EPIC-HR: Study of Oral PF-07321332/Ritonavir Compared With Placebo in Nonhospitalized High Risk Adults With COVID-19

Study Overview
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Brief Summary
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The purpose of this study is to determine whether PF-07321332/ritonavir is safe and effective for the treatment of adults who are ill with COVID-19 and do not need to be in the hospital, but are at an increased risk of developing severe illness. Throughout the study period, provision will be made to allow study visits to be conducted at a participant's home or another non-clinic location if available. The total study duration is up to 24 weeks.

Official Title
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AN INTERVENTIONAL EFFICACY AND SAFETY, PHASE 2/3, DOUBLE-BLIND, 2-ARM STUDY TO INVESTIGATE ORALLY ADMINISTERED PF-07321332/RITONAVIR COMPARED WITH PLACEBO IN NONHOSPITALIZED SYMPTOMATIC ADULT PARTICIPANTS WITH COVID-19 WHO ARE AT INCREASED RISK OF PROGRESSING TO SEVERE ILLNESS

Conditions
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COVID-19

Intervention / Treatment
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* Drug: PF-07321332
* Drug: Ritonavir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Confirmed SARS-CoV-2 infection within 5 days prior to randomization Initial onset of COVID-19 signs/symptoms within 5 days prior to the day of randomization and at least 1 of the specified COVID-19 signs/symptoms present on the day of randomization Fertile participants must agree to use a highly effective method of contraception Has at least 1 characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19 Exclusion Criteria: History of or need for hospitalization for the medical treatment of COVID-19 Prior to current disease episode, any confirmed SARS-CoV-2 infection Known medical history of active liver disease Receiving dialysis or have known moderate to severe renal impairment Known human immunodeficiency virus (HIV) infection with a viral load greater than 400 copies/mL or taking prohibited medications for HIV treatment Suspected or confirmed concurrent active systemic infection other than COVID-19 History of hypersensitivity or other contraindication to any of the components of the study intervention Current or expected use of any medications or substances that are highly dependent on CYP3A4 for clearance or are strong inducers of CYP3A4 Has received or is expected to receive convalescent COVID-19 plasma Has received or is expected to receive any dose of a SARS-CoV-2 vaccine before the Day 34 visit Participating in another interventional clinical study with an investigational compound or device, including those for COVID-19 through the long-term follow-up visit Known prior participation in this trial or other trial involving PF-07321332 Oxygen saturation of <92% on room air, or on their standard home oxygen supplementation for those who regularly receive chronic supplementary oxygen for an underlying lung condition Females who are pregnant or breastfeeding

Ages Eligible for Study
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Minimum Age: 18 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
Interventional Model Description: Eligible participants with a confirmed diagnosis of SARS-CoV-2 infection will be randomized (1:1) to receive PF-07321332/ritonavir or placebo orally every 12 hours for 5 days (10 doses total).
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-07321332/ritonavir<br>Orally administered PF-07321332+ritonavir | Drug: PF-07321332<br>* PF-07321332 (tablet)<br>Drug: Ritonavir<br>* Ritonavir (capsule)<br>|
| Placebo Comparator: Placebo<br>Orally administered placebo | Drug: Placebo<br>* Placebo (tablet or capsule)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Covid-19 Related Hospitalization or Death From Any Cause Through Day 28- Modified Intent-To-Treat (mITT) Population | Percentage of participants with COVID-19 related hospitalization or death from any cause during the first 28 days of the study was estimated using the Kaplan-Meier (KM) method. Using KM method, survival probability for each time interval was calculated as the number of participants surviving divided by the number of participants at risk. Participants who had the event, dropped out, or moved out were not counted as at risk i.e., participants who were lost were considered censored and were not counted in the denominator. | From Day 1 to Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a participant, temporarily associated with the use of study intervention, whether or not considered related to the study intervention. Serious adverse event (SAE) was any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/ incapacity; congenital anomaly/birth defect; a suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic and other important medical events. AEs included both SAEs and all non-SAEs. An AE was considered as TEAE if the event started on or after start date of study intervention. | From start of study intervention (Day 1) up to end of safety follow-up (Day 34) | 
