A Study to Learn About a Repeat 5-Day Treatment With the Study Medicines (Called Nirmatrelvir/Ritonavir) in People 12 Years Old or Older With Return of COVID-19 Symptoms and SARS-CoV-2 Positivity After Finishing Treatment With Nirmatrelvir/Ritonavir

AN INTERVENTIONAL, EFFICACY AND SAFETY, PHASE 2, RANDOMIZED, DOUBLE-BLIND, 2-ARM STUDY TO INVESTIGATE A REPEAT 5-DAY COURSE OF NIRMATRELVIR/RITONAVIR COMPARED TO PLACEBO/RITONAVIR IN PARTICIPANTS AT LEAST 12 YEARS OF AGE WITH REBOUND OF COVID-19 SYMPTOMS AND RAPID ANTIGEN TEST POSITIVITY

The purpose of this study is to learn about the safety and effects of nirmatrelvir/ritonavir for the potential treatment of COVID-19 rebound.

The study is seeking participants who:

• Have completed treatment with nirmatrelvir/ritonavir
• Have a rebound in COVID-19 symptoms
• Are SARS-CoV-2 (COVID-19) positive

All study medications will be taken 2 times a day by mouth for 5 days. The first dose of study medication is taken at the study clinic and the rest at home.

We will examine the experiences of people receiving the study medicines to those who do not. This will help us determine if the study medicines are safe and effective.

People taking part will be in this study for about 24 weeks. Enrolled participants will need to visit the study clinic at least 8 times during the study.

Study Overview

• Status: Completed
• Conditions: COVID-19
• Intervention / Treatment: Drug: nirmatrelvir; Drug: ritonavir; Drug: placebo for nirmatrelvir

