Alleviation of COVID-19 Symptoms and Reduction in Healthcare Utilization Among High-risk Patients Treated With Nirmatrelvir/Ritonavir (NMV/R): A Phase 3 Randomized Trial

Clin Infect Dis. 2025 Feb 24;80(2):323-330. doi: 10.1093/cid/ciae551.

Abstract

Background: Nirmatrelvir/ritonavir (NMV/r) is an oral antiviral treatment for mild to moderate coronavirus disease 2019 (COVID-19).

Methods: This phase 2/3, double-blind, randomized (1:1) study assessed oral NMV/r 300 mg/100 mg versus placebo every 12 hours for 5 days in high-risk, unvaccinated, nonhospitalized, symptomatic adults with COVID-19 from 343 sites across 21 countries. In testing the primary endpoint of COVID-19‒related hospitalization and all-cause deaths and key secondary endpoints, including symptom duration and COVID-19‒related medical visits, type I error was controlled with prespecified sequential testing and the Hochberg procedure.

Results: Among 2113 randomized patients enrolled from July 2021 through December 2021, 1966 (NMV/r, n = 977; placebo, n = 989) were included in the prespecified analysis population (symptom onset ≤5 days, did not receive monoclonal antibodies). NMV/r significantly reduced times to sustained alleviation (median, 13 vs 15 days; hazard ratio = 1.27, P < .0001) and resolution (16 vs 19 days; hazard ratio = 1.20, P = .0022) through day 28 and significantly reduced the number of COVID-19‒related medical visits and the proportion of patients with such visits. Hospitalized patients treated with NMV/r had shorter stays, none required intensive care unit admission or mechanical ventilation, and all were discharged to home/self-care. Fewer NMV/r-treated patients required additional treatment for COVID-19. No NMV/r-treated patients died through week 24 compared with 15 placebo-treated patients.

Conclusions: In addition to reducing COVID-19‒related hospitalization or death from any cause through day 28, NMV/r was found to also reduce duration of COVID-19 symptoms and utilization of healthcare resources versus placebo in patients at high risk of progressing to severe disease.

Clinical trial information: ClinicalTrials.gov, NCT04960202, https://clinicaltrials.gov/study/NCT04960202.

Keywords: COVID-19 drug therapy; EPIC-HR; nirmatrelvir; ritonavir; symptoms.

Publication types

  • Randomized Controlled Trial
  • Clinical Trial, Phase III
  • Clinical Trial, Phase II
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Antiviral Agents* / administration & dosage
  • Antiviral Agents* / therapeutic use
  • COVID-19 Drug Treatment*
  • COVID-19* / mortality
  • Double-Blind Method
  • Female
  • Hospitalization / statistics & numerical data
  • Humans
  • Male
  • Middle Aged
  • Patient Acceptance of Health Care* / statistics & numerical data
  • Ritonavir* / administration & dosage
  • Ritonavir* / therapeutic use
  • SARS-CoV-2 / drug effects
  • Treatment Outcome

Substances

  • Ritonavir
  • Antiviral Agents

Associated data

  • ClinicalTrials.gov/NCT04960202

Grants and funding