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: Enrolling by invitation
• Conditions: Long COVID; Long COVID-19
• Intervention / Treatment: Drug: Paxlovid 25 day dosing; Drug: Paxlovid 15 day dosing; Drug: Control

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 (Estimated): 900
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Rachel E Olson, RN MS MBA PMP; Phone Number: 9196685590; Email: recoverresearch@duke.edu
• Study Contact Backup: Name: Barrie Harper, BSMT (ASCP) PMP; Email: recoverresearch@duke.edu

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 x 25 days	Drug: Paxlovid 25 day dosing; nirmatrelvir 300mg and ritonavir 100mg taken bid for 30 days
Experimental: Paxlovid 15 day dosing; Paxlovid (nirmatrelvir 300mg, ritonavir 100mg) bid x 15 days then ritonavir 100mg plus nirmatrelvir-matching placebo x 10 days	Drug: Paxlovid 15 day dosing; nirmatrelvir 300mg and ritonavir 100mg taken bid for 15 days then ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid for 15 days
Placebo Comparator: Control; ritonavir 100mg plus nirmatrelvir-matching placebo bid x 25 days	Drug: Control; ritonavir 100mg taken bid plus nirmatrelvir matching placebo bid for 30 days

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
Occurrence of individual SAEs		Baseline to Day 90
Occurrence of one or more 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

Collaborators and Investigators

• Sponsor: Kanecia Obie Zimmerman

Study record dates

Study Major Dates

• Study Start (Actual): July 26, 2023
• Primary Completion (Estimated): July 1, 2025
• Study Completion (Estimated): October 1, 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 12, 2024
• Last Update Submitted That Met QC Criteria: March 10, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Paxlovid; PASC
• Additional Relevant MeSH Terms: Pathologic Processes; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; Disease Attributes; Chronic Disease; Post-Infectious Disorders; COVID-19; Post-Acute COVID-19 Syndrome; Anti-Infective Agents; Antiviral Agents; 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