RECOVER-VITAL: Platform Protocol, Appendix to Measure the Effects of Paxlovid 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 is an appendix of master protocol (NCT05595369) 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 sub-study is a prospective, multi-center, double-blind, randomized, controlled trial evaluating nirmatrelvir/ritonavir (Paxlovid) in two dosing durations for the treatment of Post-Acute Sequelae of SARS-CoV-2 Infection (PASC). The study is evaluating 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 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 COVID-19
• Intervention / Treatment: Drug: Paxlovid; Drug: Ritonavir; Drug: Nirmatrelvir-matching placebo

Detailed Description

For this appendix of the master protocol (NCT05595369), participants will be randomized to Paxlovid (nirmatrelvir/ritonavir) vs. ritonavir control plus nirmatrelvir-matching placebo.

When there are multiple study interventions (sub-studies) available under the master protocol (NCT05595369), randomization will occur based on the specific inclusion/exclusion criteria of each appendix.

• Study Type: Interventional
• Enrollment (Actual): 964
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • All sites listed under NCT05595369

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

See NCT NCT05595369 for RECOVER-VITAL: Platform Protocol level exclusion criteria which applies to this appendix

Additional Appendix Level Exclusion Criteria:

1. Known pregnancy*
2. Active or expected breastfeeding during the study
3. Known eGFR < 30 mL/min
4. Known severe hepatic impairment (Child-Pugh Class C)
5. Current use of drugs highly dependent on CYP3A for clearance** and for which elevated concentrations are associated with serious and/or life-threatening reactions and which cannot be interrupted during the time of study administration and within seven days before and after study drug administration

6. Current use of potent CYP3A inducers** where significantly reduced nirmatrelvir or ritonavir plasma concentrations may be associated with the potential for loss of virologic response and possible resistance

   • A pregnancy test must be performed at the Baseline Visit for participants who are capable of becoming pregnant.

     • A guide of drugs that may be contraindicated are listed in Section 4 CONTRAINDICATIONS of the Full Prescribing Information of the EUA for PAXLOVID. https://labeling.pfizer.com/ShowLabeling.aspx?id=16474&format=pdf

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: Paxlovid 25 day dosing; Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) BID (twice a day) x 25 days	Drug: Paxlovid; Nirmatrelvir 300mg and ritonavir 100mg taken BID (twice a day)
Experimental: Paxlovid 15 day dosing; Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) BID (twice a day) x 15 days then ritonavir 100mg plus nirmatrelvir-matching placebo x 10 days	Drug: Paxlovid; Nirmatrelvir 300mg and ritonavir 100mg taken BID (twice a day); Drug: Ritonavir; Ritonavir 100mg taken BID (twice a day); Drug: Nirmatrelvir-matching placebo; A nirmatrelvir-matching placebo taken BID (twice a day)
Placebo Comparator: Ritonavir plus nirmatrelvir-matching placebo; Ritonavir 100mg plus nirmatrelvir-matching placebo BID (twice a day) x 25 days	Drug: Ritonavir; Ritonavir 100mg taken BID (twice a day); Drug: Nirmatrelvir-matching placebo; A nirmatrelvir-matching placebo taken BID (twice a day)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Improved in Cognitive Dysfunction Symptom Cluster, as Measured by Patient-Reported Outcomes Measurement Information System (PROMIS) Cognitive 8a Function T-score	PROMIS Cognitive 8a is a questionnaire assessing self-reported cognitive impairments over the past 7 days using 8 items. It assesses the frequency that respondents experienced cognitive impairments on a scale ranging from 5 (never) to 1 (very often; several times a day). The total raw score is transformed into a T-score, with higher scores representing better cognitive function. The T-scores are interpreted in relation to a US reference population and are scaled to have mean = 50 and SD = 10 in the reference population. The primary endpoint for the cognitive dysfunction symptom cluster is improvement of at least 5 T-score points on the PROMIS-cognitive 8a as measured at Day 90 compared to baseline.	Baseline, Day 90
Percentage of Participants Who Improved in Autonomic Dysfunction Symptom Cluster, as Measured by the Orthostatic Hypotension Questionnaire (OHQ)	The Orthostatic Hypotension Questionnaire (OHQ) is a patient reported outcome designed to assess the severity and impact of orthostatic hypotension (OH), a condition characterized by a sudden drop in blood pressure when standing. The OHQ consists of two main components: the Orthostatic Hypotension Symptom Assessment (OHSA) and the Orthostatic Hypotension Daily Activity Scale (OHDAS). The OHSA consists of 6 items measuring severity on a scale ranging from 0 (none) to 10 (worst possible). The OHDAS assesses the extent to which OH interferes with daily life on a scale ranging from 0 (no interference) to 10 (total interference). The primary endpoint for the autonomic dysfunction symptom cluster is improvement as defined by at least a 1-point decrease in the response to OHQ question 1 at Day 90 compared to baseline.	Baseline, Day 90
Percentage of Participants Who Improved in Exercise Intolerance Symptom Cluster, as Measured by the Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM)	The Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM) is a patient-reported outcome designed to assess the frequency and severity of symptoms worsening after physical or mental exertion. The first 10 items of DSQ-PEM assess frequency and severity of the following 5 exercise-related impairments. These items were modified for the current study to use a 7-day instead of 6-month 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. The primary endpoint for the exercise symptom cluster 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, Day 90

