Clinical trial NCT04575584: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Coronavirus Disease (COVID-19)
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2020-10-05
Enrollment: 304
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Time-to-sustained Recovery
timeFrame: Up to 29 days
measure: Number of Participants With an Adverse Event (AE)
timeFrame: Up to 19 days (during treatment and 14-day follow-up)
measure: Number of Participants Who Discontinued Study Intervention Due to an AE
timeFrame: Up to 5 days
Secondary outcomes:
measure: Number of Participants With All-cause Mortality
timeFrame: Up to 29 days
measure: Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 3
timeFrame: Day 3
measure: Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on End of Treatment (EOT [Day 5])
timeFrame: EOT (Day 5)
measure: Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 10
timeFrame: Day 10
measure: Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 15
timeFrame: Day 15
measure: Odds of a More Favorable Response on Pulmonary Ordinal Outcome Score on Day 29
timeFrame: Day 29
measure: Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 3
timeFrame: Day 3
measure: Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on EOT (Day 5)
timeFrame: EOT (Day 5)
measure: Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 10
timeFrame: Day 10
measure: Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 15
timeFrame: Day 15
measure: Odds of a More Favorable Response on Pulmonary+ Ordinal Outcome Score on Day 29
timeFrame: Day 29
measure: Odds of a More Favorable Response in the Clinical Risk of Mortality Category From the National Early Warning Score
timeFrame: EOT (Day 5)
measure: Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on Day 3
timeFrame: Day 3
measure: Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on EOT (Day 5)
timeFrame: EOT (Day 5)
measure: Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on Day 10
timeFrame: Day 10
measure: Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on Day 15
timeFrame: Day 15
measure: Odds of a More Favorable Response on WHO 11-point Ordinal Outcomes Score on a Scale on Day 29
timeFrame: Day 29
Other outcomes:
Locations:
city: Harbor City
country: United States
facility: Kaiser Foundation Hospital - South Bay ( Site 1832)
state: California
city: Los Angeles
country: United States
facility: Cedars-Sinai Medical Center ( Site 1822)
state: California
city: Sacramento
country: United States
facility: University of California Davis Health ( Site 1809)
state: California
city: Gainesville
country: United States
facility: University Of Florida ( Site 1810)
state: Florida
city: Marietta
country: United States
facility: Wellstar Kennestone Hospital ( Site 1801)
state: Georgia
city: Chicago
country: United States
facility: Loretto Hospital ( Site 1838)
state: Illinois
city: Shreveport
country: United States
facility: LSU-HSC Shreveport ( Site 1824)
state: Louisiana
city: Detroit
country: United States
facility: Henry Ford Health System ( Site 1821)
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center ( Site 1846)
state: Mississippi
city: Omaha
country: United States
facility: University of Nebraska Medical Center ( Site 1835)
state: Nebraska
city: Albuquerque
country: United States
facility: University of New Mexico, Health Sciences Center ( Site 1806)
state: New Mexico
city: Charlotte
country: United States
facility: Carolinas Medical Center ( Site 1850)
state: North Carolina
city: Greenville
country: United States
facility: ECU Adult Specialty Care ( Site 1865)
state: North Carolina
city: Fargo
country: United States
facility: Sanford Health ( Site 1851)
state: North Dakota
city: Philadelphia
country: United States
facility: Temple University ( Site 1836)
state: Pennsylvania
city: Corpus Christi
country: United States
facility: CHRISTUS Institute for Innovation & Advanced Clinical Care ( Site 1864)
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital ( Site 1863)
state: Texas
city: Edmonds
country: United States
facility: Swedish Medical Center ( Site 1812)
state: Washington
city: Renton
country: United States
