Cited by 2,323COVID-19 Clinical Research StudiesSARS-CoV-2 and COVID-19 ResearchRespiratory viral infections research

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Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

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Hammond, Jennifer, Leister-Tebbe, Heidi, Gardner, Annie, Abreu, Paula, Bao, Weihang, Wisemandle, Wayne, Baniecki, MaryLynn, Hendrick, Victoria M., Damle, Bharat, Simón-Campos, Abraham, Pypstra, Rienk, Rusnak, James M.·2022·New England Journal of Medicine

DOI 10.1056/nejmoa2118542PMC PMC8908851

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Abstract

BACKGROUNDNirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M pro ) 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 log 10 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.govnumber, NCT04960202.

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Authors: Hammond, J., Leister-Tebbe, H., Gardner, A., Abreu, P., Bao, W., Wisemandle, W., Baniecki, M., Hendrick, V. M., Damle, B., Simón-Campos, A., Pypstra, R., & Rusnak, J. M.
Affiliations: Pfizer (United States) (US)
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.).
Corresponding author: Hammond, Jennifer
Venue: New England Journal of Medicine
Publisher: Massachusetts Medical Society
Published: 2022-04-14
Volume: 386
Issue: 15
Pages: 1397-1408
ISSN: 0028-4793 (ISSN-L)
1533-4406
DOI: 10.1056/nejmoa2118542
PMC: PMC8908851
OpenAlex: W4212904481
Cited by: 2,323
References: 21
Citations by year: 2026: 186 · 2025: 319 · 2024: 517 · 2023: 769 · 2022: 525
FWCI: 261.43
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.nejmgroup.org/legal/terms-of-use.htm (vor)
Locations: New England Journal of Medicine (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: Pfizer
Topics: Health Sciences › Medicine › Infectious Diseases › COVID-19 Clinical Research Studies
Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
Keywords: nirmatrelvir, COVID-19 pandemic, SARS-CoV-2, Mpro inhibitors, ritonavir, oral antiviral therapy, high-risk adults, non-hospitalized patients, viral load, unvaccinated patients, early treatment, SARS-CoV-2 variants, Omicron variant
MeSH terms: Viral Protease Inhibitors, COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Administration, Oral, Adult, Antiviral Agents, Double-Blind Method, Drug Combinations, Hospitalization, Humans, Lactams, Leucine, Nitriles, Proline, Vaccination, Treatment Outcome, Disease Progression, Ritonavir, Viral Load

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Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

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