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Who Improved in Cognitive Dysfunction Symptom Cluster, as Measured by a Neurocognitive Battery	The Neurocognitive battery is a performance measure used to assess various elements related to cognition. The neurocognitive battery consists of a cognitive assessment sequence of the following: WHO/UCLA Auditory Verbal Learning Test (WHO/UCLA AVLT) and Symbol Digit Modalities Test (SDMT). The major secondary endpoint for the cognitive dysfunction symptom cluster is a binary endpoint defined as an increase by at least 1 point in either or both of the AVLT delayed recall Z-score and/or SDMT number of correct substitutions Z-score, and no decrease exceeding 0.15 in either of these measures, at Day 90 compared to baseline.	Baseline, Day 90
Percentage of Participants Who Improved in Autonomic Dysfunction Symptom Cluster, as Measured by the Active Stand Test	The active stand test is performed to assess presence of orthostatic intolerance, orthostatic hypotension, and postural orthostatic tachycardia syndrome. The participant's blood pressure and heart rate are recorded after 5 minutes of lying and then at minutes 1, 3, 5, and 10 after standing. Changes in systolic blood pressure (SBP), diastolic blood pressure (DBP), and heart rate beats per minute (HR BPM) are assessed from lying to standing for 10 minutes. The major secondary endpoint for the autonomic dysfunction cluster is a binary endpoint defined as improvement in change from lying to standing in at least one of HR, DBP, or DBP from baseline to Day 90 (defined as an increase of at least 10mmHg in SBP, an increase of at least 5mmHg on DBP, or a decrease of at least 10 BPM on HR) and no worsening in any of HR, DBP, or DBP from baseline to Day 90 (defined as any decrease in SBP or DBP, or any increase in HR.	Baseline, Day 90
Percentage of Participants Who Improved in Exercise Intolerance Symptom Cluster, as Measured by the Endurance Shuttle Walk Test (ESWT)	The endurance shuttle walk test (ESWT) is a performance measure that consists of timed walking on a 10 meter course. The major secondary endpoint for the exercise intolerance symptom cluster is defined as an increase of at least 3 minutes in walk time at Day 90 compared to baseline.	Baseline, Day 90
Total Number of SAEs (Serious Adverse Events)		Up to 190 days
Number of Participants Experiencing One or More SAEs (Serious Adverse Events)		Up to 190 days
Number of Participants Experiencing AEs (Adverse Events) or SAEs (Serious Adverse Events) Leading to Treatment Discontinuation		Up to 25 days
Number of Participants With an Event of Special Interest (ESI)		Up to 190 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adherence as Measured by Number of Missed Doses	Each randomized participant was scheduled to take two doses of study drug per day for 25 days. The number of completed doses is calculated as 50 planned doses minus the number of planned missed doses.	Up to 25 days

Collaborators and Investigators

• Sponsor: Kanecia Obie Zimmerman

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2023
• Primary Completion (Actual): December 5, 2024
• Study Completion (Actual): March 13, 2025

Study Registration Dates

• First Submitted: July 25, 2023
• First Submitted That Met QC Criteria: July 25, 2023
• First Posted (Actual): July 28, 2023

Study Record Updates

• Last Update Posted (Actual): March 27, 2026
• Last Update Submitted That Met QC Criteria: March 5, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: Paxlovid; 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; Sulfur Compounds; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Thiazoles; Azoles; Ritonavir; nirmatrelvir and ritonavir drug combination
• Other Study ID Numbers: Pro00111697_A; 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 investigators 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