Molnupiravir and COVID-19 Mortality Reduction in the Omicron Era (MOLCOVred)

July 17, 2026 updated by: Dalibor Veselý, Charles University, Czech Republic

Effect of Molnupiravir on COVID-19 Mortality in the Omicron Era: A Real-World Target Trial Emulation Using Complete Czech Nationwide Data

This retrospective real-world target trial emulation uses complete Czech nationwide registry data to evaluate whether molnupiravir treatment is associated with lower COVID-19 mortality during the Omicron era. The study compares adults with confirmed acute COVID-19 treated with molnupiravir in addition to standard care versus matched controls treated with standard care without molnupiravir. Patients are followed for three months from time zero, and primary endpoints are the COVID-19 case fatality rate and all-cause mortality.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

This observational, retrospective, nationwide study is designed as a target trial emulation. It emulates a pragmatic randomized controlled trial comparing treatment with molnupiravir in addition to standard care versus standard care without molnupiravir in adults with confirmed acute COVID-19. The analysis uses linked national registry data administered by the Institute of Health Information and Statistics of the Czech Republic, including infectious disease records, healthcare diagnoses, prescription and medication-administration records, hospital care data, and death certificate data.

Eligible infection episodes will include adult COVID-19 cases recorded during the Omicron era, beginning January 1, 2022. Each infection episode will be analyzed separately, with reinfection defined as SARS-CoV-2 positivity occurring at least 60 days after a previous SARS-CoV-2 positivity. Time zero will be defined as the date on which a patient first meets all eligibility criteria and is assigned to one of the treatment strategies. For patients treated with molnupiravir, time zero will be the date of molnupiravir treatment initiation, proxied by dispensing; treatment initiation must occur on or after the date of the qualifying SARS-CoV-2 positivity. For controls, time zero will be the matched index date, defined as the same number of days from SARS-CoV-2 positivity as in the corresponding treated patient, so that treated and untreated patients are compared at a similar stage of infection.

To approximate treatment initiation within the recommended period for molnupiravir use, the eligible time-zero window will be defined using available registry information on the interval between symptom onset and SARS-CoV-2 positivity. Molnupiravir dispensing will be considered eligible only if the expected interval from symptom onset to treatment initiation is consistent with initiation within five days of symptom onset, in accordance with the SmPC.

Treated patients and matched controls will be followed for three months from time zero. Since registry follow-up data are available through December 31, 2024, only episodes with sufficient follow-up to ascertain three-month outcomes will be included. Patients who had died, were hospitalized in an intensive care unit, or were receiving mechanical ventilation at time zero will be excluded. Patients who received molnupiravir, monoclonal antibodies, remdesivir, or nirmatrelvir/ritonavir in the 14 days before the qualifying SARS-CoV-2 positivity will be excluded. Patients who received molnupiravir, monoclonal antibodies, remdesivir, or nirmatrelvir/ritonavir within 14 days after the qualifying SARS-CoV-2 positivity, but outside the treatment-initiation eligibility window according to the SmPC, will also be excluded.

Treated patients will be matched 1:2 with controls by exact matching on baseline covariates measured at time zero, including age group, sex, selected comorbidities, vaccination status, post-infection immunity, care setting, concomitant targeted COVID-19 therapy, and calendar half-year. The study follows STROBE guidelines and the TARGET framework for target trial emulations.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Observational

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
1814551

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Czechia
      • Prague, Czechia, 10000
        • Department of Pharmacology, Third Faculty of Medicine, Charles University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Probability Sample

Study Population

All adult patients with confirmed SARS-CoV-2 infection recorded in Czech nationwide health registry data from January 1, 2022, through December 31, 2024.

Description

Inclusion Criteria:

  • Adult infection episodes among patients aged 20 years or older.
  • Confirmed acute SARS-CoV-2 positivity recorded in the Infectious Disease Information System (ISIN) during the Omicron-era study period.
  • Eligible for analysis at time zero, defined as the date of molnupiravir dispensing for treated patients and the matched date for controls.
  • Mild-to-moderate COVID-19 suitable for oral antiviral treatment, operationalized by excluding those already dead, in ICU, or receiving mechanical ventilation at time zero.