| Number of Participants With AEs Leading to Discontinuation and Serious Adverse Events (SAEs) | An AE was any untoward medical occurrence in a participant, temporarily associated with the use of study treatment, whether or not considered related to the study treatment. An SAE was any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/ incapacity; congenital anomaly/birth defect; a suspected transmission via a Pfizer product of an infectious agent, pathogenic or non-pathogenic and other important medical events. | From start of study intervention (Day 1) up to end of safety follow-up (Day 34) | 
| Percentage of Participants With Covid-19 Related Hospitalization or Death From Any Cause Through Day 28- Modified Intent-To-Treat 1 (mITT1) Population | Percentage of participants with COVID-19 related hospitalization or death from any cause during the first 28 days of the study was estimated using the Kaplan-Meier method. | From Day 1 to Day 28 | 
| Time to Sustained Alleviation of All Targeted COVID-19 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 4 consecutive days when all symptoms scored as moderate or severe at the time of enrollment were scored as mild or absent and those scored mild or absent at the time of enrollment were scored as absent. The first day of the 4 consecutive-day period was considered date of first event. Time to sustained alleviation (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained alleviation (censored), time was calculated as censoring date (last date on which symptom alleviation was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Time to Sustained Alleviation of All Targeted COVID-19 Signs and Symptoms Through Day 28- mITT1 Population | Sustained alleviation of all targeted COVID-19 signs/symptoms was defined as the event occurring on the first 4 consecutive days when all symptoms scored as moderate or severe at the time of enrollment were scored as mild or absent and those scored mild or absent at the time of enrollment were scored as absent. The first day of the 4 consecutive-day period was considered date of first event. Time to sustained alleviation (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained alleviation (censored), time was calculated as censoring date (last date on which symptom alleviation was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Time to Sustained Alleviation of All Targeted COVID-19 Signs and Symptoms Through Day 28- Modified Intent-to-Treat 2 (mITT2) Population | Sustained alleviation of all targeted COVID-19 signs/symptoms was defined as the event occurring on the first 4 consecutive days when all symptoms scored as moderate or severe at the time of enrollment were scored as mild or absent and those scored mild or absent at the time of enrollment were scored as absent. The first day of the 4 consecutive-day period was considered date of first event. Time to sustained alleviation (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained alleviation (censored), time was calculated as censoring date (last date on which symptom alleviation was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Percentage of Participants With Severe Covid-19 Signs and Symptoms Through Day 28- mITT Population | Participants were required to record the severity of their Covid-19 symptoms over the past 24 hours daily on a 4-point scale ranging from 0 to 3, higher scores indicated more severity. The scale was reported as 0= no symptoms, 1=mild, 2=moderate and 3=severe. A participant with severe score for any targeted symptoms post-baseline was counted as severe. Percentage of participants with severe Covid-19 signs and symptoms were reported. | From Day 1 to Day 28 | 
| Percentage of Participants With Severe Covid-19 Signs and Symptoms Through Day 28- mITT1 Population | Participants were required to record the severity of their Covid-19 symptoms over the past 24 hours daily on a 4-point scale ranging from 0 to 3, higher scores indicated more severity. The scale was reported as 0= no symptoms, 1=mild, 2=moderate and 3=severe. A participant with severe score for any targeted symptoms post-baseline was counted as severe. Percentage of participants with severe Covid-19 signs and symptoms were reported. | From Day 1 to Day 28 | 
| Percentage of Participants With Severe Covid-19 Signs and Symptoms Through Day 28- mITT2 Population | Participants were required to record the severity of their Covid-19 symptoms over the past 24 hours daily on a 4-point scale ranging from 0 to 3, higher scores indicated more severity. The scale was reported as 0= no symptoms, 1=mild, 2=moderate and 3=severe. A participant with severe score for any targeted symptoms post-baseline was counted as severe. Percentage of participants with severe Covid-19 signs and symptoms were reported. | From Day 1 to Day 28 | 
