A Study to Learn About the Study Medicines (Nirmatrelvir Plus Ritonavir) in People Aged 12 Years or Older With COVID-19 and a Compromised Immune System

AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2, RANDOMIZED, DOUBLE-BLIND, 3-ARM STUDY TO INVESTIGATE NIRMATRELVIR/RITONAVIR IN NONHOSPITALIZED PARTICIPANTS AT LEAST 12 YEARS OF AGE WITH SYMPTOMATIC COVID-19 WHO ARE IMMUNOCOMPROMISED

The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called Nirmatrelvir/Ritonavir) for the possible treatment of COVID-19.

Patients with COVID-19 who have more difficulty in fighting against infections have a higher chance of severe illness. Such patients may benefit from longer treatment durations compared to the standard treatment regimen.

The study is seeking participants who:

• Have a confirmed COVID-19 infection
• Are Immunocompromised
• Experience onset of signs/symptoms attributable to the current COVID-19 infection within 5 days prior to screening and ≥1 signs/symptoms attributable to COVID-19 present on the day of randomization.

In addition, this study will also evaluate the efficacy and safety of a second treatment course of nirmatrelvir/ritonavir in people who experience that their COVID-19 is flaring up within 14 days of having taken a 5-day treatment course of nirmatrelvir/ritonavir.

For this group, the study is seeking participants who:

• Have a confirmed COVID-19 infection
• Experience a worsening of signs/symptoms after completing an initial 5-day course of nirmatrelvir/ritonavir
• The worsening of COVID-19 symptoms must occur within 14 days after completion of the initial 5-day course of nirmatrelvir/ritonavir
• Are Immunocompromised
• Experience onset of signs/symptoms attributable to the current COVID-19 infection within 48 hours prior to screening and ≥1 signs/symptoms attributable to COVID-19 present on the day of randomization.

All participants will be taking the study medicine for either 5, 10, or 15 days. The study medication will be taken by mouth 2 times a day. Participants will take part in this study for about 24 weeks. The first dose of study medication is taken at the study site and the rest at home. Selected participants will need to visit the study site at least 10 times during the study.