Exclusion Criteria:

  • Age below 20 years at time of positivity.
  • Death, ICU hospitalization, or mechanical ventilation at time zero.
  • Receipt of molnupiravir, monoclonal antibodies, remdesivir, or nirmatrelvir/ritonavir within 14 days before positivity.
  • Receipt of molnupiravir, monoclonal antibodies, remdesivir, or nirmatrelvir/ritonavir within 14 days after the qualifying SARS-CoV-2 positivity, but outside the treatment-initiation eligibility window according to the SmPC.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort

Group / Cohort

A group or subgroup of participants in an observational study that is assessed for biomedical or health outcomes.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Molnupiravir treatment in addition to standard care
Adults with confirmed COVID-19 who received molnupiravir in addition to standard care. Time zero is the date of molnupiravir treatment initiation proxied by dispensing.
Drug: Molnupiravir
800 mg of molnupiravir administered twice daily, i.e., four capsules every 12 hours for five days.
Other Names:
  • Lagevrio
  • EIDD-2801
Standard care without molnupiravir
Matched controls with confirmed COVID-19 who did not receive molnupiravir. Time zero is the matched date corresponding to the same number of days from positivity as the matched treated patient.

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
COVID-19 CFR comparing patients treated with molnupiravir versus those not treated with molnupiravir.
Time Frame: Three months from time zero.
COVID-19 case fatality rate (CFR) comparing patients treated with molnupiravir in addition to standard care versus matched controls treated with standard care without molnupiravir among patients with acute COVID-19.
Three months from time zero.
ACM comparing patients treated with molnupiravir versus those not treated with molnupiravir.
Time Frame: Three months from time zero.
All-cause mortality (ACM) comparing patients treated with molnupiravir in addition to standard care versus matched controls treated with standard care without molnupiravir among patients with acute COVID-19.
Three months from time zero.

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
CFR and ACM comparing outpatients treated with molnupiravir versus those not treated with molnupiravir.
Time Frame: Three months from time zero.
COVID-19 CFR and ACM comparing patients treated with molnupiravir in addition to standard care versus matched controls treated with standard care without molnupiravir among patients with acute COVID-19 not hospitalized at time zero.
Three months from time zero.
COVID-19 CFR and ACM comparing hospitalized patients treated with molnupiravir versus those not treated with molnupiravir.
Time Frame: Three months from time zero.
COVID-19 CFR and ACM comparing patients treated with molnupiravir in addition to standard care versus matched controls treated with standard care without molnupiravir among patients with acute COVID-19 hospitalized at time zero.
Three months from time zero.
COVID-19 CFR and ACM comparing treatment with molnupiravir versus standard care alone among patients not receiving other targeted COVID-19 agents.
Time Frame: Three months from time zero.
COVID-19 CFR and ACM comparing patients receiving molnupiravir as a standalone targeted COVID-19 agent in addition to standard care versus matched controls treated with standard care without molnupiravir or other targeted COVID-19 agents among patients with acute COVID-19.
Three months from time zero.
COVID-19 CFR and ACM comparing treatment with molnupiravir versus standard care among patients receiving other targeted COVID-19 agents.
Time Frame: Three months from time zero.
COVID-19 CFR and ACM comparing molnupiravir recipients receiving also other targeted COVID-19 agents in addition to standard care versus matched controls receiving targeted COVID-19 agents other than molnupiravir in addition to standard care among patients with acute COVID-19.
Three months from time zero.

