Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients

N Engl J Med. 2026 Apr 23;394(16):1583-1594. doi: 10.1056/NEJMoa2502457.

Abstract

Background: Nirmatrelvir-ritonavir has been shown to reduce progression to severe illness from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in unvaccinated high-risk outpatients. The effectiveness of nirmatrelvir-ritonavir in persons who have been vaccinated, infected naturally, or both is unclear.

Methods: In two open-label platform trials (PANORAMIC in the United Kingdom and CanTreatCOVID in Canada), we enrolled higher-risk adults (≥50 years of age or ≥18 years of age with coexisting conditions) in the community who tested positive for SARS-CoV-2 and had been unwell for 5 days or less. The participants were randomly assigned to receive usual care plus nirmatrelvir (300 mg)-ritonavir (100 mg) twice a day for 5 days or to receive usual care alone. The primary outcome was hospitalization or death from any cause within 28 days after randomization.

Results: From December 8, 2021, to September 30, 2024, a total of 3516 participants in the PANORAMIC trial and 716 participants in the CanTreatCOVID trial underwent randomization. In the PANORAMIC trial, 14 of 1698 participants (0.8%) in the nirmatrelvir-ritonavir group and 11 of 1673 participants (0.7%) in the usual-care group were hospitalized or died (adjusted odds ratio, 1.18; 95% Bayesian credible interval, 0.55 to 2.62; probability of superiority, 0.334). In the CanTreatCOVID trial, 2 of 343 participants (0.6%) in the nirmatrelvir-ritonavir group and 4 of 324 participants (1.2%) in the usual-care group were hospitalized or died (adjusted odds ratio, 0.48; 95% Bayesian credible interval, 0.08 to 2.23; probability of superiority, 0.830). In a substudy involving 634 participants, viral load was reduced by the end of treatment with nirmatrelvir-ritonavir. Serious adverse events with nirmatrelvir-ritonavir were reported in 9 participants in the PANORAMIC trial and in 4 participants in the CanTreatCOVID trial.

Conclusions: In two open-label trials, nirmatrelvir-ritonavir did not reduce the incidence of hospitalization or death among vaccinated higher-risk participants with SARS-CoV-2 infection. (Funded by the National Institute for Health and Care Research, and others; PANORAMIC ISRCTN number, 2021-005748-31; CanTreatCOVID ClinicalTrials.gov number, NCT05614349.).

Publication types

  • Clinical Trial, Phase III
  • Equivalence Trial
  • Multicenter Study
  • Randomized Controlled Trial

MeSH terms

  • Administration, Oral
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antiviral Agents* / administration & dosage
  • Antiviral Agents* / adverse effects
  • Azabicyclo Compounds / administration & dosage
  • Azabicyclo Compounds / adverse effects
  • COVID-19 Drug Treatment*
  • COVID-19 Vaccines / administration & dosage
  • COVID-19* / diagnosis
  • COVID-19* / mortality
  • COVID-19* / prevention & control
  • COVID-19* / virology
  • Drug Combinations
  • Female
  • Hospitalization / statistics & numerical data
  • Humans
  • Male
  • Middle Aged
  • Pyrrolidinones / administration & dosage
  • Pyrrolidinones / adverse effects
  • Ritonavir* / administration & dosage
  • Ritonavir* / adverse effects
  • SARS-CoV-2 / isolation & purification
  • Viral Load / drug effects
  • Young Adult

Substances

  • Antiviral Agents
  • Drug Combinations
  • Ritonavir
  • nirmatrelvir and ritonavir drug combination
  • Pyrrolidinones
  • Azabicyclo Compounds
  • COVID-19 Vaccines

Associated data

  • EudraCT/2021-005748-31
  • ClinicalTrials.gov/NCT05614349