Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19 (MK-4482-001)

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 rate of sustained recovery through Day 29.

Detailed Description
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This study was intended to include two parts: Part 1 was a dose-ranging phase 2 study, and Part 2 was a phase 3 study to evaluate the dose selected in Part 1. However, this study was terminated due to business reasons prior to conducting Part 2. Participants in Part 1 were followed until Month 7.

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 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 polymerase chain reaction (PCR)-confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection with sample collection ≤ 10 days prior to the day of randomization. PCR is the preferred method; however other diagnostic methods are allowed if authorized by use in the country Had initial onset of signs/symptoms attributable to COVID-19 for ≤10 days prior to the day of randomization and ≥1 sign/symptom attributable to COVID-19 present at randomization Requires medical care in the hospital for ongoing clinical manifestations of COVID-19 (not just for public health or quarantine purposes) Has mild, moderate, or severe COVID-19 Is willing and able to take oral medication Males agree to the following during the intervention period and for at least 90 days after the last dose of study intervention: Refrain from donating sperm; and 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 28 days from the start of study intervention; a WOCBP must have a negative highly sensitive pregnancy test (serum test is required) within 24 hours before the first dose of study intervention Exclusion Criteria: Has critical COVID-19 with any of the following: respiratory failure (including endotracheal intubation and mechanical ventilation, oxygen delivered by high-flow nasal cannula (flow rates >20L/min with fraction of delivered oxygen ≥ 0.5), noninvasive positive pressure ventilation, or extracorporeal membrane oxygenation (ECMO)) 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 or cluster of differentiation 4 (CD4) <200 cell/mm^3; chemotherapy required within 6 weeks before randomization; a neutrophilic granulocyte absolute count <500/mm^3; autologous or allogeneic hematopoietic stem cell transplant recipient Has history of Hepatitis B or Hepatitis C infection with any of the following: 1) cirrhosis 2) end-stage liver disease 3) hepatocellular carcinoma 4) aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) > 3 times the upper limit of normal at screening Has a history of acute pancreatitis within 3 months prior to randomization or a history of chronic pancreatitis Is taking or is anticipated to require any prohibited therapies Is unwilling to abstain from participating in another interventional clinical trial through Day 29 with an investigational compound or device, including those for COVID-19 therapeutics Is anticipated to require transfer to a non-study hospital within 72 hours Has a baseline heart rate of < 50 beats per minute at rest Has a platelet count <100,000/μL or received a platelet transfusion in the 5 days prior to randomization 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 who are expected to require mechanical ventilation within 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>|
| 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>|
| 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>|
| 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<br>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>|
| 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 |
| --- | --- | --- |
| Time-to-sustained Recovery | The median time to sustained recovery is reported. Sustained recovery is defined as 1) the participant is alive and not hospitalized; or 2) the participant is alive and medically ready for discharge as determined by the investigator. | 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 19 days (during treatment and 14-day follow-up) | 
| Number of Participants Who Discontinued Study Intervention Due to an AE | The number of participants discontinuing from study treatment 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 |
| --- | --- | --- |
| Number of Participants With All-cause Mortality | The number of participants with all-cause mortality through Day 29 is presented. All-cause mortality is defined as death due to any cause. Any participants with an unknown survival status at Day 29 were imputed as deceased. | Up to 29 days | 
| Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 3 | Pulmonary score is a score on an ordinal scale which focuses on respiratory sequalae based on oxygen requirements using 7 mutually exclusive categories. The score ranges from 1 (can independently undertake personal usual activities with minimal or no symptoms) to 7 (death) with a higher score indicating more severe respiratory sequalae. The number of participants at each score category is presented. | Day 3 | 
| Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on End of Treatment (EOT [Day 5]) | Pulmonary score is a score on an ordinal scale which focuses on respiratory sequalae based on oxygen requirements using 7 mutually exclusive categories. The score ranges from 1 (can independently undertake personal usual activities with minimal or no symptoms) to 7 (death) with a higher score indicating more severe respiratory sequalae. The number of participants at each score category is presented. | EOT (Day 5) | 
| Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 10 | Pulmonary score is a score on an ordinal scale which focuses on respiratory sequalae based on oxygen requirements using 7 mutually exclusive categories. The score ranges from 1 (can independently undertake personal usual activities with minimal or no symptoms) to 7 (death) with a higher score indicating more severe respiratory sequalae. The number of participants at each score category is presented. | Day 10 | 
| Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 15 | Pulmonary score is a score on an ordinal scale which focuses on respiratory sequalae based on oxygen requirements using 7 mutually exclusive categories. The score ranges from 1 (can independently undertake personal usual activities with minimal or no symptoms) to 7 (death) with a higher score indicating more severe respiratory sequalae. The number of participants at each score category is presented. | Day 15 | 
| Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 29 | Pulmonary score is a score on an ordinal scale which focuses on respiratory sequalae based on oxygen requirements using 7 mutually exclusive categories. The score ranges from 1 (can independently undertake personal usual activities with minimal or no symptoms) to 7 (death) with a higher score indicating more severe respiratory sequalae. The number of participants at each score category is presented. | Day 29 | 
| Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 3 | Pulmonary+ score is a score on an ordinal scale which is a 7-category assessment that captures the range of disease severity in hospitalized participants, including coagulation-related complications and respiratory dysfunction. The score ranges from 1 (can independently undertake personal usual activities with minimal or no symptoms) to 7 (death) with a higher score indicating more severe respiratory sequalae. The number of participants at each score category is presented. | Day 3 | 
| Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on EOT (Day 5) | Pulmonary+ score is a score on an ordinal scale which is a 7-category assessment that captures the range of disease severity in hospitalized participants, including coagulation-related complications and respiratory dysfunction. The score ranges from 1 (can independently undertake personal usual activities with minimal or no symptoms) to 7 (death) with a higher score indicating more severe respiratory sequalae. The number of participants at each score category is presented. | EOT (Day 5) | 
| Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 10 | Pulmonary+ score is a score on an ordinal scale which is a 7-category assessment that captures the range of disease severity in hospitalized participants, including coagulation-related complications and respiratory dysfunction. The score ranges from 1 (can independently undertake personal usual activities with minimal or no symptoms) to 7 (death) with a higher score indicating more severe respiratory sequalae. The number of participants at each score category is presented. | Day 10 | 
| Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 15 | Pulmonary+ score is a score on an ordinal scale which is a 7-category assessment that captures the range of disease severity in hospitalized participants, including coagulation-related complications and respiratory dysfunction. The score ranges from 1 (can independently undertake personal usual activities with minimal or no symptoms) to 7 (death) with a higher score indicating more severe respiratory sequalae. The number of participants at each score category is presented. | Day 15 | 
| Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 29 | Pulmonary+ score is a score on an ordinal scale which is a 7-category assessment that captures the range of disease severity in hospitalized participants, including coagulation-related complications and respiratory dysfunction. The score ranges from 1 (can independently undertake personal usual activities with minimal or no symptoms) to 7 (death) with a higher score indicating more severe respiratory sequalae. The number of participants at each score category is presented. | Day 29 | 
| Odds of a More Favorable Response in the Clinical Risk of Mortality Category From the National Early Warning Score | The National Early Warning Score (Royal College of Physicians, 2012) assesses a participant's degree of illness as assessed by clinical risk prediction categories based on a set of vital sign measurements. There are 7 physiological parameters: respiration rate, oxygen saturation, supplemental oxygen, systolic blood pressure, pulse rate, level of consciousness, and temperature. A score of 0 to 3 was allocated to each parameter except supplemental oxygen use (score of 0 [no] or 2 [yes]) and level of consciousness (score of 0 or 3 with 0 = normal health condition and 3 = worst health condition). All scores were summed to get an aggregate score. Aggregate NEWS score ranged from 0 to 19, with higher scores meaning more severity/higher risk: low risk (score 0 to 4); low to medium risk (score of 3 in any individual parameter); medium risk (score 5 to 6); high risk (score 7 to 19). The number of participants at each aggregate risk category is presented. | EOT (Day 5) | 
| Odds of a More Favorable Response 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 | 
| Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on 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) | 
| Odds of a More Favorable Response 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 | 
| Odds of a More Favorable Response 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 | 
| Odds of a More Favorable Response 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 |