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

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: Completed
• Conditions: COVID-19; SARS-CoV-2
• Intervention / Treatment: Drug: Molnupiravir

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: Observational
• Enrollment (Actual): 1814551

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• 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

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
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

Outcome Measure	Measure Description	Time Frame
COVID-19 CFR comparing patients treated with molnupiravir versus those not treated with molnupiravir.	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.	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

Outcome Measure	Measure Description	Time Frame
CFR and ACM comparing outpatients treated with molnupiravir versus those not treated with molnupiravir.	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.	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.	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.	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

Outcome Measure	Measure Description	Time Frame
Healthy-user bias assessment: Number of health care contact episodes before 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.	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.	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.	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.	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.	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.	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

• Sponsor: Charles University, Czech Republic
• Collaborators: Institute of Health Information and Statistics of the Czech Republic
• Investigators: 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

Study Major Dates

• Study Start (Actual): January 1, 2022
• Primary Completion (Actual): December 31, 2024
• Study Completion (Actual): December 31, 2024

Study Registration Dates

• First Submitted: June 14, 2026
• First Submitted That Met QC Criteria: July 17, 2026
• First Posted (Actual): July 22, 2026

Study Record Updates

• Last Update Posted (Actual): July 22, 2026
• Last Update Submitted That Met QC Criteria: July 17, 2026
• Last Verified: July 1, 2026

More Information

Terms related to this study

• Keywords: COVID-19; mortality; pandemic; SARS-CoV-2 Infection; risk factor; Omicron; CFR; Molnupiravir; real-world evidence; target trial emulation; case fatality rate
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; molnupiravir
• Other Study ID 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.