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

Coronavirus Disease (COVID-19) Clinical Trial

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

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04575584
• Other study ID #: 4482-001
• Secondary ID: MK-4482-001PHRR2
• Status: Terminated
• Phase: Phase 2/Phase 3
• Start date: October 19, 2020
• Est. completion date: August 11, 2021

Study information

• Verified date: January 2023
• Source: Merck Sharp & Dohme LLC
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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 information / eligibility

• Status: Terminated
• Enrollment: 304
• Est. completion date: August 11, 2021
• Est. primary completion date: August 11, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Coronavirus Disease (COVID-19)
• COVID-19

Intervention

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

Locations

Country	Name	City	State
Brazil	Santa Casa de Misericordia de Belo Horizonte ( Site 0100)	Belo Horizonte	Minas Gerais
Brazil	Hospital Tacchini ( Site 0107)	Bento Goncalves	Rio Grande Do Sul
Brazil	Chronos Pesquisa Clínica ( Site 0105)	Brasilia	Distrito Federal
Brazil	Hospital de Clinicas da Universidade Federal do Parana ( Site 0104)	Curitiba	Parana
Brazil	FUNFARME Hospital de Base Centro Integrado de Pesquisa ( Site 0101)	Sao Jose do Rio Preto	Sao Paulo
Canada	University Health Network - Toronto General Hospital ( Site 0201)	Toronto	Ontario
Chile	Hospital Clinico Fusat ( Site 0300)	Rancagua	Libertador General Bernardo O Higgins
Chile	Clinica Universidad de los Andes ( Site 0301)	Santiago	Region M. De Santiago
Chile	Complejo Hospitalario San Jose ( Site 0306)	Santiago	Region M. De Santiago
Chile	Hospital Sotero del Rio [Santiago, Chile] ( Site 0304)	Santiago	Region M. De Santiago
Chile	Servicio de Salud Sur Hospital Lucio Cordova ( Site 0305)	Santiago	Region M. De Santiago
Colombia	Clinica de la Costa Ltda. ( Site 0402)	Barranquilla	Atlantico
Colombia	Hospital Universitario San Ignacio ( Site 0401)	Bogota	Distrito Capital De Bogota
Colombia	Fundacion Cardiovascular de Colombia ( Site 0403)	Bucaramanca	Santander
Colombia	Fundacion Valle del Lili ( Site 0400)	Cali	Valle Del Cauca
Colombia	Hospital Pablo Tobon Uribe ( Site 0404)	Medellin	Antioquia
Colombia	Oncomedica S.A. ( Site 0406)	Monteria	Cordoba
France	Groupe Hospitalier Pellegrin ( Site 0511)	Bordeaux	Gironde
France	CHU Hopital Saint Antoine ( Site 0505)	Paris
France	Hopital Bichat - Claude Bernard ( Site 0503)	Paris
France	Pitie Salpetriere University Hospital-Infectious Disease - Tropical Diseases ( Site 0504)	Paris	Ile-de-France
France	C.H.U. de Toulouse. Hopital de Purpan ( Site 0501)	Toulouse	Midi-Pyrenees
France	Centre Hospitalier de Tourcoing ( Site 0502)	Tourcoing	Nord
Israel	Rambam Medical Center ( Site 2102)	Haifa
Israel	Hadassah Medical Center. Ein Kerem ( Site 2103)	Jerusalem
Israel	Chaim Sheba Medical Center ( Site 2100)	Ramat Gan
Italy	ASST Fatebenefratelli-Ospedale Sacco ( Site 0601)	Milano
Korea, Republic of	Chungnam National University Hospital ( Site 2202)	Daejeon	Taejon-Kwangyokshi
Korea, Republic of	Inha University Hospital ( Site 2204)	Incheon
Korea, Republic of	The Catholic University of Korea Eunpyeong St Mary s Hospital ( Site 2205)	Seoul
Mexico	Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran ( Site 0802)	Ciudad de mexico	Distrito Federal
Mexico	Hospital Civil de Guadalajara Fray Antonio Alcalde ( Site 0800)	Guadalajara	Jalisco
Mexico	Hospital Regional de Alta Especialidad del Bajio ( Site 0807)	Leon	Guanajuato
Mexico	Hospital Universitario Dr. Jose Eleuterio Gonzalez ( Site 0803)	Monterrey	Nuevo Leon
Philippines	University of the Philippines-Philippine General Hospital ( Site 0900)	Manila	National Capital Region
Philippines	Lung Center of the Philippines ( Site 0902)	Quezon City	National Capital Region
Poland	Centrum Medyczne w Lancucie Sp.zo.o. ( Site 1000)	Lancut	Podkarpackie
Poland	Wojewodzki Szpital Specjalistyczny im. dr. Wladyslawa Bieganskiego ( Site 1001)	Lodz-Baluty	Lodzkie
Poland	Samodzielny Publiczny Szpital Kliniczny Nr 1 w Lublinie ( Site 1004)	Lublin	Lubelskie
Poland	Centrum Medyczne Pratia, Mazowiecki Szpital Specjalistyczny, Oddzial Obserwacyjno - Zakazny ( Site 1	Ostroleka	Mazowieckie
Russian Federation	Republican Clinical Infectious Hospital n.a. A.F. Agafonov ( Site 1100)	Kazan	Tatarstan, Respublika
Russian Federation	Krasnogorsk City Hospital Number 1 ( Site 1119)	Krasnogorsk	Moskovskaya Oblast
Russian Federation	City Clinical Hospital #40 ( Site 1109)	Moscow	Moskva
Russian Federation	FSBI Central Hospital with Policlinics ( Site 1105)	Moscow	Moskva
Russian Federation	Moscow Clinical Hospital #52 ( Site 1103)	Moscow	Moskva
Russian Federation	City Hospital #40 ( Site 1113)	Saint Petersburg	Sankt-Peterburg