| Time to Sustained Resolution of All Targeted COVID-19 Signs and Symptoms Through Day 28- mITT Population | Sustained resolution was defined as when all targeted symptoms were scored as absent for 4 consecutive days. Time to sustained resolution (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained resolution (censored), time was calculated as censoring date (last date on which symptom resolution was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Time to Sustained Resolution of All Targeted COVID-19 Signs and Symptoms Through Day 28- mITT1 Population | Sustained resolution was defined as when all targeted symptoms were scored as absent for 4 consecutive days. Time to sustained resolution (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained resolution (censored), time was calculated as censoring date (last date on which symptom resolution was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Time to Sustained Resolution of All Targeted COVID-19 Signs and Symptoms Through Day 28- mITT2 Population | Sustained resolution was defined as when all targeted symptoms were scored as absent for 4 consecutive days. Time to sustained resolution (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained resolution (censored), time was calculated as censoring date (last date on which symptom resolution was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Time to Sustained Alleviation of Each Targeted COVID-19 Signs and Symptoms- mITT Population | Sustained alleviation of each targeted COVID-19 signs/symptoms was defined as the event occurring on the first 4 consecutive days when each symptom scored as moderate or severe at the time of enrollment were scored as mild or absent and those scored mild or absent at the time of enrollment were scored as absent. The first day of the 4 consecutive-day period was considered date of first event. Time to sustained alleviation (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained alleviation (censored), time was calculated as censoring date (last date on which symptom alleviation was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Time to Sustained Alleviation of Each Targeted COVID-19 Signs and Symptoms- mITT1 Population | Sustained alleviation of each targeted COVID-19 signs/symptoms was defined as the event occurring on the first 4 consecutive days when each symptom scored as moderate or severe at the time of enrollment were scored as mild or absent and those scored mild or absent at the time of enrollment were scored as absent. The first day of the 4 consecutive-day period was considered date of first event. Time to sustained alleviation (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained alleviation (censored), time was calculated as censoring date (last date on which symptom alleviation was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Time to Sustained Alleviation of Each Targeted COVID-19 Signs and Symptoms- mITT2 Population | Sustained alleviation of each targeted COVID-19 signs/symptoms was defined as the event occurring on the first 4 consecutive days when each symptom scored as moderate or severe at the time of enrollment were scored as mild or absent and those scored mild or absent at the time of enrollment were scored as absent. The first day of the 4 consecutive-day period was considered date of first event. Time to sustained alleviation (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained alleviation (censored), time was calculated as censoring date (last date on which symptom alleviation was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Time to Sustained Resolution of Each Targeted COVID-19 Signs and Symptoms- mITT Population | Sustained resolution was defined as when each targeted symptom was scored as absent for 4 consecutive days. Time to sustained resolution (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained resolution (censored), time was calculated as censoring date (last date on which symptom resolution was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Time to Sustained Resolution of Each Targeted COVID-19 Signs and Symptoms- mITT1 Population | Sustained resolution was defined as when each targeted symptom was scored as absent for 4 consecutive days. Time to sustained resolution (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained resolution (censored), time was calculated as censoring date (last date on which symptom resolution was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Time to Sustained Resolution of Each Targeted COVID-19 Signs and Symptoms- mITT2 Population | Sustained resolution was defined as when each targeted symptom was scored as absent for 4 consecutive days. Time to sustained resolution (event) was calculated as first event date minus first dose date plus 1, for participants with event. For participants who completed Day 28 or discontinued the study before Day 28 without sustained resolution (censored), time was calculated as censoring date (last date on which symptom resolution was assessed) minus first dose date plus 1 or Day 25 whichever occurred first. | From Day 1 (baseline) to Day 28 | 
| Number of Participants With Progression to a Worsening Status in 1 or More Self-reported COVID-19 Associated Symptoms Through Day 28-mITT Population | Participants were required to record the severity of their Covid-19 symptoms over the past 24 hours daily on a 4-point scale where 0 = no symptoms; 1= mild; 2= moderate; and 3= severe. Vomiting and diarrhea were each rated on a 4-point frequency scale where 0= no occurrence, 1= mild for 1 to 2 times, 2= moderate for 3 to 4 times, and 3= severe for 5 or greater. Progression to a worsening status for any targeted symptom was based up on increasing severity (i.e. the first time any targeted symptoms worsened after treatment relative to baseline). | From Day 1 (baseline) to Day 28 | 
