Coronavirus Disease (COVID-19)
Conditions
Brief summary
The purpose of the study is to assess if the study medication (molnupiravir, MK-4482) will prevent symptomatic coronavirus disease 2019 (COVID-19) in adults who live with someone with confirmed COVID-19 infection. This is a phase 3, multicenter, randomized, double-blind, placebo-controlled study; half of the study participants will receive molnupiravir twice daily by mouth and the other half will receive a placebo. The primary objectives of the study are to determine if molnupiravir prevents symptomatic COVID-19 disease and to evaluate its safety and tolerability. All participants who develop COVID-19 during the study are still eligible for any COVID-19 treatment recommended by their doctor.
Interventions
DRUGMolnupiravir
Four molnupiravir 200 mg capsules taken by mouth.
DRUGPlacebo
Placebo capsule matched to molnupiravir 200 mg capsules taken by mouth.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
* Lives in a household with an index case where the index case is a person with documented COVID-19 (laboratory-confirmed SARS-CoV-2 infection with symptoms case) and must have 1) a first detectable SARS-CoV-2 test result from a sample collected within ≤5 days prior to randomization of the participant, and 2) at least 1 symptom attributable to COVID-19 (e.g., fever, difficulty breathing) * Does not have confirmed or suspected COVID-19 * Is willing and able to take oral medication * For males, agrees to be abstinent from penile-vaginal intercourse OR agrees to use a highly effective contraceptive method while receiving study drug and for ≥3 months after the last dose of study drug * Is female and not pregnant/breastfeeding and at least one of the following applies during the study and for ≥4 days after: is not a woman of childbearing potential (WOCBP), is a WOCBP and uses highly effective contraception (low user dependency method OR a user dependent hormonal method in combination with a barrier method), or is a WOCBP who is abstinent from heterosexual intercourse
Exclusion criteria
* Has a prior history of laboratory-confirmed SARS-CoV-2 infection (with or without symptoms) within 6 months prior to randomization * Has either of the following: human immunodeficiency virus (HIV) with a recent viral load \>50 copies/mL (regardless of CD4 count) or an acquired immunodeficiency syndrome (AIDS)-defining illness * Has a history of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection with any of the following: cirrhosis, end-stage liver disease, hepatocellular carcinoma; aspartate transaminase (AST) and/or (ALT) \>3x upper limit of normal at screening * 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 with conditions that could limit gastrointestinal absorption of capsule contents * Has received, is taking, or is anticipated to require any prohibited therapies * Has received a COVID-19 vaccination with the first dose ≥7 days prior to randomization * 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 * Is living in a household with \>10 people
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline Nasopharyngeal (NP) Swabs and Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14 | Day 14 | Percentage of participants who had undetectable SARS-CoV-2 in baseline NP swabs and developed COVID-19 (laboratory-confirmed SARS-CoV-2 infection with symptoms) through Day 14 were reported. |
| Percentage of Participants With ≥1 Adverse Event | 29 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 Discontinuing From Study Therapy Due to AE | Up to 5 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants (Regardless of SARS-CoV-2 in Baseline NP Swabs) Who Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14 | Up to Day 14 | Participants who experienced targeted symptoms of COVID-19 (e.g., cough, sore throat) and had NP swabs tested for SARS-CoV-2 using reverse-transcription polymerase chain reaction (RT-PCR).Efficacy analysis was conducted on the mITT (modified intent to treat) population consisting of all randomized participants who received at least 1 dose of study intervention. |
| Percentage of Participants Who Had Detectable SARS-CoV-2 in Baseline NP Swabs and Developed COVID-19 (Laboratory-confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14 | Up to Day 14 | Participants who experienced targeted symptoms of COVID-19 (e.g., cough, sore throat) and had NP swabs tested for SARS-CoV-2 using RT-PCR. Efficacy analysis was conducted on the mITT (modified intent to treat) population consisting of all randomized participants who received at least 1 dose of study intervention. |
| Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline NP Swabs and Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 29 | Up to Day 29 | Participants who experienced targeted symptoms of COVID-19 (e.g., cough, sore throat) and had NP swabs tested for SARS-CoV-2 using RT-PCR. The efficacy analysis population was the mITT (modified intent to treat) population consisting of all randomized participants who received at least 1 dose of study intervention. |
| Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline NP Swabs and Developed Detectable SARS-CoV-2 in NP Swabs on or Before Day 14 | Up to Day 14 | All participants had NP swabs collected at screening and through Day 14 to test for SARS-CoV-2 using RT-PCR. Efficacy analysis was conducted on the mITT (modified intent to treat) population consisting of all randomized participants who received at least 1 dose of study intervention. |
Countries
Argentina, Brazil, Bulgaria, Colombia, Dominican Republic, Egypt, France, Guatemala, Hungary, Japan, Kenya, Malaysia, Mexico, Peru, Philippines, Romania, Russia, South Africa, Spain, Thailand, Turkey (Türkiye), Ukraine, United States
Participant flow
Recruitment details
Only eligible participants without confirmed or suspected coronavirus disease 2019 (COVID-19) were enrolled within a 5-day period of the index case's first positive severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test result and COVID-19 symptoms onset.
