Oral Nirmatrelvir-Ritonavir as Postexposure Prophylaxis for Covid-19

N Engl J Med. 2024 Jul 18;391(3):224-234. doi: 10.1056/NEJMoa2309002.

Abstract

Background: Clinical trials of treatments for coronavirus disease 2019 (Covid-19) have not shown a significant benefit of postexposure prophylaxis.

Methods: We conducted a phase 2-3 double-blind trial to assess the efficacy and safety of nirmatrelvir-ritonavir in asymptomatic, rapid antigen test-negative adults who had been exposed to a household contact with Covid-19 within 96 hours before randomization. The participants were randomly assigned in a 1:1:1 ratio to receive nirmatrelvir-ritonavir (300 mg of nirmatrelvir and 100 mg of ritonavir) every 12 hours for 5 days or for 10 days or matching placebo for 5 or 10 days. The primary end point was the development of symptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, confirmed on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or rapid antigen testing, through 14 days in participants who had a negative RT-PCR test at baseline.

Results: A total of 2736 participants were randomly assigned to a trial group - 921 to the 5-day nirmatrelvir-ritonavir group, 917 to the 10-day nirmatrelvir-ritonavir group, and 898 to the placebo group. Symptomatic, confirmed SARS-CoV-2 infection developed by day 14 in 2.6% of the participants in the 5-day nirmatrelvir-ritonavir group, 2.4% of those in the 10-day nirmatrelvir-ritonavir group, and 3.9% of those in the placebo group. In each nirmatrelvir-ritonavir group, the percentage of participants in whom symptomatic, confirmed SARS-CoV-2 infection developed did not differ significantly from that in the placebo group, with risk reductions relative to placebo of 29.8% (95% confidence interval [CI], -16.7 to 57.8; P = 0.17) in the 5-day nirmatrelvir-ritonavir group and 35.5% (95% CI, -11.5 to 62.7; P = 0.12) in the 10-day nirmatrelvir-ritonavir group. The incidence of adverse events was similar across the trial groups, with dysgeusia being the most frequently reported adverse event (in 5.9% and 6.8% of the participants in the 5-day and 10-day nirmatrelvir-ritonavir groups, respectively, and in 0.7% of those in the placebo group).

Conclusions: In this placebo-controlled trial, postexposure prophylaxis with nirmatrelvir-ritonavir for 5 or 10 days did not significantly reduce the risk of symptomatic SARS-CoV-2 infection. (Funded by Pfizer; ClinicalTrials.gov number, NCT05047601.).

Publication types

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

MeSH terms

  • Administration, Oral
  • Adult
  • Antiviral Agents* / administration & dosage
  • Antiviral Agents* / adverse effects
  • Antiviral Agents* / therapeutic use
  • COVID-19 Drug Treatment*
  • COVID-19* / prevention & control
  • Double-Blind Method
  • Drug Combinations
  • Drug Therapy, Combination
  • Female
  • Humans
  • Indazoles / adverse effects
  • Indazoles / therapeutic use
  • Indoles / administration & dosage
  • Indoles / adverse effects
  • Indoles / therapeutic use
  • Lactams
  • Leucine
  • Male
  • Middle Aged
  • Nitriles
  • Post-Exposure Prophylaxis*
  • Proline
  • Ritonavir / administration & dosage
  • Ritonavir / adverse effects
  • Ritonavir / therapeutic use
  • SARS-CoV-2*
  • Young Adult

Substances

  • Antiviral Agents
  • Drug Combinations
  • Indazoles
  • Indoles
  • Lactams
  • Leucine
  • nirmatrelvir
  • Nitriles
  • Proline
  • Ritonavir
  • nirmatrelvir and ritonavir drug combination

Associated data

  • ClinicalTrials.gov/NCT05047601

Grants and funding