facility: Valley Medical Center ( Site 1815)
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center ( Site 1861)
state: Washington
city: Brasilia
country: Brazil
facility: Chronos Pesquisa Clínica ( Site 0105)
state: Distrito Federal
city: Belo Horizonte
country: Brazil
facility: Santa Casa de Misericordia de Belo Horizonte ( Site 0100)
state: Minas Gerais
city: Curitiba
country: Brazil
facility: Hospital de Clinicas da Universidade Federal do Parana ( Site 0104)
state: Parana
city: Bento Goncalves
country: Brazil
facility: Hospital Tacchini ( Site 0107)
state: Rio Grande Do Sul
city: Sao Jose do Rio Preto
country: Brazil
facility: FUNFARME Hospital de Base Centro Integrado de Pesquisa ( Site 0101)
state: Sao Paulo
city: Toronto
country: Canada
facility: University Health Network - Toronto General Hospital ( Site 0201)
state: Ontario
city: Rancagua
country: Chile
facility: Hospital Clinico Fusat ( Site 0300)
state: Libertador General Bernardo O Higgins
city: Santiago
country: Chile
facility: Clinica Universidad de los Andes ( Site 0301)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Hospital Sotero del Rio [Santiago, Chile] ( Site 0304)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Complejo Hospitalario San Jose ( Site 0306)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Servicio de Salud Sur Hospital Lucio Cordova ( Site 0305)
state: Region M. De Santiago
city: Medellin
country: Colombia
facility: Hospital Pablo Tobon Uribe ( Site 0404)
state: Antioquia
city: Barranquilla
country: Colombia
facility: Clinica de la Costa Ltda. ( Site 0402)
state: Atlantico
city: Monteria
country: Colombia
facility: Oncomedica S.A. ( Site 0406)
state: Cordoba
city: Bogota
country: Colombia
facility: Hospital Universitario San Ignacio ( Site 0401)
state: Distrito Capital De Bogota
city: Bucaramanca
country: Colombia
facility: Fundacion Cardiovascular de Colombia ( Site 0403)
state: Santander
city: Cali
country: Colombia
facility: Fundacion Valle del Lili ( Site 0400)
state: Valle Del Cauca
city: Bordeaux
country: France
facility: Groupe Hospitalier Pellegrin ( Site 0511)
state: Gironde
city: Paris
country: France
facility: Pitie Salpetriere University Hospital-Infectious Disease - Tropical Diseases ( Site 0504)
state: Ile-de-France
city: Toulouse
country: France
facility: C.H.U. de Toulouse. Hopital de Purpan ( Site 0501)
state: Midi-Pyrenees
city: Tourcoing
country: France
facility: Centre Hospitalier de Tourcoing ( Site 0502)
state: Nord
city: Paris
country: France
facility: CHU Hopital Saint Antoine ( Site 0505)
city: Paris
country: France
facility: Hopital Bichat - Claude Bernard ( Site 0503)
city: Haifa
country: Israel
facility: Rambam Medical Center ( Site 2102)
city: Jerusalem
country: Israel
facility: Hadassah Medical Center. Ein Kerem ( Site 2103)
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center ( Site 2100)
city: Milano
country: Italy
facility: ASST Fatebenefratelli-Ospedale Sacco ( Site 0601)
city: Daejeon
country: Korea, Republic of
facility: Chungnam National University Hospital ( Site 2202)
state: Taejon-Kwangyokshi
city: Incheon
country: Korea, Republic of
facility: Inha University Hospital ( Site 2204)
city: Seoul
country: Korea, Republic of
facility: The Catholic University of Korea Eunpyeong St Mary s Hospital ( Site 2205)
city: Ciudad de mexico
country: Mexico
facility: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran ( Site 0802)
state: Distrito Federal
city: Leon
country: Mexico
facility: Hospital Regional de Alta Especialidad del Bajio ( Site 0807)
state: Guanajuato
city: Guadalajara
country: Mexico
facility: Hospital Civil de Guadalajara Fray Antonio Alcalde ( Site 0800)
state: Jalisco
city: Monterrey
country: Mexico
facility: Hospital Universitario Dr. Jose Eleuterio Gonzalez ( Site 0803)
state: Nuevo Leon
city: Manila
country: Philippines
facility: University of the Philippines-Philippine General Hospital ( Site 0900)
state: National Capital Region
city: Quezon City
country: Philippines
facility: Lung Center of the Philippines ( Site 0902)
state: National Capital Region
city: Lodz-Baluty
country: Poland
