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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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COVID-19

Intervention / Treatment
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* Drug: Nirmatrelvir
* Drug: Ritonavir
* Drug: Placebo for nirmatrelvir
* Drug: Placebo for ritonavir


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nirmatrelvir plus ritonavir for 5 days<br>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: Nirmatrelvir<br>* Participants will receive 2 tablets of nirmatrelvir every 12 hours<br>Drug: Ritonavir<br>* Participants will receive 1 capsule of ritonavir every 12 hours<br>Drug: Placebo for nirmatrelvir<br>* 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.<br>Drug: Placebo for ritonavir<br>* 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.<br>|
| Experimental: Nirmatrelvir plus ritonavir for 10 days<br>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: Nirmatrelvir<br>* Participants will receive 2 tablets of nirmatrelvir every 12 hours<br>Drug: Ritonavir<br>* Participants will receive 1 capsule of ritonavir every 12 hours<br>Drug: Placebo for nirmatrelvir<br>* 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.<br>Drug: Placebo for ritonavir<br>* 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.<br>|
| Experimental: Nirmatrelvir plus ritonavir for 15 days<br>Nirmatrelvir (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 15 days. | Drug: Nirmatrelvir<br>* Participants will receive 2 tablets of nirmatrelvir every 12 hours<br>Drug: Ritonavir<br>* Participants will receive 1 capsule of ritonavir every 12 hours<br>|

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Coronavirus disease 2019 (COVID-19), Paxlovid, Nirmatrelvir, Immunocompromised