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

• ClinicalTrials.gov Identifier: NCT04575597
• Recruitment Status: Completed
• First Posted: October 5, 2020
• Last Update Posted: March 24, 2023
• Sponsor: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): Merck Sharp & Dohme LLC

Tracking Information

• First Submitted Date: September 30, 2020
• First Posted Date: October 5, 2020
• Last Update Posted Date: March 24, 2023
• Actual Study Start Date: October 19, 2020
• Actual Primary Completion Date: May 5, 2022 (Final data collection date for primary outcome measure)

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

• Percentage of participants who are hospitalized and/or die [ Time Frame: Up to 29 days ]
  Hospitalization (all cause) is ≥24 hours of acute care in a hospital or similar acute care facility. Death is due to any cause.
• 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)

• Percentage of participants who are hospitalized and/or die [ Time Frame: Up to 29 days ]
  Hospitalization (all cause) is ≥24 hours of acute care in a hospital or similar acute care facility. Death is due to any cause.
• 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: December 22, 2020)

• Time to sustained resolution or improvement of each targeted COVID-19 sign/symptom [ Time Frame: Up to 29 days ]
  The number of days from randomization to the first day on or before study Day 29 for sustained resolution or improvement of each sign/symptom will be assessed.
• Time to progression of each targeted COVID-19 sign/symptom [ Time Frame: Up to 29 days ]
  The number of days from randomization to the first day on or before study Day 29 for each targeted self-reported sign/symptom will be assessed.
• 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 (submitted: October 2, 2020)

• Time to improvement or resolution of targeted COVID-19 signs/symptoms [ Time Frame: Up to 29 days ]
  The number of days from randomization to the first day on or before study Day 29 by which the targeted self-reported signs/symptoms improve or resolve.
• Time to progression of targeted COVID-19 signs/symptoms [ Time Frame: Up to 29 days ]
  The number of days from randomization to the first day on or before study Day 29 by which the targeted self-reported signs/symptoms are newly reported or worsen.
• 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.

• 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 Non-Hospitalized Adult Participants With COVID-19 (MK-4482-002)
• Official Title: 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.
• 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 percentage of participants who are hospitalized and/or die 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)
  Other Name: MK-4482
• 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 800 mg
  800 mg 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 *

• Caraco Y, Crofoot GE, Moncada PA, Galustyan AN, Musungaie DB, Payne B, Kovalchuk E, Gonzalez A, Brown ML, Williams-Diaz A, Gao W, Strizki JM, Grobler J, Du J, Assaid CA, Paschke A, Butterton JR, Johnson MG, De Anda C, for the MOVe-OUT Study Group. Phase 2/3 Trial of Molnupiravir for Treatment of Covid-19 in Nonhospitalized Adults.NEJM Evid 2021;1(2). DOI: 10.1056/EVIDoa2100043. Published December 16, 2021. https://evidence.nejm.org/doi/full/10.1056/EVIDoa2100043
• Johnson MG, Puenpatom A, Moncada PA, Burgess L, Duke ER, Ohmagari N, Wolf T, Bassetti M, Bhagani S, Ghosn J, Zhang Y, Wan H, Williams-Diaz A, Brown ML, Paschke A, De Anda C. Effect of Molnupiravir on Biomarkers, Respiratory Interventions, and Medical Services in COVID-19 : A Randomized, Placebo-Controlled Trial. Ann Intern Med. 2022 Aug;175(8):1126-1134. doi: 10.7326/M22-0729. Epub 2022 Jun 7.
• Jayk Bernal A, Gomes da Silva MM, Musungaie DB, Kovalchuk E, Gonzalez A, Delos Reyes V, Martin-Quiros A, Caraco Y, Williams-Diaz A, Brown ML, Du J, Pedley A, Assaid C, Strizki J, Grobler JA, Shamsuddin HH, Tipping R, Wan H, Paschke A, Butterton JR, Johnson MG, De Anda C; MOVe-OUT Study Group. Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients. N Engl J Med. 2022 Feb 10;386(6):509-520. doi: 10.1056/NEJMoa2116044. Epub 2021 Dec 16.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 23, 2023): 1735
• Original Estimated Enrollment (submitted: October 2, 2020): 1450
• Actual Study Completion Date: May 5, 2022
• Actual Primary Completion Date: May 5, 2022 (Final data collection date for primary outcome measure)

Eligibility Criteria

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.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Argentina, Brazil, Canada, Chile, Colombia, Egypt, France, Germany, Guatemala, Israel, Italy, Japan, Mexico, Philippines, Poland, Russian Federation, South Africa, Spain, Sweden, Taiwan, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT04575597
• Other Study ID Numbers: 4482-002; MK-4482-002 ( Other Identifier: Merck ); PHRR201209-003186 ( Registry Identifier: PHRR ); jRCT2031210148 ( Registry Identifier: jRCT ); 2020-003368-24 ( EudraCT Number )
• 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

• Current Responsible Party: Merck Sharp & Dohme LLC
• Original Responsible Party: Same as current
• Current Study Sponsor: Merck Sharp & Dohme LLC
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Medical Director; Merck Sharp & Dohme LLC

• PRS Account: Merck Sharp & Dohme LLC
• Verification Date: March 2023