Study Overview

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

• Study Type: Interventional
• Enrollment (Actual): 157
• Phase: Phase 2

Contacts and Locations

Study Locations

• Australia
  • Victoria
    • Melbourne, Victoria, Australia, 3000
      • Peter MacCallum Cancer Centre
    • Parkville, Victoria, Australia, 3050
      • The Royal Melbourne Hospital
    • Parkville, Victoria, Australia, 3052
      • Royal Melbourne Hospital - Royal Park Campus
• Brazil
  • Rio de Janeiro, Brazil, 20241-180
    • IBPClin - Instituto Brasil de Pesquisa Clínica
  • Rio de Janeiro, Brazil, 21040-360
    • Instituto Nacional de Infectologia Evandro Chagas
  • RIO Grande DO Norte
    • Natal, RIO Grande DO Norte, Brazil, 59025050
      • Centro de Estudos e Pesquisa em Molestias Infecciosas - CPCLIN/RN
  • SÃO Paulo
    • Jau, SÃO Paulo, Brazil, 17201130
      • CECIP - Centro de Estudos do Interior Paulista
    • São José do Rio Preto, SÃO Paulo, Brazil, 15090000
      • Fundação Faculdade Regional de Medicina de São José do Rio Preto
• Bulgaria
  • Haskovo, Bulgaria, 6305
    • Specialized Hospital for Active Treatment of Pneumo-Phthisiatric Diseases - Haskovo EOOD
  • Pleven, Bulgaria, 5804
    • MHAT - Heart and Brain
  • Plovdiv, Bulgaria, 4000
    • Medical Center Artmed
  • Plovdiv, Bulgaria, 4000
    • MHAT Sveta Karidad EAD
  • Montana
    • Lom, Montana, Bulgaria, 3600
      • Diagnostic Consultative Center - 1 Lom EOOD
  • Sofia
    • Samokov, Sofia, Bulgaria, 2000
      • MHAT Samokov
  • Sofia (stolitsa)
    • Sofia, Sofia (stolitsa), Bulgaria, 1606
      • Military Medical Academy
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6Z 2C7
      • Vancouver Infectious Diseases Centre
  • Ontario
    • Guelph, Ontario, Canada, N1H 1B1
      • Dawson Clinical Research
    • Hamilton, Ontario, Canada, L8N 4A6
      • St. Joseph's Healthcare Hamilton
    • Toronto, Ontario, Canada, M9V 4B4
      • Dr. Anil K. Gupta Medicine Professional Corporation
    • Winchester, Ontario, Canada, K0C 2K0
      • Winchester District Memorial Hospital
  • Quebec
    • Chicoutimi, Quebec, Canada, G7H 7Y8
      • Intermed groupe santé
    • Montreal, Quebec, Canada, H2L 4P9
      • Clinique Medicale lActuel
    • Sherbrooke, Quebec, Canada, J1L 0H8
      • Diex Recherche Sherbrooke Inc.
    • Sherbrooke, Quebec, Canada, J1L 0H8
      • Diex Recherche Trois-Rivieres Inc.
• Hungary
  • Budapest, Hungary, 1122
    • Semmelweis Egyetem
  • Budapest, Hungary, 1097
    • Dél-Pesti Centrumkórház Országos Hematológiai és infektológiai intézet, Szent László telep
  • Szabolcs-szatmár-bereg
    • Nyiregyhaza, Szabolcs-szatmár-bereg, Hungary, 4400
      • Medifarma 98 Kft
• Mexico
  • Durango, Mexico, 34000
    • Instituto de Investigaciones Clínicas para la Salud
  • Oaxaca, Mexico, 68000
    • Oaxaca Site Management Organization S.C.
  • Veracruz, Mexico, 91900
    • FAICIC S. de R.L. de C.V.
  • Veracruz, Mexico, 91851
    • Instituto Veracruzano en Investigacion Clínica S.C.
  • Distrito Federal
    • Mexico City, Distrito Federal, Mexico, 14080
      • Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán
  • Nuevo LEÓN
    • Monterrey, Nuevo LEÓN, Mexico, 66460
      • Hospital Universitario "Dr. Jose Eleuterio Gonzalez"
  • Yucatán
    • Mérida, Yucatán, Mexico, 97000
      • EME Red Hospitalaria
• Slovakia
  • Bratislava, Slovakia, 851 07
    • Univerzitna nemocnica Bratislava, Nemocnica sv. Cyrila a Metoda
  • Bratislava, Slovakia, 851 07
    • Univerzitna nemocnica Bratislava - Nemocnica sv. Cyrila a Metoda
  • Kosice, Slovakia, 04011
    • ARTROMAC n. o.
  • Presov, Slovakia, 080 01
    • MEDIKOMP, s.r.o
  • Spisska Nova Ves, Slovakia, 052 01
    • Plucna ambulancia Hrebenar s.r.o.
  • Spisska Nova Ves, Slovakia, 052 01
    • Plucna ambulancia Hrebenar, s.r.o.
  • Svidnik, Slovakia, 089 01
    • SANARE spol.s.r.o.
  • Topolcany, Slovakia, 955 01
    • ALERGIA s.r.o.
  • Banskobystricky KRAJ
    • Rimavska Sobota, Banskobystricky KRAJ, Slovakia, 979 01
      • REUMEX s.r.o.
  • Bratislavský KRAJ
    • Bratislava, Bratislavský KRAJ, Slovakia, 833 10
      • Narodny Onkologicky Ustav
  • Nitriansky KRAJ
    • Topolcany, Nitriansky KRAJ, Slovakia, 955 01
      • ALERGIA s.r.o.
  • Trenčiansky KRAJ
    • Pruske, Trenčiansky KRAJ, Slovakia, 01852
      • MUDr. Viliam Cibik, PhD., s.r.o.
• Spain
  • Barcelona, Spain, 08035
    • Hospital Universitari Vall d'Hebron
  • Madrid, Spain, 28046
    • Hospital Universitario La Paz
  • Salamanca, Spain, 37007
    • Hospital Universitario de Salamanca - Complejo Asistencial Universitario de Salamanca
  • Sevilla, Spain, 41014
    • Hospital Universitario Virgen De Valme
  • Valencia, Spain, 46026
    • Hospital Universitari i Politecnic La Fe
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario Valencia
  • A Coruña [LA Coruña]
    • A Coruña, A Coruña [LA Coruña], Spain, 15006
      • CHUAC-Complejo Hospitalario Universitario A Coruña
  • Barcelona [barcelona]
    • Badalona, Barcelona [barcelona], Spain, 08916
      • Hospital Germans Trias i Pujol
  • Catalunya [cataluña]
    • Barcelona, Catalunya [cataluña], Spain, 08036
      • Hospital Clinic de Barcelona
    • Barcelona, Catalunya [cataluña], Spain, 08041
      • Hospital de la Santa Creu i Sant Pau
  • Madrid, Comunidad DE
    • Madrid, Madrid, Comunidad DE, Spain, 28034
      • Hospital Universitario Ramon Y Cajal
  • Pontevedra [pontevedra]
    • Vigo, Pontevedra [pontevedra], Spain, 36312
      • CHUVI- Hospital Alvaro Cunqueiro
  • Valenciana, Comunitat
    • Valencia, Valenciana, Comunitat, Spain, 46010
      • Hospital Clínico de Valencia
• United States
  • California
    • San Francisco, California, United States, 94143
      • UCSF Helen Diller Medical Center at Parnassus Heights
    • San Francisco, California, United States, 94143
      • CRS Outpatient Services UCSF
    • San Francisco, California, United States, 94143
      • UCSf infectious disease Lab
  • District of Columbia
    • Washington, District of Columbia, United States, 20007
      • Georgetown University Medical Center
  • Florida
    • Doral, Florida, United States, 33126
      • I.V.A.M. Clinical & Investigational Center
    • Hialeah, Florida, United States, 33010
      • Qway Research LLC
    • Miami, Florida, United States, 33126
      • Premium Medical Research Corp
    • Miami, Florida, United States, 33144
      • I.V.A.M. Clinical & Investigational Center
    • Miami, Florida, United States, 33135
      • Global Health Clinical Trials
    • Pompano Beach, Florida, United States, 33064
      • Napa Research
    • Tampa, Florida, United States, 33615
      • Santos Research Center
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • The Emory Clinic
    • Atlanta, Georgia, United States, 30322
      • Emory University School of Medicine
    • Atlanta, Georgia, United States, 30322
      • Emory University Hospital-Georgia Clinical Research Center
  • Maryland
    • Bethesda, Maryland, United States, 20892
      • National Institute of Health
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
    • Royal Oak, Michigan, United States, 48073
      • Beaumont Infectious Diseases Research
    • Sterling Heights, Michigan, United States, 48312
      • Revival Research Institute
  • Missouri
    • Saint Joseph, Missouri, United States, 64506
      • Medisearch Clinical Trials
  • New York
    • New York, New York, United States, 10029
      • Icahn School of Medicine at Mount Sinai
  • Texas
    • Corpus Christi, Texas, United States, 78404
      • South Texas Clinical Research
    • Dallas, Texas, United States, 75246
      • Baylor University Medical Center
    • Dallas, Texas, United States, 75246
      • North Texas Infectious Diseases Consultants, P.A
    • Fort Worth, Texas, United States, 76104
      • Texas Centers for Infectious Disease Associates
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutchinson Cancer Center - COVID Clinical Research Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria (applicable for both the main population and population with rebound):