Other Outcome Measures

Other Outcome Measures

For clinical trials, a planned measurement described in the protocol that is used to determine the effect of an intervention/treatment on participants. For observational studies, a measurement or observation that is used to describe patterns of diseases or traits, or associations with exposures, risk factors, or treatment. Types of outcome measures include primary outcome measure and secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Healthy-user bias assessment: Number of health care contact episodes before SARS-CoV-2 positivity.
Time Frame: One year preceding the patient's qualifying SARS-CoV-2 positivity.
Evaluation of health care utilization during the period preceding the qualifying SARS-CoV-2 positivity in patients with confirmed acute COVID-19, comparing matched molnupiravir-treated patients with matched controls not treated with molnupiravir. Health care utilization is measured as the total number of documented episodes of contact with the health care system.
One year preceding the patient's qualifying SARS-CoV-2 positivity.
Healthy-user bias assessment: Number of hospitalization episodes before SARS-CoV-2 positivity.
Time Frame: One year preceding the patient's qualifying SARS-CoV-2 positivity. Hospitalizations on the day of SARS-CoV-2 positivity are not counted, including hospitalizations that began before that day and were ongoing at the time of SARS-CoV-2 positivity.
Evaluation of health care utilization during the period preceding the qualifying SARS-CoV-2 positivity in patients with confirmed acute COVID-19, comparing matched molnupiravir-treated patients with matched controls not treated with molnupiravir. Health care utilization is measured as the total number of documented hospitalization episodes.
One year preceding the patient's qualifying SARS-CoV-2 positivity. Hospitalizations on the day of SARS-CoV-2 positivity are not counted, including hospitalizations that began before that day and were ongoing at the time of SARS-CoV-2 positivity.
Healthy-user bias assessment: Number of hospitalization days before SARS-CoV-2 positivity.
Time Frame: One year preceding the patient's qualifying SARS-CoV-2 positivity. Hospitalization days from a hospitalization that was ongoing on the day of SARS-CoV-2 positivity are not counted.
Evaluation of health care utilization during the period preceding the qualifying SARS-CoV-2 positivity in patients with confirmed acute COVID-19, comparing matched molnupiravir-treated patients with matched controls not treated with molnupiravir. Health care utilization is measured as the total number of documented hospitalization days across all hospitalization episodes.
One year preceding the patient's qualifying SARS-CoV-2 positivity. Hospitalization days from a hospitalization that was ongoing on the day of SARS-CoV-2 positivity are not counted.
Negative control outcomes for residual confounding assessment: Traumatic/injury-related CFR.
Time Frame: Three months from time zero.
Evaluation of traumatic or injury-related death occurring after time zero as a negative control outcome that should not plausibly be influenced by molnupiravir treatment or the clinical course of COVID-19. The outcome is assessed in patients with confirmed acute COVID-19 by comparing matched molnupiravir-treated patients with matched controls not treated with molnupiravir.
Three months from time zero.
Negative control outcomes for residual confounding assessment: Malignant neoplasm CFR.
Time Frame: Three months from time zero.
Evaluation of malignant neoplasm death occurring after time zero as a negative control outcome that should not plausibly be influenced by molnupiravir treatment or the clinical course of COVID-19. The outcome is assessed in patients with confirmed acute COVID-19 by comparing matched molnupiravir-treated patients with matched controls not treated with molnupiravir.
Three months from time zero.
Negative control outcomes for residual confounding assessment: Digestive disease CFR.
Time Frame: Three months from time zero.
Evaluation of digestive disease death occurring after time zero as a negative control outcome that should not plausibly be influenced by molnupiravir treatment or the clinical course of COVID-19. The outcome is assessed in patients with confirmed acute COVID-19 by comparing matched molnupiravir-treated patients with matched controls not treated with molnupiravir.
Three months from time zero.
Adverse event reports associated with molnupiravir.
Time Frame: 1.1.2022 - 31.12.2024
An assessment of the number and severity of adverse effects associated with the administration of molnupiravir to determine the drug's safety profile.
1.1.2022 - 31.12.2024

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Charles University, Czech Republic

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Institute of Health Information and Statistics of the Czech Republic

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Dalibor Veselý, M.D., Charles University, Prague, Third Faculty of Medicine
  • Study Director: Jiří Slíva, M.D., Ph.D., Charles University, Prague, Third Faculty of Medicine

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2022

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
December 31, 2024

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
December 31, 2024

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 14, 2026

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 17, 2026

First Posted (Actual)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
July 22, 2026

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 22, 2026

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 17, 2026

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2026

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • COVID-OMICRON-MPN-CFR

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

YES

IPD Plan Description

Anonymized/blurred data suitable for public sharing. The raw non-public National Health Information System (NHIS)/Institute of Health Information and Statistics of the Czech Republic (IHIS) data cannot be published due to personal data protection regulations; permission was granted to publish individual-level data with matching parameters for COVID-19-positive patients from the study period as a public appendix. These data are anonymized and blurred to prevent re-identification while allowing reproduction of analyses.

IPD Sharing Time Frame

Planned with manuscript publication as a public appendix.

IPD Sharing Access Criteria

Public appendix of a manuscript.

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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