Efficacy and Safety of Molnupiravir (MK-4482) in Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002)

Study Overview
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Brief Summary
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This study aims to evaluate the safety, tolerability and efficacy of molnupiravir (MK-4482) compared to placebo. The primary hypothesis is that molnupiravir is superior to placebo as assessed by the percentage of participants who are hospitalized and/or die through Day 29

Official Title
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A Phase 2/3, Randomized, Placebo-Controlled, Double-Blind Clinical Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of MK-4482 in Non-Hospitalized Adults With COVID-19.

Conditions
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Coronavirus Disease (COVID-19)

Intervention / Treatment
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* Drug: Molnupiravir
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Has documentation of laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with sample collection ≤5 days prior to the day of randomization. PCR is the preferred method; however with evolving approaches to laboratory confirmation of SARS-CoV-2 infection, other molecular or antigen tests that detect viral ribonucleic acid (RNA) or protein are allowed if authorized for use in the country. Serological tests that detect host antibodies generated in response to recent or prior infection are not allowed. Had initial onset of signs/symptoms attributable to COVID-19 for ≤5 days prior to the day of randomization and at least 1 of the following sign/symptom attributable to COVID-19 on the day of randomization. Has mild or moderate COVID-19. Has at least 1 characteristic or underlying medical condition associated with an increased risk of severe illness from COVID-19. Males agree to the following during the intervention period and for at least 4 days after the last dose of study intervention: Either abstain from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent; or must agree to use contraception. Females are not pregnant or breastfeeding, and at least one of the following conditions applies: Is not a woman of child bearing potential (WOCBP); or is a WOCBP and using a contraceptive method that is highly effective (a low user dependency method OR a user dependent method in combination with barrier method), or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis) for at least 4 days after the last dose of study intervention; a WOCBP must have a negative highly sensitive pregnancy test (urine or serum test is required) within 24 hours before the first dose of study intervention. Exclusion Criteria: Is currently hospitalized or is expected to need hospitalization for COVID-19 within 48 hours of randomization. Is on dialysis or has reduced estimated glomerular filtration rate (eGFR) <30 mL/min/1.73m^2 by the Modification of Diet in Renal Disease (MDRD) equation. Has any of the following conditions: human immunodeficiency virus (HIV) with a recent viral load >50 copies/mL (regardless of CD4 count) or an AIDS-defining illness in the past 6 months, participants with HIV may only be enrolled if on a stable antiretroviral therapy regimen; a neutrophilic granulocyte absolute count <500/mm^3. Has a history of hepatitis B virus (HBV) or hepatitis C virus (HCV) with cirrhosis, end-stage liver disease, hepatocellular carcinoma, aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) >3X upper limit of normal at screening. Has a platelet count <100,000/μL or received a platelet transfusion in the 5 days prior to randomization. Is taking or is anticipated to require any prohibited therapies. Is unwilling to abstain from participating in another interventional clinical study through Day 29 with an investigational compound or device, including those for COVID-19 therapeutics. Has hypersensitivity or other contraindication to any of the components of the study interventions as determined by the investigator. Has any condition for which, in the opinion of the investigator, participation would not be in the best interest of the participant or that could prevent, limit, or confound the protocol-specified assessments including but not limited to: participants who are not expected to survive longer than 48 hours after randomization, or participants with a recent history of mechanical ventilation, or participants with conditions that could limit gastrointestinal absorption of capsule contents.