• Participants aged 12 years or older and weighing ≥40 kg at screening.
• Immunocompromised
• ≥1 signs/symptoms attributable to COVID-19 present on the day of randomization.

Participants for the main population must have:

- Confirmed SARS-CoV-2 infection as determined by RT-PCR or other acceptable test method in any specimen collected within 5 days prior to randomization for the main study population.

Participants form the rebound population must have:

- Confirmed SARS-CoV-2 infection as determined by RT-PCR or rapid antigen testing in any specimen collected within 24h prior to randomization and collected within 14 days after the completion of the initial 5-day treatment course of nirmatrelvir/ritonavir for the population with rebound.

Exclusion Criteria:

• Current need for hospitalization or anticipated need for hospitalization within 24 h after randomization
• Known medical history of active liver disease
• Known HIV infection with a viral load >400 copies/mL or taking prohibited medications for human immunodeficiency virus (HIV)
• 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
• 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

3

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 followed by placebo for nirmatrelvir (2 tablets) plus placebo for ritonavir (1 capsule) every 12 hours for 10 days	Drug: Ritonavir; Participants will receive 1 capsule of ritonavir every 12 hours; Drug: Nirmatrelvir; Participants will receive 2 tablets of nirmatrelvir 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.; Drug: Placebo for ritonavir; Participants will receive 1 capsule of placebo for ritonavir every 12 hours. A placebo does not have any medicine in it but looks just like the medicine being studied.
Experimental: Nirmatrelvir plus ritonavir for 10 days; Nirmatrelvir (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 10 days followed by placebo for nirmatrelvir (2 tablets) plus placebo for ritonavir (1 capsule) every 12 hours for 5 days	Drug: Ritonavir; Participants will receive 1 capsule of ritonavir every 12 hours; Drug: Nirmatrelvir; Participants will receive 2 tablets of nirmatrelvir 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.; Drug: Placebo for ritonavir; Participants will receive 1 capsule of placebo for ritonavir every 12 hours. A placebo does not have any medicine in it but looks just like the medicine being studied.
Experimental: Nirmatrelvir plus ritonavir for 15 days; Nirmatrelvir (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 15 days.	Drug: Ritonavir; Participants will receive 1 capsule of ritonavir every 12 hours; Drug: Nirmatrelvir; Participants will receive 2 tablets of nirmatrelvir every 12 hours

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with sustained nasopharyngeal swab SARS-CoV-2 ribonucleic acid (RNA) <lower limit of quantitation (LLOQ) (defined as <2.0 log10 copies/mL).	To describe the effect of nirmatrelvir/ritonavir on viral RNA levels in nasopharyngeal swabs over time for the treatment of COVID-19 in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	From Day 15 through Day 44

