RECOVER-VITAL: Platform Protocol, Appendix to Measure the Effects of Paxlovid on Long COVID Symptoms

Phase 2

Completed

• Conditions: Long COVID-19; Long COVID
• Interventions: Drug: Paxlovid 25 day dosing; Drug: Paxlovid 15 day dosing; Drug: Control

• Registration Number: NCT05965726
• Lead Sponsor: Kanecia Obie Zimmerman

Brief Summary

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.

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 Timeline

• Study First Submitted: 2023-07-25
• Study First Submitted QC: 2023-07-25
• Study Start: 2023-07-26
• Study First Posted: 2023-07-28
• Primary Completion: 2024-12-05
• Study Completion: 2025-03-13
• Status Verified: 2025-04
• Last Update Submitted: 2025-04-17
• Last Update Posted: 2025-04-18

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 900

Inclusion Criteria

Not provided

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Paxlovid 25 day dosing	Paxlovid 25 day dosing	Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 25 days
Paxlovid 15 day dosing	Paxlovid 15 day dosing	Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 15 days then ritonavir 100mg plus nirmatrelvir-matching placebo x 10 days
Control	Control	ritonavir 100mg plus nirmatrelvir-matching placebo bid x 25 days

Primary Outcome Measures

Name	Time	Method
Change in cognitive dysfunction symptom cluster, as measured by Patient-Reported Outcomes Measurement Information System (PROMIS) cognitive function T-score	Baseline to Day 90	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.
Change in autonomic dysfunction symptom cluster, as measured by the orthostatic hypotension questionnaire (OHQ)	Baseline to Day 90	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.
Change in exercise intolerance symptom cluster, as measured by the Modified Depaul Symptom Questionnaire-Post Exertional Malaise (DSQ-PEM)	Baseline to Day 90	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.

Secondary Outcome Measures

Name	Time	Method
Change in cognitive dysfunction symptom cluster, as measured by a neurocognitive battery	Baseline to Day 90	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).
Change in autonomic dysfunction symptom cluster, as measured by the active stand test	Baseline to Day 90	The active stand test outcome is a binary indicator of whether the follow-up active stand test result was abnormal or normal.
Change in exercise intolerance symptom cluster, as measured by the endurance shuttle walk test (ESWT)	Baseline to Day 90	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.
Occurrence of individual SAEs	Baseline to Day 190
Occurrence of one or more SAEs	Baseline to Day 190
Occurrence of AEs and SAEs leading to discontinuation	Baseline to Day 25
Occurrence of Events of Special Interest (ESIs)	Baseline to Day 190
Adherence in intervention versus control groups as measured by number of missed doses	Baseline to Day 25

Trial Locations

Locations (1)

All sites listed under NCT05595369; 🇺🇸 Durham, North Carolina, United States