In the planned interim analysis of patients treated within 3 days after symptom onset (revised intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19Crelated hospitalization or death by day 28 was reduced 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 individuals) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 individuals) in the placebo group, with 7 deaths. ?3.59; P 0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 individuals) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 individuals) in the placebo group, with 7 deaths. Efficacy was managed in the final analysis involving the 1379 individuals in the revised intention-to-treat human 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. GDC-0834 Racemate The viral weight was lower with nirmaltrelvir 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 CIP1 symptoms. The incidence of adverse events that emerged during the treatment period was comparable in the two groups (any adverse GDC-0834 Racemate event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; severe 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. Conclusions Treatment 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 obvious safety issues. (Supported by Pfizer; ClinicalTrials.gov number, “type”:”clinical-trial”,”attrs”:”text”:”NCT04960202″,”term_id”:”NCT04960202″NCT04960202.) Contamination GDC-0834 Racemate with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and illness with the associated coronavirus disease 2019 (Covid-19) continue to threaten global health.1 Persons with particular characteristics such as older age, current smoking, or underlying clinical conditions such as cardiovascular disease, diabetes, obesity, and cancer are at high risk for severe Covid-19 and associated adverse outcomes.2-5 In a meta-analysis, patients with prespecified coexisting conditions were approximately twice as likely to have progression to severe Covid-19 and five occasions as likely to die from Covid-19 as patients without those conditions.4 Mortality among older adults may be greater than that among persons with prespecified coexisting conditions.2,3,6 A need exists for safe and effective oral Covid-19 treatments that can prevent the progression of infection to more severe disease, hospitalization, and death; shorten the time to clinical recovery; and reduce the transmission rate. Such treatments would help reduce current strains on health care systems, including overwhelmed hospital facilities and lack of beds in rigorous care models. For nonhospitalized patients with mild-to-moderate Covid-19, treatment options include monoclonal antibodies, which are currently available under emergency use authorization by the Food and Drug Administration for patients at high risk for progression to severe Covid-19.7-10 Although monoclonal antibodies significantly reduce the risk of progression to severe Covid-19,11-13 limitations to their use include the need for administration and monitoring in a health care setting and the potential for reduced efficacy against emerging SARS-CoV-2 variants.10 Nirmatrelvir (PF-07321332) is an orally administered antiviral agent targeting the SARS-CoV-2 3-chymotrypsinClike cysteine protease enzyme (Mpro).14 Mpro is an attractive antiviral target because it is essential in the viral replication cycle (i.e., in processing viral polyproteins into functional models)15 and has a low likelihood of off-target activity, owing to the absence of acknowledged human analogues.16 Nirmatrelvir exhibited potent inhibition of Mpro activity and virus replication across a wide spectrum of coronaviruses in vitro; oral administration was associated with SARS-CoV-2 lung titers that were significantly lower than titers associated with placebo in a mouse model.14 Nirmatrelvir is metabolized mainly by CYP3A4.14 Coadministration of nirmatrelvir with a low dose (100 mg) of ritonavir, a CYP3A4 inhibitor, enhances nirmatrelvir pharmacokinetics.14,17 A first-in-human study in healthy participants (ClinicalTrials.gov number, “type”:”clinical-trial”,”attrs”:”text”:”NCT04756531″,”term_id”:”NCT04756531″NCT04756531) showed a clinically acceptable security profile up to the highest dose and exposure evaluated (500 mg of nirmatrelvir plus 100 mg of ritonavir twice daily for 10 days). Simulations showed that twice-daily administration of 300 mg of nirmatrelvir plus 100 mg of ritonavir achieves and maintains plasma trough concentrations approximately five to six occasions the in vitro 90% effective concentration of nirmatrelvir (i.e., the concentration at which 90% inhibition of SARS-CoV-2 viral replication is usually observed) (data on file). The EPIC-HR trial (Evaluation of Protease Inhibition for Covid-19 in High-Risk Patients) evaluated the security and efficacy of nirmatrelvir plus ritonavir in nonhospitalized adults with mild-to-moderate Covid-19 at high risk for progression to severe disease. Methods Objectives, Patients, and Oversight This.