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Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19. BACKGROUND: Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (Mpro) 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 nirmatrelvir 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 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.).

This phase 2–3, double-blind, randomized, placebo-controlled trial evaluated the efficacy, viral load, and safety associated with the use of nirmatrelvir plus ritonavir among nonhospitalized, symptomatic adults with Covid-19 who were at high risk for progression to severe disease. Eligible patients were required to be at least 18 years old; to have confirmed SARS-CoV-2 infection and symptom onset no more than 5 days before randomization, with at least one sign or symptom of Covid-19 on the day of randomization (see Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org); and to have at least one characteristic or coexisting condition associated with high risk of progression to severe Covid-19.2-4,6 The trial was approved by an ethics committee at each site, and all participants provided written informed consent. Key exclusion criteria were previous confirmed SARS-CoV-2 infection or hospitalization for Covid-19, anticipated need for hospitalization within 48 hours after randomization, and prior receipt of convalescent Covid-19 plasma or SARS-CoV-2 vaccine. The Supplementary Appendix provides additional inclusion and exclusion criteria and information on prohibited prior or concomitant therapies, trial blinding, ethical conduct, and responsibilities of the sponsor. All the data were available to all the authors, who vouch for the accuracy and completeness of the data as well as the adherence of the trial to the protocol, which is available at NEJM.org and includes the statistical analysis plan.

itant therapies, trial blinding, ethical conduct, and responsibilities of the sponsor. All the data were available to all the authors, who vouch for the accuracy and completeness of the data as well as the adherence of the trial to the protocol, which is available at NEJM.org and includes the statistical analysis plan. Eligible patients were randomly assigned in a 1:1 ratio, by means of an interactive response technology system, to receive either nirmatrelvir plus ritonavir or matched placebo every 12 hours for 5 days (10 doses total). Randomization was stratified by geographic region and by receipt or expected receipt (based on investigator opinion) of Covid-19 monoclonal antibodies. Nirmatrelvir and matching placebo were manufactured by Pfizer, ritonavir tablets were manufactured and tested by Hetero Labs, and blinding of the tablets was performed by Pfizer through over-encapsulation. The assessment schedule is outlined in Figure S1.

ased on investigator opinion) of Covid-19 monoclonal antibodies. Nirmatrelvir and matching placebo were manufactured by Pfizer, ritonavir tablets were manufactured and tested by Hetero Labs, and blinding of the tablets was performed by Pfizer through over-encapsulation. The assessment schedule is outlined in Figure S1. The primary objective of the trial was to assess the efficacy of nirmatrelvir plus ritonavir as compared with placebo by comparing the percentage of patients with Covid-19–related hospitalization or death from any cause through day 28 in the two groups. This comparison was performed in the modified intention-to-treat population, which included patients whose treatment began within 3 days after the onset of Covid-19 signs and symptoms and excluded patients who at randomization had received or were expected to receive monoclonal antibody treatment (see Table S2 for definitions of all analysis populations). A key secondary end point was the primary comparison analyzed similarly among patients whose treatment began within 5 days after the onset of Covid-19 signs and symptoms. A supplementary analysis was conducted to include patients who had received or were expected to receive monoclonal antibody treatment. Prespecified subgroup analyses of primary and secondary end points were conducted, and nominal 95% confidence intervals were provided to evaluate whether the treatment effect varied according to age, sex, race, body-mass index (BMI, the weight in kilograms divided by the square of the height in meters), baseline serology status and viral load, and number of baseline coexisting conditions and risk factors (see the Supplementary Appendix for details on the serology methods).

treatment effect varied according to age, sex, race, body-mass index (BMI, the weight in kilograms divided by the square of the height in meters), baseline serology status and viral load, and number of baseline coexisting conditions and risk factors (see the Supplementary Appendix for details on the serology methods). Detection and quantification of SARS-CoV-2 viral load in nasopharyngeal swabs by reverse-transcriptase–polymerase-chain-reaction assay was a secondary end point. Nasopharyngeal or nasal swabs were collected on day 1 (baseline) and days 3, 5, 10, and 14. Safety end points included adverse events that emerged during or after the treatment period (starting on or before day 34), serious adverse events, and adverse events leading to discontinuation of the trial drug or placebo, as coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 24.0. Incidence data were provided for each treatment group within the safety analysis population, which included all patients who received at least one dose of drug or placebo. Investigators actively collected safety information through day 34.