• Study Type: Interventional
• Enrollment (Actual): 436
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Guelph, Ontario, Canada, N1H 1B1
      • Dawson Clinical Research
    • Hamilton, Ontario, Canada, L8M 1K7
      • Hamilton Medical Research Group
    • Oshawa, Ontario, Canada, L1G 4T3
      • Medical Trust Clinics
    • Winchester, Ontario, Canada, K0C 2K0
      • Winchester District Memorial Hospital
• Greece
  • Athens, Greece, 11527
    • General Hospital of Athens "Laiko"
  • Thessaloniki, Greece, 54636
    • Ahepa University General Hospital of Thessaloniki
  • Attica
    • Athens, Attica, Greece, 11527
      • Thoracic General Hospital of Athens "I Sotiria"
  • Attikí
    • Athens, Attikí, Greece, 106 76
      • Evangelismos General Hospital of Athens
    • Athens, Attikí, Greece, 115 28
      • Alexandra General Hospital of Athens
• Italy
  • Pavia, Italy, 27100
    • Fondazione IRCCS Policlinico San Matteo
  • Lombardia
    • Milano, Lombardia, Italy, 20122
      • Fondazione IRCCS Ca Granda Ospedale Maggiore Policlinico
  • Milano
    • Milan, Milano, Italy, 20157
      • ASST Fatebenefratelli Sacco
  • Sicilia
    • Palermo, Sicilia, Italy, 90129
      • A.O.U. Policlinico Paolo Giaccone
• Taiwan
  • Taichung, Taiwan, 407
    • Taichung Veterans General Hospital
  • Taipei, Taiwan, 10002
    • National Taiwan University Hospital
  • Taipei, Taiwan, 11217
    • Taipei Veterans General Hospital
  • NEW Taipei
    • New Taipei City, NEW Taipei, Taiwan, 220
      • Far Eastern Memorial Hospital
• United States
  • Arizona
    • Mesa, Arizona, United States, 85210
      • The Institute for Liver Health dba Arizona Clinical Trials
    • Phoenix, Arizona, United States, 85031
      • Abby's Research Institute
    • Surprise, Arizona, United States, 85378
      • Epic Medical Research - Surprise
  • California
    • Anaheim, California, United States, 92806
      • Smart Cures Clinical Research
    • Canoga Park, California, United States, 91303
      • Hope Clinical Research, Inc.
    • Fullerton, California, United States, 92835
      • Ascada Research
    • Fullerton, California, United States, 92835
      • Ascada Health PC dba Ascada Research
    • La Mesa, California, United States, 91942
      • Paradigm Clinical Research Centers, Inc
    • Long Beach, California, United States, 90806
      • CVS Health - 8876 - Long Beach
    • North Hollywood, California, United States, 91606
      • Carbon Health - North Hollywood - NoHo West
  • Colorado
    • Wheat Ridge, Colorado, United States, 80033
      • Paradigm Clinical Research Centers, Inc
  • District of Columbia
    • Washington, District of Columbia, United States, 20011
      • Emerson Clinical Research Institute
    • Washington, District of Columbia, United States, 20009
      • Emerson Clinical Research Institute - Washington - Connecticut Avenue
  • Florida
    • Brandon, Florida, United States, 33511
      • Palm Harbor Dermatology PA d/b/a TrueBlue Clinical Research
    • Coral Gables, Florida, United States, 33134
      • Herco Medical and Research Center Inc
    • Hialeah, Florida, United States, 33016
      • Sweet Hope Research Specialty, Inc
    • Hialeah, Florida, United States, 33016
      • NeoClinical Research
    • Hialeah Gardens, Florida, United States, 33018
      • Unlimited Medical Research Group LLC
    • Lutz, Florida, United States, 33549
      • Asclepes Research Center - Spring Hill
    • Miami, Florida, United States, 33126
      • LCC Medical Research Institute
    • Miami, Florida, United States, 33126
      • Premium Medical Research Corp
    • Miami, Florida, United States, 33176
      • Entrust Clinical Research
    • Miami, Florida, United States, 33176
      • Reed Medical Research
    • Miami, Florida, United States, 33165
      • Reliant Medical Research
    • Miami, Florida, United States, 33135
      • South Florida Research Center
    • Miami, Florida, United States, 33185
      • Kendall South Medical Center
    • Miami, Florida, United States, 33175
      • Innova Pharma Research
    • Miami, Florida, United States, 33135
      • Global Health Clinical Trials
    • Miami Gardens, Florida, United States, 33014
      • Pro-Care Research Center, Corp.
    • Orlando, Florida, United States, 32808
      • Omega Research Orlando
    • Pompano Beach, Florida, United States, 33064
      • NAPA Research
    • Saint Petersburg, Florida, United States, 33705
      • GCP Research, Global Clinical professionals
    • Saint Petersburg, Florida, United States, 33710
      • Theia Clinical Research - 5th Avenue North
    • Spring Hill, Florida, United States, 34609
      • Asclepes Research Center - Spring Hill
    • Tampa, Florida, United States, 33615
      • Santos Research Center
    • Tampa, Florida, United States, 33609
      • Palm Harbor Dermatology PA d/b/a TrueBlue Clinical Research
    • Winter Park, Florida, United States, 32789
      • Clinical Site Partners, LLC dba CSP Orlando
    • Winter Park, Florida, United States, 32789
      • Clinical Site Partners, LLC dba Flourish Research
  • Idaho
    • Blackfoot, Idaho, United States, 83221
      • Bingham Memorial Hospital
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Medical Center
  • Maryland
    • Elkridge, Maryland, United States, 21075
      • Centennial Medical Group
  • Massachusetts
    • Worcester, Massachusetts, United States, 01655
      • University of Massachusetts Chan Medical School
  • Michigan
    • Bay City, Michigan, United States, 48706
      • Great Lakes Research Group, Inc.
    • Detroit, Michigan, United States, 48201
      • C.S. Mott Clinical Research Center (CRC)
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Infectious Diseases Research
  • Mississippi
    • Olive Branch, Mississippi, United States, 38654
      • Olive Branch Family Medical Center
  • Montana
    • Butte, Montana, United States, 59701
      • Mercury Street Medical Group, PLLC
  • Nevada
    • Las Vegas, Nevada, United States, 89109
      • Excel Clinical Research, LLC
  • New Jersey
    • East Brunswick, New Jersey, United States, 08816
      • CVS Health - Site 02815 East Brunswick
    • Neptune, New Jersey, United States, 07753
      • Hackensack Meridian Jersey Shore University Medical Center
  • New York
    • Bronx, New York, United States, 10467
      • Montefiore Medical Center
  • North Carolina
    • Charlotte, North Carolina, United States, 28208
      • Onsite Clinical Solutions
    • Charlotte, North Carolina, United States, 28208
      • Onsite Clinical Solutions (secondary location)
    • Wilmington, North Carolina, United States, 28401
      • Accellacare - Wilmington
  • Ohio
    • Columbus, Ohio, United States, 43214
      • WellNow Urgent Care and Research - Columbus
  • Oregon
    • Eugene, Oregon, United States, 97404
      • Willamette Valley Clinical Studies
  • Pennsylvania
    • Beaver, Pennsylvania, United States, 15009
      • Heritage Valley Multispecialty Group, Inc
  • Tennessee
    • Union City, Tennessee, United States, 38261
      • Premier Primary Care
  • Texas
    • Andrews, Texas, United States, 79714
      • Nayak Research, LLC
    • Brownsville, Texas, United States, 78526
      • Headlands Research - Brownsville
    • Dallas, Texas, United States, 75235
      • Southwest Family Medicine Associates
    • Houston, Texas, United States, 77057
      • Next Level Urgent Care
    • Houston, Texas, United States, 77021
      • Next Innovative Clinical Research
    • Humble, Texas, United States, 77338
      • Accurate Clinical Research - East Humble
    • Humble, Texas, United States, 77338
      • Accurate Clinical Research, Inc
    • San Antonio, Texas, United States, 78215
      • Sun Research Institute
  • Washington
    • Redmond, Washington, United States, 98052
      • Eastside Research Associates

