Paxlovid (nirmatrelvir-ritonavir) is an orally administered SARS-CoV-2 main protease inhibitor designed to be prescribed at the first sign of infection. The Food and Drug Administration (FDA) has issued an emergency use authorization for its use in the treatment of mild to moderate COVID-19 in adults and pediatric patients ages 12 and older who are at high risk for progression to severe COVID. A phase 2/ phase 3 trial was undertaken to evaluate the medication's use in patients at standard risk for developing severe COVID.

The study enrolled 1,153 patients who had (1) a confirmed diagnosis of SARS-CoV-2 infection within five days of randomization, (2) onset of symptoms within five days of randomization, and (3) at least one characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19 and who were fully vaccinated against COVID-19 or had no characteristics associated with risk of severe COVID and were unvaccinated. Patients were randomized to receive either the study drug or placebo orally twice a day for five days.

Patient data showed a nonsignificant 51% relative risk reduction in the primary end point of self-reported sustained alleviation of all symptoms for four consecutive days in the treatment arm. A subgroup analysis of 721 vaccinated adults with at least one risk factor for progression to severe disease showed a nonsignificant 57% relative risk reduction in hospitalization or death. There was a nominally significant 62% reduction in COVID-related medical visits per day in all patients receiving Paxlovid, relative to placebo. Additionally, there was a 72% reduction in the average number of days in the hospital among Paxlovid-treated patients compared with patients receiving placebo. No patients in the treatment group were admitted to the ICU compared with three in the placebo group, and no patients in the treatment arm died compared with one in the placebo arm.

Treatment-related adverse events and the rates of serious adverse events and the discontinuation of treatment were comparable in the treatment and placebo groups.

Enrollment in the trial was discontinued because of very low rates of hospitalization or death in the standard-risk patient population, and the data were included in the planned new drug submission to the FDA for use of Paxlovid in people at high risk for progression to severe illness.