ding to the Medical Dictionary for Regulatory Activities (MedDRA), version 24.0. Incidence data were provided for each treatment group within the safety analysis population, which included all patients who received at least one dose of drug or placebo. Investigators actively collected safety information through day 34. The trial planned to enroll approximately 3000 patients. Of these, 1717 were to be included in the primary analysis to ensure 90% power, accounting for an interim analysis, to detect a 50% difference in Covid-19–related hospitalization or death from any cause with nirmatrelvir plus ritonavir, as compared with placebo (anticipated event rate with placebo, 7.0%)11 in patients who had undergone randomization within 3 days after symptom onset and who received no monoclonal antibodies. The primary analysis compared proportions of patients in the two groups who were hospitalized for Covid-19 or died from any cause through day 28, using the Kaplan–Meier method to account for all patients, including those prematurely withdrawn from the trial or lost to follow-up. A z-test was used for the comparison, with standard errors estimated from Greenwood’s formula. The end points were tested sequentially (i.e., first the primary end point, then the first key secondary end point, and finally other secondary end points) to ensure the overall alpha level of 0.05.

rial or lost to follow-up. A z-test was used for the comparison, with standard errors estimated from Greenwood’s formula. The end points were tested sequentially (i.e., first the primary end point, then the first key secondary end point, and finally other secondary end points) to ensure the overall alpha level of 0.05. Changes from baseline to day 5 in log10-transformed viral load were compared between treatment groups with an analysis of covariance (ANCOVA) model adjusted for baseline viral load and serology status. Patients without detectable virus at baseline were excluded from the analysis. Viral loads below the limit of detection (2 log10 copies per milliliter) were imputed as 1.70 log10 copies per milliliter. On the basis of a group sequential design utilizing a Lan–DeMets alpha-spending function with an O’Brien–Fleming stopping boundary,18,19 a prespecified interim analysis of the primary end point for efficacy, futility, and sample size re-estimation was performed by an external data monitoring committee once approximately 45% of patients in the primary analysis population had completed assessments through day 28. The prespecified significance level for early termination was 0.002 for efficacy and 0.9184 for futility. See the Supplementary Appendix for additional details regarding the statistical analyses, including handling of missing data.

Eligible patients were randomly assigned in a 1:1 ratio, by means of an interactive response technology system, to receive either nirmatrelvir plus ritonavir or matched placebo every 12 hours for 5 days (10 doses total). Randomization was stratified by geographic region and by receipt or expected receipt (based on investigator opinion) of Covid-19 monoclonal antibodies. Nirmatrelvir and matching placebo were manufactured by Pfizer, ritonavir tablets were manufactured and tested by Hetero Labs, and blinding of the tablets was performed by Pfizer through over-encapsulation. The assessment schedule is outlined in Figure S1.

The primary objective of the trial was to assess the efficacy of nirmatrelvir plus ritonavir as compared with placebo by comparing the percentage of patients with Covid-19–related hospitalization or death from any cause through day 28 in the two groups. This comparison was performed in the modified intention-to-treat population, which included patients whose treatment began within 3 days after the onset of Covid-19 signs and symptoms and excluded patients who at randomization had received or were expected to receive monoclonal antibody treatment (see Table S2 for definitions of all analysis populations). A key secondary end point was the primary comparison analyzed similarly among patients whose treatment began within 5 days after the onset of Covid-19 signs and symptoms. A supplementary analysis was conducted to include patients who had received or were expected to receive monoclonal antibody treatment. Prespecified subgroup analyses of primary and secondary end points were conducted, and nominal 95% confidence intervals were provided to evaluate whether the treatment effect varied according to age, sex, race, body-mass index (BMI, the weight in kilograms divided by the square of the height in meters), baseline serology status and viral load, and number of baseline coexisting conditions and risk factors (see the Supplementary Appendix for details on the serology methods).

Detection and quantification of SARS-CoV-2 viral load in nasopharyngeal swabs by reverse-transcriptase–polymerase-chain-reaction assay was a secondary end point. Nasopharyngeal or nasal swabs were collected on day 1 (baseline) and days 3, 5, 10, and 14.

Safety end points included adverse events that emerged during or after the treatment period (starting on or before day 34), serious adverse events, and adverse events leading to discontinuation of the trial drug or placebo, as coded according to the Medical Dictionary for Regulatory Activities (MedDRA), version 24.0. Incidence data were provided for each treatment group within the safety analysis population, which included all patients who received at least one dose of drug or placebo. Investigators actively collected safety information through day 34.