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Documentation of nirmatrelvir/ritonavir treatment with patient-reported 100% compliance. Symptom alleviation or resolution in COVID-19 signs/symptoms followed by a worsening (rebound) of signs/symptoms after completing an initial 5-day course of nirmatrelvir/ritonavir
• Onset of rebound in COVID-19 symptoms within 2 weeks (14 days) after the completion of the initial 5-day course of nirmatrelvir/ritonavir.
• Onset of rebound in signs/symptoms attributable to COVID-19 within 48 hours prior to randomization and ≥1 sign/symptom attributable to COVID-19 present on the day of randomization.
• SARS-CoV-2 infection as determined by rapid antigen testing within 24 hours prior to randomization
• At least 1 characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19.

Exclusion Criteria:

• Current need for hospitalization, hospitalized for the COVID-19 infection or anticipated need for hospitalization within 24 hours after randomization
• History of severe chronic liver disease
• Receiving dialysis or have known age-specific estimated glomerular filtration rate (eGFR) or estimated creatinine clearance (eCrCl) <30 mL/min/1.73 m2 at screening as measured by a serum creatinine point of care device
• Oxygen saturation of <92% on room air obtained at rest within 24 hours prior to randomization
• Immunocompromised.
• Current use of any prohibited concomitant medication(s)
• Females who are pregnant and <14 weeks gestation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: nirmatrelvir plus ritonavir for 5 days; Nirmatrelvir (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 5 days	Drug: nirmatrelvir; Participants will receive 2 tablets of nirmatrelvir every 12 hours; Drug: ritonavir; Participants will receive 1 capsule of ritonavir every 12 hours
Other: placebo plus ritonavir for 5 days; placebo (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 5 days	Drug: ritonavir; Participants will receive 1 capsule of ritonavir every 12 hours; Drug: placebo for nirmatrelvir; Participants will receive 2 tablets of placebo for nirmatrelvir every 12 hours. A placebo does not have any medicine in it but looks just like the medicine being studied.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Day 5 in Viral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Ribonucleic Acid (RNA) Level in Nasopharyngeal (NP) Swabs: mITT Population	Baseline was defined as the latest measurement between Day -1 and Day 1, but post-dose samples that were collected within 1 hour post start of dosing were also treated as baseline. Samples with result "< lower limit of quantification (LLOQ)" were imputed as 1.7 log10 copies/milliliter (mL), and samples with result "Not Detected" were imputed as 0.0 log10 copies/mL.	Baseline, Day 5