Pre-assignment details
Index cases were enrolled but did not receive study treatment upon randomization and with the exception of characteristics collected at baseline and optional exploratory swab collection, no other data were collected.Index participants were not followed up for survival and no mortality data were collected per protocol.Index cases were not included in protocol specified outcome measure data collection.
Participants by arm
| Arm | Count |
|---|---|
| Molnupiravir Participants were treated with molnupiravir 800 mg every 12 hours (Q12H) on Days 1 to 5. | 768 |
| Placebo Participants were given placebo Q12H on Days 1 to 5. | 771 |
| Index Participants Index case was a participant with documented COVID-19 infection. Index participants were enrolled but did not receive study intervention. Index participants resided in the same household as enrolled participants who received study intervention. | 902 |
| Total | 2,441 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Discotinued per protocol | 0 | 0 | 902 |
| Overall Study | Lost to Follow-up | 0 | 5 | 0 |
| Overall Study | Physician Decision | 1 | 0 | 0 |
| Overall Study | Randomized By Mistake Without Study Treatment | 1 | 0 | 0 |
| Overall Study | Unkown | 6 | 3 | 0 |
| Overall Study | Withdrawal by Subject | 10 | 11 | 0 |
Baseline characteristics
| Characteristic | Molnupiravir | Placebo | Index Participants | Total |
|---|---|---|---|---|
| Age, Continuous | 37.0 years STANDARD_DEVIATION 15.6 | 37.0 years STANDARD_DEVIATION 15.5 | 38.0 years STANDARD_DEVIATION 17.7 | 37.0 years STANDARD_DEVIATION 15.6 |
| Age, Customized <18 | 0 Participants | 0 Participants | 76 Participants | 76 Participants |
| Age, Customized >=75 years | 26 Participants | 18 Participants | 25 Participants | 69 Participants |
| Age, Customized Adults (18-49 years) | 563 Participants | 568 Participants | 548 Participants | 1679 Participants |
| Age, Customized From 50 to 64 years | 144 Participants | 141 Participants | 199 Participants | 484 Participants |
| Age, Customized From 65 to 74 years | 35 Participants | 44 Participants | 54 Participants | 133 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 323 Participants | 340 Participants | 341 Participants | 1004 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 445 Participants | 430 Participants | 552 Participants | 1427 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 9 Participants | 10 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 85 Participants | 90 Participants | 80 Participants | 255 Participants |
| Race (NIH/OMB) Asian | 48 Participants | 40 Participants | 62 Participants | 150 Participants |
| Race (NIH/OMB) Black or African American | 62 Participants | 60 Participants | 77 Participants | 199 Participants |
| Race (NIH/OMB) More than one race | 119 Participants | 129 Participants | 128 Participants | 376 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 4 Participants | 2 Participants | 7 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 453 Participants | 446 Participants | 552 Participants | 1451 Participants |
| Sex: Female, Male Female | 366 Participants | 342 Participants | 541 Participants | 1249 Participants |
| Sex: Female, Male Male | 402 Participants | 429 Participants | 361 Participants | 1192 Participants |
| Stratification Factor at Randomization Collected via IRT: Age Group <=60 | 680 Participants | 680 Participants | 0 Participants | 1360 Participants |
| Stratification Factor at Randomization Collected via IRT: Age Group >=60 | 88 Participants | 91 Participants | 0 Participants | 179 Participants |
| Stratification Factor at Randomization Collected via IRT: Household Size <=3 | 269 Participants | 271 Participants | 0 Participants | 540 Participants |
| Stratification Factor at Randomization Collected via IRT: Household Size >=3 | 499 Participants | 500 Participants | 0 Participants | 999 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 768 | 1 / 771 |
| other Total, other adverse events | 0 / 763 | 0 / 765 |
| serious Total, serious adverse events | 3 / 763 | 2 / 765 |
Outcome results
Primary
Percentage of Participants Discontinuing From Study Therapy Due to AE
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.
Time frame: Up to 5 days
Population: Safety Analyses was conducted in the APaT population, which consists of all randomized participants who received at least 1 dose of study intervention. Index participants were not included in OM analysis per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Molnupiravir | Percentage of Participants Discontinuing From Study Therapy Due to AE | 3 Participants |
| Placebo | Percentage of Participants Discontinuing From Study Therapy Due to AE | 1 Participants |
Comparison: 95% CIs (Tier 2 endpoints) was provided for between treatment differences in the percentage of participants with events; these analyses was performed using the Miettinen and Nurminen method.95% CI: [-0.4, 1]Miettinen & Nurminen method.
Primary
Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline Nasopharyngeal (NP) Swabs and Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14
Percentage of participants who had undetectable SARS-CoV-2 in baseline NP swabs and developed COVID-19 (laboratory-confirmed SARS-CoV-2 infection with symptoms) through Day 14 were reported.
