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

Phase 2

Terminated

Conditions: Coronavirus Disease (COVID-19)

Interventions: Drug: Molnupiravir
Drug: Placebo

Registration Number: NCT04575584

Lead Sponsor: Merck Sharp & Dohme LLC

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 304

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

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part 1: Molnupiravir 200 mg	Molnupiravir	200 mg molnupiravir administered orally every 12 hours for 5 days (10 doses total)
Part 1: Molnupiravir 400 mg	Molnupiravir	400 mg molnupiravir administered orally every 12 hours for 5 days (10 doses total)
Part 1: Molnupiravir 800 mg	Molnupiravir	800 mg molnupiravir administered orally every 12 hours for 5 days (10 doses total)
Part 1: Placebo	Placebo	Placebo matching molnupiravir administered orally every 12 hours for 5 days (10 doses total)
Part 2: Molnupiravir	Molnupiravir	Molnupiravir (dose to be selected) administered orally every 12 hours for 5 days (10 doses total)
Part 2: Placebo	Placebo	Placebo matching molnupiravir administered orally every 12 hours for 5 days (10 doses total)

Primary Outcome Measures

Name	Time	Method
Time-to-sustained Recovery	Up to 29 days	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.
Number of Participants With an Adverse Event (AE)	Up to 19 days (during treatment and 14-day follow-up)	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.
Number of Participants Who Discontinued Study Intervention Due to an AE	Up to 5 days	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.

Secondary Outcome Measures

Name	Time	Method
Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 29	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.
Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 3	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.
Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 10	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.
Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 15	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.
Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 29	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.
Odds of a More Favorable Response in the Clinical Risk of Mortality Category From the National Early Warning Score	EOT (Day 5)	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.
Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on Day 3	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.
Number of Participants With All-cause Mortality	Up to 29 days	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.
Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 3	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.
Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on End of Treatment (EOT [Day 5])	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.
Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 10	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.
Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 15	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.
Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on EOT (Day 5)	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.
Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on EOT (Day 5)	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.
Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on Day 10	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.
Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on Day 15	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.
Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on Day 29	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.

Trial Locations

Locations (89): Kaiser Foundation Hospital - South Bay ( Site 1832)
🇺🇸
Harbor City, California, United States
Cedars-Sinai Medical Center ( Site 1822)
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Los Angeles, California, United States
University of California Davis Health ( Site 1809)
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Sacramento, California, United States
University Of Florida ( Site 1810)
🇺🇸
Gainesville, Florida, United States
Wellstar Kennestone Hospital ( Site 1801)
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Marietta, Georgia, United States
Loretto Hospital ( Site 1838)
🇺🇸
Chicago, Illinois, United States
LSU-HSC Shreveport ( Site 1824)
🇺🇸
Shreveport, Louisiana, United States
Henry Ford Health System ( Site 1821)
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Detroit, Michigan, United States
University of Mississippi Medical Center ( Site 1846)
🇺🇸
Jackson, Mississippi, United States
University of Nebraska Medical Center ( Site 1835)
🇺🇸
Omaha, Nebraska, United States
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Kaiser Foundation Hospital - South Bay ( Site 1832)
🇺🇸Harbor City, California, United States