EPIC‐HR 2021.

Study characteristics
Methods	Trial design: double‐blind RCT with 2 parallel arms Type of publication: journal publication Setting: outpatient Recruitment dates: 16 July to 9 December 2021 Country: worldwide Language: English Number of centres: 343 sites  Study purpose (treatment, prevention): treatment Trial registration number: NCT04960202 Date of registration: 13 July 2021
Participants	Number of participants (randomized/analyzed): 2246/2224 Study populations: full analysis set: all patients randomly assigned to study intervention (intervention/comparator 1120/1126) safety analysis set: all patients randomly assigned to study intervention who received ≥ 1 dose of study intervention. (intervention/comparator 1109/1115) mITT: all patients randomly assigned to study intervention who received ≥ 1 dose of study intervention and had ≥ 1 post‐baseline visit, did not receive or were not expected to receive COVID‐19 monoclonal antibody treatment and were treated ≤ 3 days following symptom onset. (intervention/comparator 697/682) mITT1: all patients randomly assigned to study intervention who received ≥ 1 dose of study intervention and had ≥ 1 post‐baseline visit and did not receive or were not expected to receive COVID‐19 monoclonal antibody treatment (intervention/comparator 1039/1046) mITT2: all patients randomly assigned to study intervention who received ≥ 1 dose of study intervention and had ≥ 1 post‐baseline visit. (intervention/comparator 1109/1115) Age median (IQR): 46 (18‐88)  Males, n: 1148 (51.1%) Race/ethnicity: 1607 (71.5%) White, 315 (14%) Asian, 110 (4.9%) Black  Severity of condition according to study definition: non‐hospitalized, symptomatic Severity of condition according to WHO scale: 2 to 3 Comorbidities: 20.3% ≥ 2 comorbidities (mITT1) Overweight: 80.5% BMI>25 Diabetes mellitus: 252 (12.1%)(mITT1) Respiratory disease: 92 (4.4%)(mITT1) Hypertension: 689 (33%) (mITT1) Immunosuppression: 12 (1%) (mITT1) Vaccination status: unvaccinated (exclusion criterion) Virus detection performed at baseline (test‐positive at baseline): RT‐PCR, molecular or antigen tests (100%) Inclusion criteria: non‐hospitalized, symptomatic adults with COVID‐19, at high risk for progression to severe disease, confirmed SARS‐CoV‐2 infection, symptom onset no more than 5 days before randomization with at least one sign or symptom of COVID‐19 on the day of randomization and at least one characteristic or coexisting condition associated with high risk of progression to severe COVID‐19 Exclusion criteria: previous confirmed SARS‐CoV‐2 infection or hospitalization for COVID‐19, anticipated need for hospitalization within 48 hours after randomization, prior receipt of convalescent COVID‐19 plasma or SARS‐CoV‐2 vaccine, prohibited prior or concomitant therapies included medications highly dependent on CYP3A4 for clearance, concurrent active systemic infection, pregnancy, breastfeeding
Interventions	Treatment details of intervention group  Type and dose: nirmatrelvir/ritonavir 300 mg, twice daily for 5 days  Route of administration: oral Treatment details of control group  Placebo Concomitant therapy: monoclonal antibodies allowed, otherwise no further information Duration of follow‐up: 34 days Treatment cross‐overs: none
Outcomes	Primary study outcome (as defined by the study) Proportion of participants with COVID‐19 related hospitalization or death from any cause at 28 days Relevant review outcomes reported Proportion of participants with COVID‐19 related hospitalization or death from any cause at 28 days Incidence of treatment‐related adverse events (TRAEs) of nirmatrelvir/ritonavir relative to placebo at 34 days Incidence of treatment‐emergent adverse events (TEAEs) of nirmatrelvir/ritonavir relative to placebo at 34 days Incidence of adverse events leading to discontinuation of nirmatrelvir/ritonavir or placebo at 34 days Incidence of serious adverse events (SAEs) of nirmatrelvir/ritonavir relative to placebo at 34 days Proportion of participants with death (all cause) at 28 days Additional study outcomes reported Viral titers measured by Reverse Transcription Polymerase Chain Reaction (RT‐PCR) in nasal swabs at day 14
Notes	Date of publication: 16 Febuary 2022 Sponsor/funding: Pfizer Information on ethics votum: trial sites in the countries HU, ES, CZ and BG provided information on ethics approval in their trial registry entries and obtained the necessary permissions.

mITT: modified intention to treat;RT‐PCR: reverse transcription polymerase chain reaction; SAEs: serious adverse events; TEAEs: treatment‐emergent adverse events; TRAEs: treatment‐related adverse events; WHO: World Health Organization.