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to Two Consecutive Negative Rapid Antigen Test (RAT) Results At Least 24 Hours Apart Through Day 28: mITT Population	The event of 2 consecutive negative RAT results obtained at least 24 (-2) hours apart through Day 28 was defined as achieving 2 consecutive non-missing RATs with negative results through Day 28, where the 2 tests were at least 22 hours and at most 7 days apart. For the event of 2 consecutive negative RAT results obtained at least 24 hours apart through Day 28, the date of the first negative RAT result was considered the first event date. Time to 2 consecutive negative RAT results obtained at least 24 hours apart defined as: for participant achieving event, time to event = (first event date) -(first dose date) + 1. For participant not achieving event (censored), censoring date was at last date of RAT measurement, time = (censoring date) - (first dose date) + 1 or Day 27 whichever occurred first (Day 27 was last possible day to achieve 2 consecutive negative RAT results obtained at least 24 hours apart through Day 28).	Day 1 of dosing maximum up to Day 28 or censoring date, whichever occurred first
Time to Sustained Alleviation of All Targeted Signs and Symptoms Through Day 28: mITT Population	Sustained alleviation of all targeted COVID-19 signs/symptoms was defined as the event occurring on the first of 2 consecutive days when all symptoms scored as moderate or severe at study entry are scored as mild or absent and all symptoms scored mild or absent at study entry are scored as absent. The first day of the 2 consecutive-day period was considered the first event date. The time to sustained symptom alleviation was defined as for a participant with sustained symptom alleviation, time to event was calculated as (First Event Date) - (First Dose Date) +1. For a participant that either completed Day 28 of the study or discontinued from the study before Day 28 without sustained symptom alleviation (censored), censoring date was at the last date on which symptom alleviation was assessed, and time was calculated as (Censoring Date) - (First Dose Date) +1 or Day 27 whichever occurred first.	Day 1 of dosing maximum up to Day 28 or censoring date, whichever occurred first
Number of Participants With Treatment Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs) and Adverse Events (AEs) Leading to Discontinuation From Study	An AE was any untoward medical occurrence in a participant temporally associated with the use of study intervention, whether or not considered related to the study intervention. SAE was any untoward medical occurrence at any dose that: resulted in death, was life threatening (risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), resulted in congenital anomaly/birth defect, was a suspected transmission via a Pfizer product of an infectious agent, pathogenic or nonpathogenic. TEAEs were defined as AE that started on or after study medication on Day 1 up to Week 24 follow-up. AEs included both SAEs and all non-SAEs.	Day 1 of dosing up to maximum Week 24 follow-up

Collaborators and Investigators

• Sponsor: Pfizer
• Investigators: Study Director: Pfizer CT.gov Call Center, Pfizer

Publications and helpful links

Helpful Links

• To obtain contact information for a study center near you, click here.

Study record dates

Study Major Dates

• Study Start (Actual): October 19, 2022
• Primary Completion (Actual): September 27, 2023
• Study Completion (Actual): February 9, 2024

Study Registration Dates

• First Submitted: October 3, 2022
• First Submitted That Met QC Criteria: October 3, 2022
• First Posted (Actual): October 5, 2022

Study Record Updates

• Last Update Posted (Actual): October 8, 2024
• Last Update Submitted That Met QC Criteria: September 17, 2024
• Last Verified: September 1, 2024

More Information

Terms related to this study

• Keywords: Paxlovid; Nirmatrelvir; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Coronavirus disease 2019 (COVID-19); COVID-19 rebound
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Pneumonia, Viral; Pneumonia; Lung Diseases; COVID-19; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Anti-HIV Agents; Anti-Retroviral Agents; Protease Inhibitors; Cytochrome P-450 CYP3A Inhibitors; Cytochrome P-450 Enzyme Inhibitors; HIV Protease Inhibitors; Viral Protease Inhibitors; Ritonavir; Nirmatrelvir
• Other Study ID Numbers: C4671042; 2022-002827-36 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No