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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part 1: Molnupiravir 200 mg<br>200 mg molnupiravir administered orally every 12 hours for 5 days (10 doses total) | Drug: Molnupiravir<br>* Molnupiravir administered orally in capsule form every 12 hours for 5 days (10 doses total)<br>* Other names: MK-4482;|
| Experimental: Part 1: Molnupiravir 400 mg<br>400 mg molnupiravir administered orally every 12 hours for 5 days (10 doses total) | Drug: Molnupiravir<br>* Molnupiravir administered orally in capsule form every 12 hours for 5 days (10 doses total)<br>* Other names: MK-4482;|
| Experimental: Part 1: Molnupiravir 800 mg<br>800 mg molnupiravir administered orally every 12 hours for 5 days (10 doses total) | Drug: Molnupiravir<br>* Molnupiravir administered orally in capsule form every 12 hours for 5 days (10 doses total)<br>* Other names: MK-4482;|
| Placebo Comparator: Part 1: Placebo<br>Placebo matching molnupiravir administered orally every 12 hours for 5 days (10 doses total) | Drug: Placebo<br>* Placebo matching molnupiravir administered orally in capsule form every 12 hours for 5 days (10 doses total)<br>|
| Experimental: Part 2: Molnupiravir 800 mg<br>800 mg Molnupiravir (dose to be selected) administered orally every 12 hours for 5 days (10 doses total) | Drug: Molnupiravir<br>* Molnupiravir administered orally in capsule form every 12 hours for 5 days (10 doses total)<br>* Other names: MK-4482;|
| Placebo Comparator: Part 2: Placebo<br>Placebo matching molnupiravir administered orally every 12 hours for 5 days (10 doses total) | Drug: Placebo<br>* Placebo matching molnupiravir administered orally in capsule form every 12 hours for 5 days (10 doses total)<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Who Were Hospitalized and/or Died Through Day 29 (Primary Pre-specified Analysis) | The percentage of participants who were hospitalized and/or died through Day 29 is presented. Hospitalization (all cause) is defined as at least 24 hours of acute care in a hospital or similar acute care facility. Death was due to any cause. Any participants with an unknown survival status at Day 29 were treated as failure. The analysis in Part 2 was based on all participants enrolled by the pre-specified futility/early efficacy analysis and was used for demonstration of superiority to placebo for the primary efficacy outcome measure. | Up to 29 days | 
| Number of Participants With an Adverse Event (AE) | The number of participants with at least 1 AE is presented. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to 318 days | 
| Number of Participants Who Discontinued Study Intervention Due to an AE | The number of participants who discontinued study intervention due to an AE is presented. An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. | Up to 5 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Cough | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Sore Throat | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Nasal Congestion | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Rhinorrhea | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Shortness of Breath or Difficulty Breathing | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Muscles or Body Aches | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Fatigue | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Feeling Hot or Feverish | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Chills | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Headache | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Nausea | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Vomiting | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Diarrhea | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Loss of Taste | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Sustained Resolution or Improvement of Each Targeted COVID-19 Sign/Symptom - Loss of Smell | Time to sustained resolution or improvement of the targeted sign/symptom was defined as the number of days from randomization to the first of three consecutive days when resolution or improvement of the targeted sign/symptom was demonstrated and did not worsen by Day 29. The median number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement is presented. Per protocol, participants without the targeted sign/symptom reported at randomization were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Cough | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Sore Throat | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Nasal Congestion | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Rhinorrhea | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Shortness of Breath or Difficulty Breathing | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Muscle or Body Aches | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Fatigue | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Feeling Hot or Feverish | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Chills | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Headache | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Nausea | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Vomiting | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Diarrhea | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Loss of Taste | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Time to Progression of Each Targeted COVID-19 Sign/Symptom - Loss of Smell | Time to progression of the targeted sign/symptom was defined as the number of days from randomization to the first of two consecutive days when the targeted sign/symptom was worsened. The median number of days from randomization to the first day on or before study Day 29 for progression/worsening is presented. Per protocol, participants with symptoms reported at randomization as severe for the targeted sign/symptom were not included in the analysis. | Up to 29 days | 
| Number of Participants With Responses on WHO 11-point Ordinal Outcomes Score on a Scale on Day 3 | The World Health Organization (WHO) outcome scale is an 11-point ordinal score that categorizes clinical progression. Score ranges from 0 (uninfected) to 10 (dead) with higher score indicating clinical progression. The number of participants at each score category is presented. | Day 3 | 
| Number of Participants With Responses on WHO 11-point Ordinal Outcomes Score on a Scale on End of Treatment (EOT [Day 5]) | The World Health Organization (WHO) outcome scale is an 11-point ordinal score that categorizes clinical progression. Score ranges from 0 (uninfected) to 10 (dead) with higher score indicating clinical progression. The number of participants at each score category is presented. | EOT (Day 5) | 
| Number of Participants With Responses on WHO 11-point Ordinal Outcomes Score on a Scale on Day 10 | The World Health Organization (WHO) outcome scale is an 11-point ordinal score that categorizes clinical progression. Score ranges from 0 (uninfected) to 10 (dead) with higher score indicating clinical progression. The number of participants at each score category is presented. | Day 10 | 
| Number of Participants With Responses on WHO 11-point Ordinal Outcomes Score on a Scale on Day 15 | The World Health Organization (WHO) outcome scale is an 11-point ordinal score that categorizes clinical progression. Score ranges from 0 (uninfected) to 10 (dead) with higher score indicating clinical progression. The number of participants at each score category is presented. | Day 15 | 
| Number of Participants With Responses on WHO 11-point Ordinal Outcomes Score on a Scale on Day 29 | The World Health Organization (WHO) outcome scale is an 11-point ordinal score that categorizes clinical progression. Score ranges from 0 (uninfected) to 10 (dead) with higher score indicating clinical progression. The number of participants at each score category is presented. | Day 29 |