| Number of Participants With Progression to a Worsening Status in 1 or More Self-reported COVID-19 Associated Symptoms Through Day 28-mITT1 Population | Participants were required to record the severity of their Covid-19 symptoms over the past 24 hours daily on a 4-point scale where 0 = no symptoms; 1= mild; 2= moderate; and 3= severe. Vomiting and diarrhea were each rated on a 4-point frequency scale where 0= no occurrence, 1= mild for 1 to 2 times, 2= moderate for 3 to 4 times, and 3= severe for 5 or greater. Progression to a worsening status for any targeted symptom was based up on increasing severity (i.e. the first time any targeted symptoms worsened after treatment relative to baseline). | From Day 1 (baseline) to Day 28 | 
| Number of Participants With Progression to a Worsening Status in 1 or More Self-reported COVID-19 Associated Symptoms Through Day 28-mITT2 Population | Participants were required to record the severity of their Covid-19 symptoms over the past 24 hours daily on a 4-point scale where 0 = no symptoms; 1= mild; 2= moderate; and 3= severe. Vomiting and diarrhea were each rated on a 4-point frequency scale where 0= no occurrence, 1= mild for 1 to 2 times, 2= moderate for 3 to 4 times, and 3= severe for 5 or greater. Progression to a worsening status for any targeted symptom was based up on increasing severity (i.e. the first time any targeted symptoms worsened after treatment relative to baseline). | From Day 1 (baseline) to Day 28 | 
| Percentage of Participants With a Resting Peripheral Oxygen Saturation >=95% at Days 1 and 5- mITT Population | In this outcome measure, the percentage of participants with a resting peripheral oxygen saturation >=95% were reported. | Day 1, 5 | 
| Percentage of Participants With a Resting Peripheral Oxygen Saturation >=95% at Days 1 and 5- mITT1 Population | In this outcome measure, the percentage of participants with a resting peripheral oxygen saturation >=95% were reported. | Day 1, 5 | 
| Percentage of Participants With a Resting Peripheral Oxygen Saturation >=95% at Days 1 and 5- mITT2 Population | In this outcome measure, the percentage of participants with a resting peripheral oxygen saturation >=95% were reported. | Day 1, 5 | 
| Percentage of Participants Who Died Through Week 24- mITT Population | In this outcome measure, percentage of participants with death due to any cause was presented. | From Day 1 up to Week 24 | 
| Percentage of Participants Who Died Through Week 24- mITT1 Population | In this outcome measure, percentage of participants with death due to any cause was presented. | From Day 1 up to Week 24 | 
| Percentage of Participants Who Died Through Week 24- mITT2 Population | In this outcome measure, percentage of participants with death due to any cause was presented. | From Day 1 up to Week 24 | 
| Plasma Concentration Versus Time Summary of PF-07321332 |  | 1 Hour post-dose on Day 1 and pre-dose on Day 5 | 
| Change From Baseline in Logarithm to Base10 (Log10) Transformed Viral Load at Day 3, 5, 10 and 14- mITT Population | The viral load was measured in nasal or nasopharyngeal samples using reverse transcription polymerase chain reaction (RT-PCR). | Baseline, Day 3, 5, 10 and 14 | 
| Change From Baseline in Log10 Transformed Viral Load at Day 3, 5, 10 and 14- mITT1 Population | The viral load was measured in nasal or nasopharyngeal samples using RT-PCR. | Baseline, Day 3, 5, 10 and 14 | 
| Change From Baseline in Log10 Transformed Viral Load at Day 3, 5, 10 and 14- mITT2 Population | The viral load was measured in nasal or nasopharyngeal samples using RT-PCR. | Baseline, Day 3, 5, 10 and 14 | 
| Number of COVID-19 Related Medical Visits- mITT Population | Medical visits included emergency room, practitioner's office, home healthcare services, urgent care, telephone consultation, outpatient infusion center, other, COVID-19-related-hospitalization (intensive care unit [ICU] and non-ICU stays). In this outcome measure, COVID-19-related medical visits of participants were reported. | From Day 1 up to Day 34 | 
| Number of COVID-19 Related Medical Visits- mITT1 Population | Medical visits included emergency room, practitioner's office, home healthcare services, urgent care, telephone consultation, outpatient infusion center, other, COVID-19-related-hospitalization (ICU and non-ICU stays). In this outcome measure, COVID-19-related medical visits of participants were reported. | From Day 1 up to Day 34 | 
| Number of COVID-19 Related Medical Visits- mITT2 Population | Medical visits included emergency room, practitioner's office, home healthcare services, urgent care, telephone consultation, outpatient infusion center, other, COVID-19-related-hospitalization (ICU and non-ICU stays). In this outcome measure, COVID-19-related medical visits of participants were reported. | From Day 1 up to Day 34 | 
| Number of Days in Hospital and ICU for the Treatment of COVID-19- mITT Population |  | From Day 1 up to Day 34 | 
| Number of Days in Hospital and ICU for the Treatment of COVID-19- mITT1 Population |  | From Day 1 up to Day 34 | 
| Number of Days in Hospital and ICU for the Treatment of COVID-19- mITT2 Population |  | From Day 1 up to Day 34 | 

 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)