The trial planned to enroll approximately 3000 patients. Of these, 1717 were to be included in the primary analysis to ensure 90% power, accounting for an interim analysis, to detect a 50% difference in Covid-19–related hospitalization or death from any cause with nirmatrelvir plus ritonavir, as compared with placebo (anticipated event rate with placebo, 7.0%)11 in patients who had undergone randomization within 3 days after symptom onset and who received no monoclonal antibodies. The primary analysis compared proportions of patients in the two groups who were hospitalized for Covid-19 or died from any cause through day 28, using the Kaplan–Meier method to account for all patients, including those prematurely withdrawn from the trial or lost to follow-up. A z-test was used for the comparison, with standard errors estimated from Greenwood’s formula. The end points were tested sequentially (i.e., first the primary end point, then the first key secondary end point, and finally other secondary end points) to ensure the overall alpha level of 0.05. Changes from baseline to day 5 in log10-transformed viral load were compared between treatment groups with an analysis of covariance (ANCOVA) model adjusted for baseline viral load and serology status. Patients without detectable virus at baseline were excluded from the analysis. Viral loads below the limit of detection (2 log10 copies per milliliter) were imputed as 1.70 log10 copies per milliliter.

n treatment groups with an analysis of covariance (ANCOVA) model adjusted for baseline viral load and serology status. Patients without detectable virus at baseline were excluded from the analysis. Viral loads below the limit of detection (2 log10 copies per milliliter) were imputed as 1.70 log10 copies per milliliter. On the basis of a group sequential design utilizing a Lan–DeMets alpha-spending function with an O’Brien–Fleming stopping boundary,18,19 a prespecified interim analysis of the primary end point for efficacy, futility, and sample size re-estimation was performed by an external data monitoring committee once approximately 45% of patients in the primary analysis population had completed assessments through day 28. The prespecified significance level for early termination was 0.002 for efficacy and 0.9184 for futility. See the Supplementary Appendix for additional details regarding the statistical analyses, including handling of missing data.

Between July 16 and December 9, 2021, a total of 2246 patients were enrolled at 343 sites worldwide; 1120 received nirmatrelvir plus ritonavir and 1126 received placebo (Figure 1). Of the 2246 patients, 2102 completed safety follow-up (day 34); no patients had completed long-term follow-up at the time of this analysis (i.e., through week 24). Patient characteristics were similar in the two groups (Table 1) and were largely representative of the expected patient population (Table S3). The median age was 46 years; 1148 patients (51.1%) were male, and 1607 (71.5%) and 315 (14.0%) were White and Asian, respectively. The most common prespecified characteristics and coexisting conditions associated with a risk of progression to severe Covid-19 at baseline were a BMI of 25 or above (1807 patients [80.5%]), current smoking (876 [39.0%]), and hypertension (739 [32.9%]); 1370 patients (61.0%) had two or more such characteristics or coexisting conditions. Most patients (2106 [93.8%]) had not received or were not expected to receive monoclonal antibodies for Covid-19 treatment at randomization, and 1489 (66.3%) received the first dose of the trial drug or placebo within 3 days after the onset of symptoms. Before receiving the trial drug or placebo, 4 patients had received monoclonal antibodies for Covid-19 treatment (3 in the nirmatrelvir group and 1 in the placebo group).

Covid-19 treatment at randomization, and 1489 (66.3%) received the first dose of the trial drug or placebo within 3 days after the onset of symptoms. Before receiving the trial drug or placebo, 4 patients had received monoclonal antibodies for Covid-19 treatment (3 in the nirmatrelvir group and 1 in the 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), significantly fewer recipients of nirmatrelvir plus ritonavir had Covid-19–related hospitalization or death by day 28 (3 of 389 patients [0.77%]; 0 deaths) than placebo recipients (27 of 385 [7.01%]; 7 deaths), a difference of −6.32 percentage points (95% CI, –9.04 to –3.59; P<0.001). The relative risk reduction was 89.1%.

