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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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COVID-19

Intervention / Treatment
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* Drug: nirmatrelvir
* Drug: ritonavir
* Drug: placebo for nirmatrelvir


Participation Criteria
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Eligibility Criteria
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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

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 | 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>|
| Other: placebo plus ritonavir for 5 days<br>placebo (2 tablets) plus ritonavir (1 capsule) will be given by mouth every 12 hours for 5 days | 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>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The change in viral SARS-CoV-2 RNA level as measured in nasopharyngeal (NP) swabs | To compare the effect of nirmatrelvir/ritonavir to placebo/ritonavir on viral RNA level in NP swabs in participants with mild-to-moderate COVID-19. | Baseline to Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to 2 consecutive negative rapid antigen test results obtained at least 24 hours apart through Day 28 | To compare the effect of nirmatrelvir/ritonavir to placebo/ritonavir on the duration of viral shedding. | Day 1 through Day 28 | 
| Time to sustained alleviation of all targeted signs and symptoms defined as the first of two consecutive days when symptoms scored moderate/severe at baseline are scored mild/absent and symptoms scored mild/absent at baseline are scored absent. | To compare the effect of nirmatrelvir/ritonavir to placebo/ritonavir on the duration and severity of signs and symptoms in participants with mild-to-moderate COVID-19. | Day 1 through Day 28 | 
| Incidence of treatment emergent adverse events. | To describe the safety and tolerability of nirmatrelvir/ritonavir in participants with mild-to-moderate COVID-19. | Day 1 through Week 24 | 
| Incidence of serious adverse events and adverse events leading to discontinuation. | To describe the safety and tolerability of nirmatrelvir/ritonavir in participants with mild-to-moderate COVID-19. | Day 1 through Week 24 | 

 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), COVID-19 rebound, Paxlovid, Nirmatrelvir