Tweet
N Engl J Med
. 2026 Apr 23;394(16):1583-1594.
doi: 10.1056/NEJMoa2502457.
Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients
Christopher C Butler 1 , Andrew D Pinto 2 3 4 5 , Victoria Harris 1 , Jane Holmes 1 , Najib M Rahman 6 7 8 , Lucy Cureton 1 , Gail Hayward 1 , Duncan B Richards 9 , David M Lowe 10 , Joseph F Standing 10 , Judith Breuer 11 , Kerenza Hood 12 , May Ee Png 1 , Stavros Petrou 1 , Jienchi Dorward 1 13 , Mahendra G Patel 1 , Nicholas P B Thomas 14 15 16 , Philip Evans 14 17 , Nigel D Hart 18 , Bhautesh D Jani 19 , Banafshe Hosseini 2 4 5 , Srinivas Murthy 20 , Kerry McBrien 21 22 , Amanda Condon 23 , Emily G McDonald 24 , Peter Daley 25 , Michelle Greiver 4 26 , Bruno R da Costa 5 27 , Peter Selby 4 5 , Peter Jüni 5 27 , Todd C Lee 24 , Haolun Shi 28 , Michelle A Detry 29 , Christina T Saunders 29 , Mark Fitzgerald 29 , Nicholas S Berry 29 , Benjamin R Saville 29 30 , Saye H Khoo 31 , Jonathan S Nguyen-Van-Tam 32 , F D Richard Hobbs 1 , Ly-Mee Yu 1 , Paul Little 33 ; PANORAMIC Trial and CanTreatCOVID Trial Collaborative Groups
Collaborators, Affiliations
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.).
. 2026 Apr 23;394(16):1583-1594.
doi: 10.1056/NEJMoa2502457.
Oral Nirmatrelvir-Ritonavir for Covid-19 in Higher-Risk Outpatients
Christopher C Butler 1 , Andrew D Pinto 2 3 4 5 , Victoria Harris 1 , Jane Holmes 1 , Najib M Rahman 6 7 8 , Lucy Cureton 1 , Gail Hayward 1 , Duncan B Richards 9 , David M Lowe 10 , Joseph F Standing 10 , Judith Breuer 11 , Kerenza Hood 12 , May Ee Png 1 , Stavros Petrou 1 , Jienchi Dorward 1 13 , Mahendra G Patel 1 , Nicholas P B Thomas 14 15 16 , Philip Evans 14 17 , Nigel D Hart 18 , Bhautesh D Jani 19 , Banafshe Hosseini 2 4 5 , Srinivas Murthy 20 , Kerry McBrien 21 22 , Amanda Condon 23 , Emily G McDonald 24 , Peter Daley 25 , Michelle Greiver 4 26 , Bruno R da Costa 5 27 , Peter Selby 4 5 , Peter Jüni 5 27 , Todd C Lee 24 , Haolun Shi 28 , Michelle A Detry 29 , Christina T Saunders 29 , Mark Fitzgerald 29 , Nicholas S Berry 29 , Benjamin R Saville 29 30 , Saye H Khoo 31 , Jonathan S Nguyen-Van-Tam 32 , F D Richard Hobbs 1 , Ly-Mee Yu 1 , Paul Little 33 ; PANORAMIC Trial and CanTreatCOVID Trial Collaborative Groups
Collaborators, Affiliations
- PMID: 42019019
- DOI: 10.1056/NEJMoa2502457
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.).