ificantly fewer recipients of nirmatrelvir plus ritonavir had Covid-19–related hospitalization or death by day 28 (3 of 389 patients [0.77%]; 0 deaths) than placebo recipients (27 of 385 [7.01%]; 7 deaths), a difference of −6.32 percentage points (95% CI, –9.04 to –3.59; P<0.001). The relative risk reduction was 89.1%. In the final analysis of patients who commenced treatment within 3 days after symptom onset and did not receive monoclonal antibodies (modified intention-to-treat population, comprising 1379 of the 2246 patients in the full analysis population), 5 of 697 patients (0.72%) in the nirmatrelvir group and 44 of 682 (6.45%) in the placebo group were hospitalized for Covid-19 or died from any cause through day 28 (Figure 2A). With use of the Kaplan–Meier method, the estimated event rates of Covid-19–related hospitalization or death from any cause at 28 days were 0.72% and 6.53% in the nirmatrelvir and placebo groups, respectively, corresponding to a difference of −5.81 percentage points (95% CI, –7.78 to –3.84; P<0.001) and an 88.9% relative risk reduction in Covid-19–related hospitalization or death from any cause. Nine deaths were reported in the placebo group and none in the nirmatrelvir group.

e nirmatrelvir and placebo groups, respectively, corresponding to a difference of −5.81 percentage points (95% CI, –7.78 to –3.84; P<0.001) and an 88.9% relative risk reduction in Covid-19–related hospitalization or death from any cause. Nine deaths were reported in the placebo group and none in the nirmatrelvir group. After results of the primary analysis were found to be significant, the first key secondary analysis was performed among patients who commenced treatment within 5 days after symptom onset to evaluate hospitalization for Covid-19 or death from any cause. In the final analysis of this population, 8 of 1039 patients (0.77%) in the nirmatrelvir group and 66 of 1046 (6.31%) in the placebo group were hospitalized for Covid-19 or died from any cause through day 28 (P<0.001), corresponding to an 87.8% relative risk reduction (Figure 2A and 2B). When 139 patients who received or were expected to receive monoclonal antibody treatment were included in the evaluation (6.25% of the total analysis population), hospitalizations due to Covid-19 or deaths from any cause were 0.81% and 6.10% in the nirmatrelvir and placebo groups, respectively (Table S4). Results from subgroup analyses were consistent, regardless of age, sex, race, BMI, baseline serology status, viral load, coexisting conditions, or number of coexisting conditions at baseline (Figure 2C and Fig. S2A through C).

y cause were 0.81% and 6.10% in the nirmatrelvir and placebo groups, respectively (Table S4). Results from subgroup analyses were consistent, regardless of age, sex, race, BMI, baseline serology status, viral load, coexisting conditions, or number of coexisting conditions at baseline (Figure 2C and Fig. S2A through C). Data on SARS-CoV-2 viral load collected at baseline and day 5 were evaluated in 1574 patients (i.e., in 70% of the 2246 patients). After adjustment for baseline viral load, serology status, and geographic region, nirmatrelvir plus ritonavir reduced viral load at day 5 by an adjusted mean (±SE) of an additional 0.868±0.105 log10 copies per milliliter (95% CI, –1.074 to –0.6615; P<0.001) when treatment was initiated within 3 days after symptom onset, a decrease in viral load by a factor of 10 relative to placebo, and 0.695±0.085 log10 copies per milliliter (95% CI, –0.861 to –0.530; P<0.001) when treatment was initiated within 5 days after symptom onset (Figure 3A and Fig. S3A). When patients who received or were expected to receive monoclonal antibodies for Covid-19 treatment were included in the analysis, nirmatrelvir plus ritonavir showed a similar antiviral effect (nirmatrelvir plus ritonavir reduced viral load at day 5 by an additional 0.689±0.082 log10 copies per milliliter; 95% CI, –0.849 to –0.529 relative to placebo) (Fig. S4). Results from subgroup analyses were consistent with those in the overall population regardless of baseline viral load and serology status (Figure 3B through E and Fig. S3B through E). Preliminary analysis of 731 matched samples from day 1 and day 5 with available sequencing data suggests no significant associations between Mpro mutations and treatment failure.

tent with those in the overall population regardless of baseline viral load and serology status (Figure 3B through E and Fig. S3B through E). Preliminary analysis of 731 matched samples from day 1 and day 5 with available sequencing data suggests no significant associations between Mpro mutations and treatment failure. The incidence of adverse events that emerged during or after the treatment period was similar among recipients of nirmatrelvir plus ritonavir (22.6%) and recipients of placebo (23.9%) (Table 2). The most frequently reported such events (affecting at least 1% of patients) — both events considered by the investigator to be related to the assigned drug or placebo and those not considered to be related — among recipients of nirmatrelvir plus ritonavir were dysgeusia (5.6%, as compared with 0.3% of placebo recipients), diarrhea (3.1% vs. 1.6%), fibrin D-dimer increase (1.9% vs. 2.8%), alanine aminotransferase increase (1.5% vs. 2.4%), headache (1.4% vs. 1.3%), creatinine renal clearance decrease (1.4% vs. 1.6%), nausea (1.4% vs. 1.7%), and vomiting (1.1% vs. 0.8%); these adverse events were nonserious, were mostly grade 1 or 2, and resolved (Table S5).

