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

• ClinicalTrials.gov Identifier: NCT04575584
• Recruitment Status: Recruiting
• First Posted: October 5, 2020
• Last Update Posted: April 2, 2021
• Sponsor: Merck Sharp & Dohme Corp.
• Information provided by (Responsible Party): Merck Sharp & Dohme Corp.

Tracking Information

• First Submitted Date: September 30, 2020
• First Posted Date: October 5, 2020
• Last Update Posted Date: April 2, 2021
• Actual Study Start Date: October 19, 2020
• Estimated Primary Completion Date: June 27, 2021 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: December 22, 2020)

• Time-to-sustained recovery [ Time Frame: Up to 29 days ]
  Sustained recovery is defined as: the participant is alive and not hospitalized; or the participant is alive and medically ready for discharge as determined by the investigator.
• Percentage of participants with an adverse event (AE) [ Time Frame: Up to 7 months ]
  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.
• Percentage of participants who discontinued study intervention due to an AE [ Time Frame: Up to 6 days ]
  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.

Original Primary Outcome Measures (submitted: October 2, 2020)

• Time-to-sustained recovery [ Time Frame: Up to 29 days ]
  Sustained recovery is defined as: the participant is alive and not hospitalized; or the participant is alive and medically ready for discharge as determined by the investigator.
• Percentage of participants with an adverse event (AE) [ Time Frame: Up to 19 days ]
  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.
• Percentage of participants who discontinued study intervention due to an AE [ Time Frame: Up to 6 days ]
  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.

Current Secondary Outcome Measures (submitted: October 2, 2020)

• Percentage of participants with all-cause mortality [ Time Frame: Up to 29 days ]
  All-cause mortality is death due to any cause
• Pulmonary score on a scale [ Time Frame: Up to 29 days ]
  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 to 7 with a higher score indicating more severe respiratory sequalae.
• Pulmonary+ score on a scale [ Time Frame: Up to 29 days ]
  Pulmonary+ score is a score on an ordinal scale which is a 7-category assessment that captures the range of disease severity, including coagulation-related complications and respiratory dysfunction. The score ranges from 1 to 7 with a higher score indicating more severe sequalae.
• National Early Warning Score on a scale [ Time Frame: End of Treatment (EOT) (Up to 6 days) ]
  The National Early Warning Score assesses a participant's degree of illness as assessed by clinical risk prediction categories for poor clinical outcomes including mortality within 24 hours of a set of vital sign measurements. There are 7 physiological parameters, of which 6 are assigned a point value ranging from 0 to 3, and 1 is assigned a point value ranging from 0 to 2. The total aggregate score may range from 0 to 20 with an increasing aggregate score indicating increasing clinical risk.
• WHO 11-point outcomes score on a scale [ Time Frame: Up to 29 days ]
  The World Health Organization (WHO) outcome scale is an 11-point ordinal score that categorizes clinical progression. Score ranges from 0 to 10 with higher score indicating clinical progression.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Efficacy and Safety of Molnupiravir (MK-4482) in Hospitalized Adult Participants With COVID-19 (MK-4482-001)
• Official Title: 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
• 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: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2; Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Double (Participant, Investigator); Primary Purpose: Treatment
• Condition: Coronavirus Disease (COVID-19)

Intervention

• Drug: Molnupiravir
  Molnupiravir administered orally in capsule form every 12 hours for 5 days (10 doses total)
• Drug: Placebo
  Placebo matching molnupiravir administered orally in capsule form every 12 hours for 5 days (10 doses total)

Study Arms

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

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 2, 2020): 1300
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: December 30, 2021
• Estimated Primary Completion Date: June 27, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Toll Free Number; 1-888-577-8839; Trialsites@merck.com

• Listed Location Countries: Brazil, Canada, Chile, Colombia, France, Israel, Italy, Korea, Republic of, Mexico, Philippines, Poland, Russian Federation, South Africa, Spain, Ukraine, United Kingdom, United States
• Removed Location Countries: Japan

Administrative Information

• NCT Number: NCT04575584
• Other Study ID Numbers: 4482-001; 2020-003367-26 ( EudraCT Number ); MK-4482-001 ( Other Identifier: Merck ); PHRR201210-003189 ( Registry Identifier: PHRR ); jRCT2031200404 ( Registry Identifier: jRCT )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf
• URL: http://engagezone.msd.com/ds_documentation.php

• Responsible Party: Merck Sharp & Dohme Corp.
• Study Sponsor: Merck Sharp & Dohme Corp.
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme Corp.

• PRS Account: Merck Sharp & Dohme Corp.
• Verification Date: March 2021