• Jennifer Hammond, Heidi Leister-Tebbe, Annie Gardner, Paula Abreu, Weihang Bao, Wayne Wisemandle, MaryLynn Baniecki, Victoria M Hendrick, Bharat Damle, Abraham Simón-Campos, Rienk Pypstra, James M Rusnak, and EPIC-HR Investigators.
• From Global Product Development, Pfizer, Collegeville, PA (J.H., H.L.-T.); Global Product Development (A.G.) and Early Clinical Development (M.L.B.), Pfizer, Cambridge, MA; Global Product Development, Pfizer, New York (P.A., W.B., B.D., R.P.); Global Product Development, Pfizer, Lake Forest, IL (W.W.); Medical and Safety, Pfizer, Sandwich, United Kingdom (V.M.H.); Köhler and Milstein Research, Mérida, Yucatan, Mexico (A.S.-C.); and Global Product Development, Pfizer, Tampa, FL (J.M.R.).
• N. Engl. J. Med. 2022 Apr 14; 386 (15): 139714081397-1408.

BackgroundNirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) inhibitor with potent pan-human-coronavirus activity in vitro.MethodsWe conducted a phase 2-3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19-related hospitalization or death from any cause through day 28, viral load, and safety were evaluated.ResultsA total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19-related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], -9.04 to -3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of -5.81 percentage points (95% CI, -7.78 to -3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmatrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo.ConclusionsTreatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).Copyright © 2022 Massachusetts Medical Society.

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