1.6%), fibrin D-dimer increase (1.9% vs. 2.8%), alanine aminotransferase increase (1.5% vs. 2.4%), headache (1.4% vs. 1.3%), creatinine renal clearance decrease (1.4% vs. 1.6%), nausea (1.4% vs. 1.7%), and vomiting (1.1% vs. 0.8%); these adverse events were nonserious, were mostly grade 1 or 2, and resolved (Table S5). Adverse events considered by the site investigator to be related to the trial drug or placebo were more common among recipients of nirmatrelvir plus ritonavir (7.8%) than among placebo recipients (3.8%). This difference was largely attributed to dysgeusia (4.5% vs. 0.2%) and diarrhea (1.3% vs. 0.2%), which were the only treatment-related adverse events reported in at least 1% of recipients of nirmatrelvir plus ritonavir; the majority of such events were resolved and were grade 1 or 2, with the exception of one case of grade 3 dysgeusia. Percentages were lower and similar across groups for related grade 3 events (nirmatrelvir plus ritonavir, 0.5%; placebo, 0.4%) and grade 4 events (nirmatrelvir plus ritonavir, 0; placebo, <0.1%).

navir; the majority of such events were resolved and were grade 1 or 2, with the exception of one case of grade 3 dysgeusia. Percentages were lower and similar across groups for related grade 3 events (nirmatrelvir plus ritonavir, 0.5%; placebo, 0.4%) and grade 4 events (nirmatrelvir plus ritonavir, 0; placebo, <0.1%). Patients who received nirmatrelvir plus ritonavir reported fewer grade 3 or 4 adverse events than placebo recipients (4.1% vs. 8.3%), fewer serious adverse events (1.6% vs. 6.6%), and fewer adverse events leading to discontinuation of the drug or placebo (2.1% vs. 4.2%) (Table 2). The most frequently reported serious adverse events (those occurring in at least 2 patients) among recipients of nirmatrelvir plus ritonavir were Covid-19 pneumonia (6 patients [0.5%], as compared with 37 [3.3%] in the placebo group), Covid-19 (2 patients [0.2%], as compared with 8 [0.7%]), and decreased renal creatinine clearance (2 patients [0.2%], as compared with 3 [0.3%]); none were considered by the investigator to be related to nirmatrelvir or placebo (Table S6). Through day 34, no serious adverse events resulted in death among recipients of nirmatrelvir plus ritonavir; there were 13 deaths among placebo recipients, and all the deaths were Covid-19–related (Covid-19 pneumonia, 8 patients; Covid-19, 3 patients; pneumonitis, 1 patient; and acute respiratory failure, 1 patient). Adverse events that led to discontinuation of the trial drug or placebo in more than one patient in either treatment group (listed in order of frequency across treatment groups) were Covid-19 pneumonia, nausea, decreased renal creatinine clearance, vomiting, Covid-19, decreased glomerular filtration rate, pneumonia, pneumonitis, decreased white-cell count, and dysgeusia. Among recipients of nirmatrelvir plus ritonavir who discontinued the drug owing to an adverse event, events were mostly mild-to-moderate (grade 1 or 2) and were resolved or resolving at the time of this analysis. Twelve patients had an adverse event that was life-threatening (grade 4) (2 recipients of nirmatrelvir plus ritonavir and 10 placebo recipients). Few events (≤0.8%) leading to discontinuation of drug or placebo in either treatment group were considered by the investigator to be related to the trial drug or placebo.

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), significantly fewer recipients of nirmatrelvir plus ritonavir had Covid-19–related hospitalization or death by day 28 (3 of 389 patients [0.77%]; 0 deaths) than placebo recipients (27 of 385 [7.01%]; 7 deaths), a difference of −6.32 percentage points (95% CI, –9.04 to –3.59; P<0.001). The relative risk reduction was 89.1%. In the final analysis of patients who commenced treatment within 3 days after symptom onset and did not receive monoclonal antibodies (modified intention-to-treat population, comprising 1379 of the 2246 patients in the full analysis population), 5 of 697 patients (0.72%) in the nirmatrelvir group and 44 of 682 (6.45%) in the placebo group were hospitalized for Covid-19 or died from any cause through day 28 (Figure 2A). With use of the Kaplan–Meier method, the estimated event rates of Covid-19–related hospitalization or death from any cause at 28 days were 0.72% and 6.53% in the nirmatrelvir and placebo groups, respectively, corresponding to a difference of −5.81 percentage points (95% CI, –7.78 to –3.84; P<0.001) and an 88.9% relative risk reduction in Covid-19–related hospitalization or death from any cause. Nine deaths were reported in the placebo group and none in the nirmatrelvir group.

