Oral nirmatrelvir-ritonavir for COVID-19 in higher risk outpatients

BACKGROUND: Nirmatrelvir-ritonavir reduced progression to severe SARS-CoV2 infection in unvaccinated high-risk outpatients. The effectiveness of nirmatrelvir-ritonavir in vaccinated populations has yet to be demonstrated. METHODS: In two open-label platform trials (PANORAMIC in the UK and CanTreatCOVID in Canada), community-dwelling adults (aged ≥ 50 or ≥18 with comorbidities) who tested positive for SARS-CoV-2 and were unwell for ≤5 days were randomized to receive either usual care plus nirmatrelvir-ritonavir (300mg/100mg BID x 5 days) or to usual care alone. Primary outcome was all-cause hospitalization or death within 28 days. RESULTS: From December 8, 2021 to September 30, 2024, 3516 participants in PANORAMIC and 716 in CanTreatCOVID were randomized. Nirmatrelvir–ritonavir did not reduce hospitalization or death ((PANORAMIC: 4/1698 (0.8%) vs 11/1673 (0.7%); adjusted-odds ratio [OR], 1.18; 95% Bayesian credible interval [BCI], 0.55 to 2.62; probability of superiority 0.505, CanTreatCOVID: 2/343 (0.6%) vs 4/324 (1.2%); adjusted-OR, 0.48; 95% BCI, 0.08 to 2.23; probability of superiority 0.830). Nirmatrelvir–ritonavir increased early sustained recovery and reduced self-reported time-to-recovery In nirmatrelvir–ritonavir. Viral load was reduced by the end of treatment. 10 serious adverse events were reported for nirmatrelvir-ritonavir in PANORAMIC and 4 in CanTreatCOVID. CONCLUSIONS: In both open-label trial, nirmatrelvir–ritonavir did not reduce the incidence of hospitalization and/or death in vaccinated high-risk patients, but reduced self-reported time-to-recovery. (PANORAMIC funding: National Institute for Health and Care Research; EudraCT Number 2021-005748-31; CanTreatCOVID: Canadian Institutes of Health Research (CIHR) and Health Canada, supported by Public Health Agency of Canada; ClinicalTrials.gov number NCT05614349).