Russian Federation	City Pokrovskaya hospital ( Site 1116)	Saint-Petersburg	Sankt-Peterburg
Russian Federation	City Clinical Hospital #1 ( Site 1112)	Smolensk	Smolenskaya Oblast
South Africa	IATROS International ( Site 1202)	Bloemfontein	Free State
South Africa	TREAD Research ( Site 1201)	Cape Town	Western Cape
South Africa	Wits Baragwanath Clinical Trial Site ( Site 1204)	Soweto	Gauteng
South Africa	Clinical Projects Research Centre ( Site 1205)	Worcester	Western Cape
Spain	Hospital Clinic ( Site 1304)	Barcelona
Spain	Hospital Universitari Germans Trias i Pujol ( Site 1303)	Barcelona
Spain	Hospital Universitari Vall d Hebron ( Site 1305)	Barcelona	Cataluna
Spain	Hospital Universitario Gregorio Maranon ( Site 1302)	Madrid
Spain	Hospital Universitario La Paz ( Site 1300)	Madrid
Spain	Hospital Universitario Ramon y Cajal ( Site 1301)	Madrid
Ukraine	CNE Central city clinical hospital of Ivano-Frankivsk city council ( Site 1604)	Ivano-Frankivsk	Ivano-Frankivska Oblast
Ukraine	Ivano-Frankivsk Regional Clinical Infectious Diseases Hospital ( Site 1605)	Ivano-Frankivsk	Ivano-Frankivska Oblast
Ukraine	MNE Ivano-Frankivsk Regional Phthisiology-Pulmonology Center ( Site 1603)	Ivano-Frankivsk	Ivano-Frankivska Oblast
Ukraine	CNPE of Kharkiv RC Regional Clinical Infectious Diseases Hospital ( Site 1606)	Kharkiv	Kharkivska Oblast
Ukraine	?ommunal non-com. Institution Oleksandrivska clinical hospital Kyiv ( Site 1600)	Kyiv	Kyivska Oblast
Ukraine	Volyn Regional Clinical Hospital ( Site 1613)	Lutsk	Volynska Oblast
Ukraine	Odesa City Clinical Infectious Hospital ( Site 1611)	Odesa	Odeska Oblast
Ukraine	Communal Non-Commercial Enterprise Central City Hospital ( Site 1615)	Rivne	Rivnenska Oblast
United Kingdom	King's College Hospital ( Site 1705)	London	London, City Of
United Kingdom	Royal Free London NHS Foundation Trust ( Site 1700)	London	London, City Of
United Kingdom	North Manchester General Hospital ( Site 1701)	Manchester
United States	University of New Mexico, Health Sciences Center ( Site 1806)	Albuquerque	New Mexico
United States	Carolinas Medical Center ( Site 1850)	Charlotte	North Carolina
United States	Loretto Hospital ( Site 1838)	Chicago	Illinois
United States	CHRISTUS Institute for Innovation & Advanced Clinical Care ( Site 1864)	Corpus Christi	Texas
United States	Henry Ford Health System ( Site 1821)	Detroit	Michigan
United States	Swedish Medical Center ( Site 1812)	Edmonds	Washington
United States	Sanford Health ( Site 1851)	Fargo	North Dakota
United States	University Of Florida ( Site 1810)	Gainesville	Florida
United States	ECU Adult Specialty Care ( Site 1865)	Greenville	North Carolina
United States	Kaiser Foundation Hospital - South Bay ( Site 1832)	Harbor City	California
United States	Houston Methodist Hospital ( Site 1863)	Houston	Texas
United States	University of Mississippi Medical Center ( Site 1846)	Jackson	Mississippi
United States	Cedars-Sinai Medical Center ( Site 1822)	Los Angeles	California
United States	Wellstar Kennestone Hospital ( Site 1801)	Marietta	Georgia
United States	University of Nebraska Medical Center ( Site 1835)	Omaha	Nebraska
United States	Temple University ( Site 1836)	Philadelphia	Pennsylvania
United States	Valley Medical Center ( Site 1815)	Renton	Washington
United States	University of California Davis Health ( Site 1809)	Sacramento	California
United States	Swedish Medical Center ( Site 1861)	Seattle	Washington
United States	LSU-HSC Shreveport ( Site 1824)	Shreveport	Louisiana

Sponsors (1)

Lead Sponsor	Collaborator
Merck Sharp & Dohme LLC

Countries where clinical trial is conducted

United States,  Brazil,  Canada,  Chile,  Colombia,  France,  Israel,  Italy,  Korea, Republic of,  Mexico,  Philippines,  Poland,  Russian Federation,  South Africa,  Spain,  Ukraine,  United Kingdom, 

References & Publications (1)

Arribas JR, Bhagani S, Lobo SM, Khaertynova I, Mateu L, Fishchuk R, Park WY, Hussein K, Kim SW, Ghosn J, Brown ML, Zhang Y, Gao W, Assaid C, Grobler JA, Strizki J, Vesnesky M, Paschke A, Butterton JR, De Anda C, for the MOVe-IN study group. Randomized Tri

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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)
Primary	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	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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
Secondary	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)
Secondary	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
Secondary	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)
Secondary	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
Secondary	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
Secondary	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