facility: Wojewodzki Szpital Specjalistyczny im. dr. Wladyslawa Bieganskiego ( Site 1001)
state: Lodzkie
city: Lublin
country: Poland
facility: Samodzielny Publiczny Szpital Kliniczny Nr 1 w Lublinie ( Site 1004)
state: Lubelskie
city: Ostroleka
country: Poland
facility: Centrum Medyczne Pratia, Mazowiecki Szpital Specjalistyczny, Oddział Obserwacyjno - Zakaźny ( Site 1
state: Mazowieckie
city: Lancut
country: Poland
facility: Centrum Medyczne w Lancucie Sp.zo.o. ( Site 1000)
state: Podkarpackie
city: Krasnogorsk
country: Russian Federation
facility: Krasnogorsk City Hospital Number 1 ( Site 1119)
state: Moskovskaya Oblast
city: Moscow
country: Russian Federation
facility: City Clinical Hospital #40 ( Site 1109)
state: Moskva
city: Moscow
country: Russian Federation
facility: FSBI Central Hospital with Policlinics ( Site 1105)
state: Moskva
city: Moscow
country: Russian Federation
facility: Moscow Clinical Hospital #52 ( Site 1103)
state: Moskva
city: Saint Petersburg
country: Russian Federation
facility: City Hospital #40 ( Site 1113)
state: Sankt-Peterburg
city: Saint-Petersburg
country: Russian Federation
facility: City Pokrovskaya hospital ( Site 1116)
state: Sankt-Peterburg
city: Smolensk
country: Russian Federation
facility: City Clinical Hospital #1 ( Site 1112)
state: Smolenskaya Oblast
city: Kazan
country: Russian Federation
facility: Republican Clinical Infectious Hospital n.a. A.F. Agafonov ( Site 1100)
state: Tatarstan, Respublika
city: Bloemfontein
country: South Africa
facility: IATROS International ( Site 1202)
state: Free State
city: Soweto
country: South Africa
facility: Wits Baragwanath Clinical Trial Site ( Site 1204)
state: Gauteng
city: Cape Town
country: South Africa
facility: TREAD Research ( Site 1201)
state: Western Cape
city: Worcester
country: South Africa
facility: Clinical Projects Research Centre ( Site 1205)
state: Western Cape
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d Hebron ( Site 1305)
state: Cataluna
city: Barcelona
country: Spain
facility: Hospital Clinic ( Site 1304)
city: Barcelona
country: Spain
facility: Hospital Universitari Germans Trias i Pujol ( Site 1303)
city: Madrid
country: Spain
facility: Hospital Universitario Gregorio Maranon ( Site 1302)
city: Madrid
country: Spain
facility: Hospital Universitario Ramon y Cajal ( Site 1301)
city: Madrid
country: Spain
facility: Hospital Universitario La Paz ( Site 1300)
city: Ivano-Frankivsk
country: Ukraine
facility: Ivano-Frankivsk Regional Clinical Infectious Diseases Hospital ( Site 1605)
state: Ivano-Frankivska Oblast
city: Ivano-Frankivsk
country: Ukraine
facility: CNE Central city clinical hospital of Ivano-Frankivsk city council ( Site 1604)
state: Ivano-Frankivska Oblast
city: Ivano-Frankivsk
country: Ukraine
facility: MNE Ivano-Frankivsk Regional Phthisiology-Pulmonology Center ( Site 1603)
state: Ivano-Frankivska Oblast
city: Kharkiv
country: Ukraine
facility: CNPE of Kharkiv RC Regional Clinical Infectious Diseases Hospital ( Site 1606)
state: Kharkivska Oblast
city: Kyiv
country: Ukraine
facility: Сommunal non-com. Institution Oleksandrivska clinical hospital Kyiv ( Site 1600)
state: Kyivska Oblast
city: Odesa
country: Ukraine
facility: Odesa City Clinical Infectious Hospital ( Site 1611)
state: Odeska Oblast
city: Rivne
country: Ukraine
facility: Communal Non-Commercial Enterprise Central City Hospital ( Site 1615)
state: Rivnenska Oblast
city: Lutsk
country: Ukraine
facility: Volyn Regional Clinical Hospital ( Site 1613)
state: Volynska Oblast
city: London
country: United Kingdom
facility: Royal Free London NHS Foundation Trust ( Site 1700)
state: London, City Of
city: London
country: United Kingdom
facility: King's College Hospital ( Site 1705)
state: London, City Of
city: Manchester
country: United Kingdom
facility: North Manchester General Hospital ( Site 1701)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: 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. Randomized Trial of Molnupiravir or Placebo in Patients Hospitalized with Covid-19. NEJM Evid. 2022 Feb;1(2):EVIDoa2100044. doi: 10.1056/EVIDoa2100044. Epub 2021 Dec 16.