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time to first nasopharyngeal swab SARS-CoV-2 RNA<LLOQ (<2.0 log10 copies/mL) for participants with nasopharyngeal swab SARS-CoV-2 RNA ≥LLOQ at baseline.	To describe the effect of nirmatrelvir/ritonavir treatment duration on the rate of sustained virologic clearance in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Week 24
Time to sustained nasopharyngeal swab SARS-CoV-2 RNA <LLOQ (<2.0 log10 copies/mL) for participants with nasopharyngeal swab SARS-CoV-2 RNA ≥LLOQ at baseline.	To describe the effect of nirmatrelvir/ritonavir treatment duration on the rate of sustained virologic clearance in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Day 44
Proportion of participants with SARS-CoV-2 RNA <LLOQ in plasma over time.	To describe the effect of nirmatrelvir/ritonavir on viral clearance for the treatment of COVID-19 in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Week 24
Proportion of participants with SARS-CoV-2 RNA level in nasopharyngeal swabs <2.0 log10 copies/mL at each study visit.	To describe the effect of nirmatrelvir/ritonavir on viral clearance for the treatment of COVID-19 in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Day 44
Change from baseline in SARS-CoV-2 RNA level in nasopharyngeal swabs and in plasma over time.	To describe the effect of nirmatrelvir/ritonavir on viral clearance for the treatment of COVID-19 in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Week 24
Rebound in SARS-CoV-2 RNA level in nasopharyngeal swabs at follow up, defined as a half (0.5) log10 copies/mL increase or greater in SARS-CoV-2 RNA level, with a follow-up viral RNA level ≥2.5 log10 copies/mL	To describe the effect of nirmatrelvir/ritonavir on viral clearance for the treatment of COVID-19 in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	End of treatment through Day 44
Incidence of treatment emergent adverse events.	To describe the safety and tolerability of nirmatrelvir/ritonavir for the treatment of COVID-19 in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Week 24
Incidence of serious adverse events and adverse events leading to discontinuations.	To describe the safety and tolerability of nirmatrelvir/ritonavir for the treatment of COVID-19 in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Week 24
Proportion of participants with COVID-19-related hospitalization >24 hours, or death from any cause.	To describe the effect of nirmatrelvir/ritonavir on hospitalization and all-cause mortality in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Day 28
Proportion of participants with death (all cause).	To describe the effect of nirmatrelvir/ritonavir on hospitalization and all-cause mortality in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Week 24
Proportion of participants with COVID-19-related hospitalization of any duration.	To describe COVID-19 related healthcare resource utilization in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised and treated with nirmatrelvir/ritonavir.	Day 1 through Week 24
Proportion of participants with COVID-19-related intensive care unit (ICU) admission of any duration.	To describe COVID-19 related healthcare resource utilization in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised and treated with nirmatrelvir/ritonavir.	Day 1 through Week 24
Proportion of participants requiring invasive mechanical ventilation or Extracorporeal membrane oxygenation.	To describe COVID-19 related healthcare resource utilization in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised and treated with nirmatrelvir/ritonavir.	Day 1 through Week 24
Number of days in hospital and ICU stay in participants with COVID-19-related hospitalization.	To describe COVID-19 related healthcare resource utilization in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised and treated with nirmatrelvir/ritonavir.	Day 1 through Week 24
Plasma concentration of nirmatrelvir		Day 1, Day 5, Day 10, and Day 15
Plasma concentration of ritonavir		Day 1, Day 5, Day 10, and Day 15
Number of COVID-19-related medical visits through Day 44 and through Week 24.	To describe COVID-19 related healthcare resource utilization in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised and treated with nirmatrelvir/ritonavir.	Day 1 through Day 44 and Week 24
Duration of each targeted COVID-19 signs/symptoms.	To evaluate nirmatrelvir/ritonavir for the duration and severity of signs and symptoms in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Day 44
Proportion of participants with severe signs/symptoms attributed to COVID-19.	To evaluate nirmatrelvir/ritonavir for the duration and severity of signs and symptoms in nonhospitalized symptomatic participants ≥12 years of age with COVID-19 who are immunocompromised.	Day 1 through Day 44

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): August 3, 2022
• Primary Completion (Actual): July 17, 2023
• Study Completion (Actual): November 13, 2023

Study Registration Dates

• First Submitted: June 28, 2022
• First Submitted That Met QC Criteria: June 28, 2022
• First Posted (Actual): June 30, 2022

Study Record Updates

• Last Update Posted (Actual): January 25, 2024
• Last Update Submitted That Met QC Criteria: January 24, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Paxlovid; Nirmatrelvir; Immunocompromised; Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2); Coronavirus disease 2019 (COVID-19)
• 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: C4671034; 2022-001362-35 (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