Time frame: Day 14
Population: Efficacy analysis was conducted on the mITT (modified intent to treat) population consisting of all randomized participants who received at least 1 dose of study intervention. Index participants were not included in OM analysis per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Molnupiravir | Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline Nasopharyngeal (NP) Swabs and Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14 | 41 Percentage of Participants |
| Placebo | Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline Nasopharyngeal (NP) Swabs and Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14 | 54 Percentage of Participants |
Comparison: Adjusted differences and the corresponding confidence intervals are based on Miettinen \& Nurminen method stratified by age and household size.p-value: =0.084895% CI: [-5, 0.9]Miettinen & Nurminen method
Primary
Percentage of Participants With ≥1 Adverse Event
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.
Time frame: 29 days
Population: Safety Analyses was conducted in the APaT population, which consists of all randomized participants who received at least 1 dose of study intervention. Index participants were not included in OM analysis per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Molnupiravir | Percentage of Participants With ≥1 Adverse Event | 94 Participants |
| Placebo | Percentage of Participants With ≥1 Adverse Event | 105 Participants |
Comparison: 95% CIs (Tier 2 endpoints) was provided for between treatment differences in the percentage of participants with events; these analyses was performed using the Miettinen and Nurminen method.95% CI: [-4.8, 2]Miettinen & Nurminen method
Secondary
Percentage of Participants (Regardless of SARS-CoV-2 in Baseline NP Swabs) Who Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14
Participants who experienced targeted symptoms of COVID-19 (e.g., cough, sore throat) and had NP swabs tested for SARS-CoV-2 using reverse-transcription polymerase chain reaction (RT-PCR).Efficacy analysis was conducted on the mITT (modified intent to treat) population consisting of all randomized participants who received at least 1 dose of study intervention.
Time frame: Up to Day 14
Population: Index participants were not included in OM analysis per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Molnupiravir | Percentage of Participants (Regardless of SARS-CoV-2 in Baseline NP Swabs) Who Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14 | 78 Participants |
| Placebo | Percentage of Participants (Regardless of SARS-CoV-2 in Baseline NP Swabs) Who Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14 | 103 Participants |
Comparison: Adjusted differences and the corresponding confidence intervals are based on Miettinen \& Nurminen method stratified by age and household size.p-value: =0.020595% CI: [-6.3, -0.1]Miettinen & Nurminen method
Secondary
Percentage of Participants Who Had Detectable SARS-CoV-2 in Baseline NP Swabs and Developed COVID-19 (Laboratory-confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14
Participants who experienced targeted symptoms of COVID-19 (e.g., cough, sore throat) and had NP swabs tested for SARS-CoV-2 using RT-PCR. Efficacy analysis was conducted on the mITT (modified intent to treat) population consisting of all randomized participants who received at least 1 dose of study intervention.
Time frame: Up to Day 14
Population: Index participants were not included in OM analysis per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Molnupiravir | Percentage of Participants Who Had Detectable SARS-CoV-2 in Baseline NP Swabs and Developed COVID-19 (Laboratory-confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14 | 35 Participants |
| Placebo | Percentage of Participants Who Had Detectable SARS-CoV-2 in Baseline NP Swabs and Developed COVID-19 (Laboratory-confirmed SARS-CoV-2 Infection With Symptoms) Through Day 14 | 47 Participants |
Comparison: Adjusted differences and the corresponding confidence intervals are based on Miettinen \& Nurminen method stratified by age and household size.95% CI: [-22.7, 2]Miettinen & Nurminen method
Secondary
Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline NP Swabs and Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 29
Participants who experienced targeted symptoms of COVID-19 (e.g., cough, sore throat) and had NP swabs tested for SARS-CoV-2 using RT-PCR. The efficacy analysis population was the mITT (modified intent to treat) population consisting of all randomized participants who received at least 1 dose of study intervention.
Time frame: Up to Day 29
Population: Index participants were not included in OM analysis per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Molnupiravir | Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline NP Swabs and Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 29 | 51 Participants |
| Placebo | Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline NP Swabs and Developed COVID-19 (Laboratory-Confirmed SARS-CoV-2 Infection With Symptoms) Through Day 29 | 65 Participants |
Comparison: Adjusted differences and the corresponding confidence intervals are based on Miettinen \& Nurminen method stratified by age and household size.95% CI: [-5.4, 1]Miettinen & Nurminen method
Secondary
Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline NP Swabs and Developed Detectable SARS-CoV-2 in NP Swabs on or Before Day 14
All participants had NP swabs collected at screening and through Day 14 to test for SARS-CoV-2 using RT-PCR. Efficacy analysis was conducted on the mITT (modified intent to treat) population consisting of all randomized participants who received at least 1 dose of study intervention.
Time frame: Up to Day 14
Population: Index participants were not included in OM analysis per protocol.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Molnupiravir | Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline NP Swabs and Developed Detectable SARS-CoV-2 in NP Swabs on or Before Day 14 | 65 Participants |
| Placebo | Percentage of Participants Who Had Undetectable SARS-CoV-2 in Baseline NP Swabs and Developed Detectable SARS-CoV-2 in NP Swabs on or Before Day 14 | 85 Participants |
Comparison: Adjusted differences and the corresponding confidence intervals are based on Miettinen \& Nurminen method stratified by age and household size.95% CI: [-6.9, 0.8]