A Study to Learn About the Medicine Called Nirmatrelvir Used in Combination With Ritonavir in People With Weakened Immune Systems or at Increased Risk for Poor Outcomes Who Are Hospitalized Due to Severe COVID-19

Study Overview
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Brief Summary
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A Study to Learn About the Medicine Called Nirmatrelvir Used in Combination With Ritonavir in People with Weakened Immune Systems or at Increased Risk for Poor Outcomes who are Hospitalized Due to Severe COVID-19

Official Title
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AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2, DOUBLE-BLIND, 2-ARM STUDY TO INVESTIGATE ORALLY ADMINISTERED NIRMATRELVIR/RITONAVIR COMPARED WITH PLACEBO/RITONAVIR FOR THE TREATMENT OF SEVERE COVID-19 IN HOSPITALIZED PARTICIPANTS WHO ARE IMMUNOCOMPROMISED OR AT INCREASED RISK FOR SEVERE COVID-19 OUTCOMES

Conditions
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Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Coronavirus Disease 2019 (COVID-19), Immunocompromised, Hospitalization, Child, Hospitalized

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: Meeting 1 of the 2 categories of COVID-19 risk: Category A: Immunocompromised Category B: Non-Immunocompromised, but with ≥2 risk factors Onset of signs/symptoms attributable to COVID-19 ≤10 days prior to the day of randomization for non-immunocompromised participants (Category B). Confirmed SARS-CoV-2 infection as determined by Reverse transcription polymerase chain reaction (RT-PCR) or acceptable test method performed by a health care provider in any specimen collected within 48 hours prior to randomization. Hospitalized for inpatient care for the treatment of clinical manifestations of severe COVID-19. Requirement for oxygen supplementation (via nasal cannula, mask, non-invasive ventilation [NIV] or high flow oxygen) to maintain SpO2 ≥94% at the time of Screening and Randomization. Exclusion Criteria: Critical illness, defined by ≥1 of the following: Requirement for mechanical ventilation or extracorporeal membrane oxygenation (ECMO) at randomization, or likely to require intermittent mandatory ventilation (IMV) or ECMO within 12 hours of randomization . Multi-organ dysfunction/failure. Hemodynamically unstable, eg. septic shock, cardiac failure or requiring vasopressors. Participant not expected to survive 24 hours from time of randomization. History of severe chronic liver disease Receiving dialysis of any kind or severe renal impairment Use of nirmatrelvir/ritonavir as an outpatient to treat the current COVID-19 related illness ≤7 days of randomization

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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nirmatrelvir/ritonavir<br>Participants will receive nirmatrelvir/ ritonavir 300 mg/100 mg (or 150 mg/100 mg for participants with estimated glomerular filtration rate (eGFR) or estimated creatinine clearance (eCrCl) ≥30 to <60 mL/min) every 12 hours from Day 1 through Day 15 | Drug: Nirmatrelvir<br>* Participants will receive 2 tablets of nirmatrelvir (or 1 tablet for participants with eGFR or eCrCl ≥30 to <60 mL/min) every 12 hours<br>* Other names: Paxlovid;Drug: Ritonavir<br>* Participants will receive 1 capsule of ritonavir every 12 hours<br>* Other names: Norvir;|
| Experimental: Placebo/ritonavir<br>Participants will receive placebo 0 mg/ritonavir 100 mg every 12 hours for 15 days. | Drug: Ritonavir<br>* Participants will receive 1 capsule of ritonavir every 12 hours<br>* Other names: Norvir;Drug: Placebo for nirmatrelvir<br>* Participants will receive 2 tablets of placebo for nirmatrelvir (or 1 tablet for participants with eGFR or eCrCl ≥30 to <60 mL/min) 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 |
| --- | --- | --- |
| Change from baseline in SARS-CoV-2 RNA level in nasopharyngeal (NP) swabs | Evaluate effect of nirmatrelvir/ritonavir compared to placebo/ritonavir on SARS-CoV-2 viral RNA levels in NP swabs in hospitalized participants. | Day 1 through Day 5 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to sustained clinical recovery. | Evaluate effect of nirmatrelvir/ritonavir compared to placebo/ritonavir treatment on clinical outcomes when added to background usual care, for the treatment of severe COVID-19 in hospitalized participants. Time to sustained clinical recovery is defined as the first day during the 30 days after randomization in which a participant attains a score of 1, 2, or 3 on the 8-point ordinal scale (ie, remains alive and is either not hospitalized or is hospitalized but no longer requires ongoing inpatient medical care for COVID-19) for at least 7 consecutive days. | Day 1 through Day 30 | 
| Proportion of participants with death from any cause or initiation of invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO) | Evaluate effect of nirmatrelvir/ritonavir compared to placebo/ritonavir treatment on clinical outcomes when added to background usual care, for the treatment of severe COVID-19 in hospitalized participants. | Day 1 through Day 30 | 
| Proportion of participants with SARS-CoV-2 RNA <Lower Limit of Quantitation (<LLOQ) (defined as <2.0 log10 copies/mL) in NP swabs | Evaluate effect of nirmatrelvir/ritonavir compared to placebo/ritonavir on SARS-CoV-2 viral RNA levels in NP swabs in hospitalized participants. | Day 1 through Day 15 | 
| Proportion of participants with sustained NP swab SARS-CoV-2 RNA <LLOQ (defined as <2.0 log10 copies/mL) | To evaluate the effect of nirmatrelvir/ritonavir compared to placebo/ritonavir on SARS-CoV-2 viral RNA levels in NP swabs in hospitalized participants. | Day 15 through Day 45 | 
| Incidence of Treatment-Related Adverse Events (TEAEs) | To describe the safety and tolerability of nirmatrelvir/ritonavir relative to placebo/ritonavir for the treatment of severe COVID-19 in hospitalized participants. | Day 1 through Day 45 | 
| Incidence of Adverse Events (AEs) or Serious Adverse Events (SAEs) leading to discontinuations | To describe the safety and tolerability of nirmatrelvir/ritonavir relative to placebo/ritonavir for the treatment of severe COVID-19 in hospitalized participants. | Day 1 through Day 45 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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COVID-19, Respiratory Tract Infections, Infections, Pneumonia, Viral, Pneumonia, Virus Diseases, Coronavirus Infections, Coronaviridae Infections, Nidovirales Infections, Ribonucleic acid (RNA) virus Infections, Lung Diseases, Respiratory Tract Diseases, Ritonavir, HIV Protease Inhibitors, Viral Protease Inhibitors, Protease Inhibitors, Enzyme Inhibitors, Molecular Mechanisms, Pharmacological Action, Anti-human immunodeficiency virus (HIV) Agents, Anti-Retroviral Agents, Antiviral Agents, Anti-Infective Agents, Cytochrome P-450 CYP3A Inhibitors, Cytochrome P-450 Enzyme Inhibitors, Paxlovid, Nirmatrelvir