 minutes of walking time at follow-up compared to baseline.	Baseline to Day 90

Collaborators and Investigators

• Sponsor: Kanecia Obie Zimmerman
• Investigators: Study Chair: Kanecia Zimmerman, MD PhD, Duke University; Study Chair: Richard Whitley, MD, University of Alabama at Birmingham Medical Center

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2023
• Primary Completion (Actual): August 6, 2024
• Study Completion (Actual): March 13, 2025

Study Registration Dates

• First Submitted: October 11, 2022
• First Submitted That Met QC Criteria: October 24, 2022
• First Posted (Actual): October 27, 2022

Study Record Updates

• Last Update Posted (Actual): December 2, 2025
• Last Update Submitted That Met QC Criteria: November 17, 2025
• Last Verified: November 1, 2025

More Information

Terms related to this study

• Keywords: PASC
• Additional Relevant MeSH Terms: Post-Infectious Disorders; COVID-19; Pathologic Processes; Chronic Disease; Disease Attributes; Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; Pathological Conditions, Signs and Symptoms; Post-Acute COVID-19 Syndrome; Anti-Infective Agents; Antiviral Agents; Nirmatrelvir and ritonavir drug combination
• Other Study ID Numbers: Pro00111697; OTA-21-015G (Other Grant/Funding Number: NIH grant to RTI; RTI subcontracting with DCRI)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: The PIs will share the summary of results on the study website: https://recovercovid.org/

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No