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

NCT05965726 | Completed Phase 2 Results DMC FDA Drug

• 2 other identifiers: Pro00111697_AOTA-21-015G
• Study Type: interventional
• Target: 964
• Locations: 1 country
• Sites: 1

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.

Conditions

Long COVID-19; Long COVID

Keywords

PASC; Paxlovid

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (7)

• Percentage of Participants Who Improved in Cognitive Dysfunction Symptom Cluster, as Measured by a Neurocognitive Battery

  Baseline, Day 90

• Percentage of Participants Who Improved in Autonomic Dysfunction Symptom Cluster, as Measured by the Active Stand Test

  Baseline, Day 90

• Percentage of Participants Who Improved in Exercise Intolerance Symptom Cluster, as Measured by the Endurance Shuttle Walk Test (ESWT)

  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

Other Outcomes (1)

• Adherence as Measured by Number of Missed Doses

  Up to 25 days

Study Arms (3)

Paxlovid 25 day dosing

EXPERIMENTAL

Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) BID (twice a day) x 25 days

Drug: Paxlovid

Paxlovid 15 day dosing

EXPERIMENTAL

Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) BID (twice a day) x 15 days then ritonavir 100mg plus nirmatrelvir-matching placebo x 10 days

Drug: Paxlovid; Drug: Ritonavir; Drug: Nirmatrelvir-matching placebo

Ritonavir plus nirmatrelvir-matching placebo

PLACEBO COMPARATOR

Ritonavir 100mg plus nirmatrelvir-matching placebo BID (twice a day) x 25 days

Drug: Ritonavir; Drug: Nirmatrelvir-matching placebo

Interventions

Paxlovid DRUG

Nirmatrelvir 300mg and ritonavir 100mg taken BID (twice a day)

Paxlovid 15 day dosing; Paxlovid 25 day dosing

Ritonavir DRUG

Ritonavir 100mg taken BID (twice a day)

Paxlovid 15 day dosing; Ritonavir plus nirmatrelvir-matching placebo

Nirmatrelvir-matching placebo DRUG

A nirmatrelvir-matching placebo taken BID (twice a day)

Paxlovid 15 day dosing; Ritonavir plus nirmatrelvir-matching placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may not qualify if:

• Known pregnancy\*
• Active or expected breastfeeding during the study
• Known eGFR \< 30 mL/min
• Known severe hepatic impairment (Child-Pugh Class C)
• 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
• 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

Sponsors & Collaborators

• Kanecia Obie Zimmerman: lead

Study Sites (1)

All sites listed under NCT05595369

Durham, North Carolina, 27710, United States

Location

MeSH Terms

Conditions

Post-Acute COVID-19 Syndrome

Interventions

nirmatrelvir and ritonavir drug combination; Ritonavir

Condition Hierarchy (Ancestors)

COVID-19; Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Post-Infectious Disorders; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Kanecia Zimmerman, MD, PhD, MPH
• Organization: Duke University

kanecia.zimmerman@duke.edu

(919) 668-8651

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Masking Details: Double-blind
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Pediatrics

Model Details: As part of screening, potential participants will answer symptom questions. Eligible participants will then complete relevant Symptom Cluster assessments at the Screening visit. Participants will subsequently be assigned to one of the three Symptom Clusters based on the assessments. Participants must meet certain criteria within a specific symptom cluster in order to be included in the cluster. After study enrollment and initial cluster assignment, further assessments will be performed. Participants will undergo assessments for the symptom clusters for which the participants qualify.

Study Record Dates

• First Submitted: July 25, 2023
• First Posted: July 28, 2023
• Study Start: July 26, 2023
• Primary Completion: December 5, 2024
• Study Completion: March 13, 2025
• Last Updated: March 27, 2026
• Results First Posted: March 27, 2026

Record last verified: 2026-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)