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

Long COVID Clinical Trial

— RECOVER-VITAL  

Official title:

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)

Clinical Trial Details — Status: Enrolling by invitation

Administrative data

• NCT number: NCT05595369
• Other study ID #: Pro00111697
• Secondary ID: OTA-21-015G
• Status: Enrolling by invitation
• Phase: Phase 2
• Start date: July 26, 2023
• Est. completion date: October 2025

Study information

• Verified date: May 2024
• Source: Duke University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Enrolling by invitation
• Enrollment: 900
• Est. completion date: October 2025
• Est. primary completion date: July 2025
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Long COVID

Intervention

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: 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: Control
Drug: Control ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid bid x 25 days See NCT05965726 (Paxlovid Sub-study)

Locations

Country	Name	City	State
Puerto Rico	Hispanic Alliance for Clinical and Translational Research, Univ of Puerto Rico	San Juan
United States	University of New Mexico Health Science Center	Albuquerque	New Mexico
United States	Atlanta VA Medical Center	Atlanta	Georgia
United States	Grady Memorial Hospital	Atlanta	Georgia
United States	Morehouse School of Medicine	Atlanta	Georgia
United States	University of Colorado	Aurora	Colorado
United States	Johns Hopkins Hospital	Baltimore	Maryland
United States	University of Alabama at Birmingham	Birmingham	Alabama
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston Medical Center	Boston	Massachusetts
United States	Brigham and Womens Hospital	Boston	Massachusetts
United States	Tufts Medical Center	Boston	Massachusetts
United States	St. Lawrence Health Medical Campus	Canton	New York
United States	University of North Carolina	Chapel Hill	North Carolina
United States	University of Virginia	Charlottesville	Virginia
United States	Northwestern Memorial Hospital	Chicago	Illinois
United States	Rush University Medical Center	Chicago	Illinois
United States	University of Illinois at Chicago	Chicago	Illinois
United States	University of Cincinnati Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic, Case Western Reserve University	Cleveland	Ohio
United States	MetroHealth System	Cleveland	Ohio
United States	University Hospitals Cleveland Medical Center	Cleveland	Ohio
United States	Vermont Lung Center, University of Vermont	Colchester	Vermont
United States	Emory Health Care	Decatur	Georgia
United States	North Shore University Health System	Evanston	Illinois
United States	Lillestol Research, LLC	Fargo	North Dakota
United States	Clinical Trials Center of Middle Tennessee	Franklin	Tennessee
United States	East Carolina University	Greenville	North Carolina
United States	Houston Methodist Hospital	Houston	Texas
United States	University of Texas Health Science Center at Houston	Houston	Texas
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	University of Florida College of Medicine Jacksonville	Jacksonville	Florida
United States	Duke Clinical and Translational Science Institute	Kannapolis	North Carolina
United States	University of Kansas Medical Center	Kansas City	Kansas
United States	Dartmouth Hitchcock Medical Center	Lebanon	New Hampshire
United States	Cedars Sinai Medical Center	Los Angeles	California
United States	Valencia Medical and Research Center	Miami	Florida
United States	West Virginia Clinical and Translational Science Institute	Morgantown	West Virginia
United States	Koch Family Medicine	Morton	Illinois
United States	Rutgers University-Robert Wood Johnson Medical School	New Brunswick	New Jersey
United States	Icahn School of Medicine at Mount Sinai	New York	New York
United States	Weil Cornell Medicine	New York	New York
United States	Hoag Memorial Hospital	Newport Beach	California
United States	Sentara Norfolk General Hospital	Norfolk	Virginia
United States	Oklahoma Clinical and Translational Science Institute	Oklahoma City	Oklahoma
United States	Methodist Medical Center of Illinois	Peoria	Illinois
United States	Saint Francis Medical Center	Peoria	Illinois
United States	University of Arizona/Banner University Medical Center Phoenix	Phoenix	Arizona
United States	UPMC Presbyterian Shadyside	Pittsburgh	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	Mayo Clinic	Rochester	Minnesota
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	University of Texas Health Science Center at San Antonio	San Antonio	Texas
United States	University of California San Francisco General Hospital	San Francisco	California
United States	Swedish Health Services	Seattle	Washington
United States	University of Washington	Seattle	Washington
United States	Jadestone Clinical Research, LLC	Silver Spring	Maryland
United States	Avera McKennan Hospital & University Health Center	Sioux Falls	South Dakota
United States	Providence Medical Research Center	Spokane	Washington
United States	Stanford University	Stanford	California
United States	Los Angeles Biomedical Institute at Harbor-UCLA Medical Center	Torrance	California
United States	University of Arizona Banner Medical Center	Tucson	Arizona
United States	Howard University Hospital	Washington	District of Columbia
United States	Wake Forest University	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
Kanecia Obie Zimmerman

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in Cognitive dysfunction symptom cluster, as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) cognitive function T-score	The PROMIS cognitive function-8a (PRO assessment) T-score is a quantitative measure of current cognitive function. The primary endpoint for cognitive dysfunction is improvement of at least 5 T-score points on the PROMIS-cognitive function as measured at 90 days compared to baseline.	Baseline to Day 90
Primary	Change in Autonomic dysfunction symptom cluster, as measured by the orthostatic hypotension questionnaire (OHQ)	The OHQ [Orthostatic Hypotension Questionnaire [PRO assessment)] is a measure of orthostatic intolerance, which has been the primary presentation of patients with PASC-related autonomic dysfunction. This measure includes the Orthostatic Intolerance Daily Activity Scale (OIDAS) and the Orthostatic Intolerance Symptom Assessment (OISA). The primary endpoint for autonomic dysfunction is improvement in autonomic function as defined by a = 1-point decrease in the OHQ question 1 at 90 days compared to baseline.	Baseline to Day 90
Primary	Change in Exercise intolerance symptom cluster, as measured by the Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM)	DSQ-PEM assesses symptom frequency and severity over a 6-month look back period, however, for the purposes of this study, it will be modified to assess over a 1-week look back period. Frequency is rated on a 5-point Likert scale: 0 = none of the time, 1 = a little of the time, 2 = about half the time, 3 = most of the time, and 4 = all of the time. Severity is also rated on a 5-point Likert scale: 0 = symptom not present, 1 = mild, 2 = moderate, 3 = severe, 4 = very severe. For exercise intolerance, the primary endpoint is improvement in PEM, defined as having no symptoms of moderate or greater severity with 50% or more frequency as determined by the DSQ-PEM short form at day 90.	Baseline to Day 90
Secondary	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
Secondary	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
Secondary	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
Secondary	Occurrence of individual SAEs		Baseline to Day 90
Secondary	Occurrence of AEs and SAEs leading to discontinuation		Baseline to Day 90
Secondary	Occurrence of Events of Special Interest (ESIs)		Baseline to Day 90
Secondary	Duration of ESIs		Baseline to Day 90
Secondary	Adherence in intervention versus control groups as measured by number of missed doses		Baseline to Day 90

External Links

•   Related Info