tetano
Editor, Senior Moderator
N Engl J Med
. 2022 Feb 16.
doi: 10.1056/NEJMoa2118542. Online ahead of print.
Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19
Jennifer Hammond[SUP] 1 [/SUP], Heidi Leister-Tebbe[SUP] 1 [/SUP], Annie Gardner[SUP] 1 [/SUP], Paula Abreu[SUP] 1 [/SUP], Weihang Bao[SUP] 1 [/SUP], Wayne Wisemandle[SUP] 1 [/SUP], MaryLynn Baniecki[SUP] 1 [/SUP], Victoria M Hendrick[SUP] 1 [/SUP], Bharat Damle[SUP] 1 [/SUP], Abraham Simón-Campos[SUP] 1 [/SUP], Rienk Pypstra[SUP] 1 [/SUP], James M Rusnak[SUP] 1 [/SUP], EPIC-HR Investigators
Affiliations
Abstract
Background: Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M[SUP]pro[/SUP]) inhibitor with potent pan-human-coronavirus activity in vitro.
Methods: We 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.
Results: A 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 nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log[SUB]10[/SUB] 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.
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 evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).
. 2022 Feb 16.
doi: 10.1056/NEJMoa2118542. Online ahead of print.
Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19
Jennifer Hammond[SUP] 1 [/SUP], Heidi Leister-Tebbe[SUP] 1 [/SUP], Annie Gardner[SUP] 1 [/SUP], Paula Abreu[SUP] 1 [/SUP], Weihang Bao[SUP] 1 [/SUP], Wayne Wisemandle[SUP] 1 [/SUP], MaryLynn Baniecki[SUP] 1 [/SUP], Victoria M Hendrick[SUP] 1 [/SUP], Bharat Damle[SUP] 1 [/SUP], Abraham Simón-Campos[SUP] 1 [/SUP], Rienk Pypstra[SUP] 1 [/SUP], James M Rusnak[SUP] 1 [/SUP], EPIC-HR Investigators
Affiliations
- PMID: 35172054
- DOI: 10.1056/NEJMoa2118542
Abstract
Background: Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M[SUP]pro[/SUP]) inhibitor with potent pan-human-coronavirus activity in vitro.
Methods: We 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.
Results: A 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 nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of -0.868 log[SUB]10[/SUB] 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.
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 evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202.).