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

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.