Data on SARS-CoV-2 viral load collected at baseline and day 5 were evaluated in 1574 patients (i.e., in 70% of the 2246 patients). After adjustment for baseline viral load, serology status, and geographic region, nirmatrelvir plus ritonavir reduced viral load at day 5 by an adjusted mean (±SE) of an additional 0.868±0.105 log10 copies per milliliter (95% CI, –1.074 to –0.6615; P<0.001) when treatment was initiated within 3 days after symptom onset, a decrease in viral load by a factor of 10 relative to placebo, and 0.695±0.085 log10 copies per milliliter (95% CI, –0.861 to –0.530; P<0.001) when treatment was initiated within 5 days after symptom onset (Figure 3A and Fig. S3A). When patients who received or were expected to receive monoclonal antibodies for Covid-19 treatment were included in the analysis, nirmatrelvir plus ritonavir showed a similar antiviral effect (nirmatrelvir plus ritonavir reduced viral load at day 5 by an additional 0.689±0.082 log10 copies per milliliter; 95% CI, –0.849 to –0.529 relative to placebo) (Fig. S4). Results from subgroup analyses were consistent with those in the overall population regardless of baseline viral load and serology status (Figure 3B through E and Fig. S3B through E). Preliminary analysis of 731 matched samples from day 1 and day 5 with available sequencing data suggests no significant associations between Mpro mutations and treatment failure.

The incidence of adverse events that emerged during or after the treatment period was similar among recipients of nirmatrelvir plus ritonavir (22.6%) and recipients of placebo (23.9%) (Table 2). The most frequently reported such events (affecting at least 1% of patients) — both events considered by the investigator to be related to the assigned drug or placebo and those not considered to be related — among recipients of nirmatrelvir plus ritonavir were dysgeusia (5.6%, as compared with 0.3% of placebo recipients), diarrhea (3.1% vs. 1.6%), fibrin D-dimer increase (1.9% vs. 2.8%), alanine aminotransferase increase (1.5% vs. 2.4%), headache (1.4% vs. 1.3%), creatinine renal clearance decrease (1.4% vs. 1.6%), nausea (1.4% vs. 1.7%), and vomiting (1.1% vs. 0.8%); these adverse events were nonserious, were mostly grade 1 or 2, and resolved (Table S5). Adverse events considered by the site investigator to be related to the trial drug or placebo were more common among recipients of nirmatrelvir plus ritonavir (7.8%) than among placebo recipients (3.8%). This difference was largely attributed to dysgeusia (4.5% vs. 0.2%) and diarrhea (1.3% vs. 0.2%), which were the only treatment-related adverse events reported in at least 1% of recipients of nirmatrelvir plus ritonavir; the majority of such events were resolved and were grade 1 or 2, with the exception of one case of grade 3 dysgeusia. Percentages were lower and similar across groups for related grade 3 events (nirmatrelvir plus ritonavir, 0.5%; placebo, 0.4%) and grade 4 events (nirmatrelvir plus ritonavir, 0; placebo, <0.1%).

Results from this phase 2–3 trial in unvaccinated persons demonstrate the efficacy of oral administration of nirmatrelvir (300 mg) with ritonavir (100 mg) every 12 hours for 5 days. This regimen, commencing within 3 days after the onset of Covid-19 symptoms, was found to be efficacious at the planned interim analysis, with an 89.1% relative risk reduction in Covid-19–related hospitalization or death from any cause by day 28 among nonhospitalized adults at high risk for progression to severe disease. At the full analysis, relative risk reductions of 88.9% and 87.8% were observed among patients commencing treatment within 3 days and within 5 days after symptom onset, respectively, with 0 deaths occurring in the group that received nirmatrelvir plus ritonavir and 13 deaths occurring in the placebo group. This efficacy was supported by subgroup analyses of the primary end point; patients treated with nirmatrelvir plus ritonavir either had no Covid-19–related hospitalization or death from any cause or had a risk that was significantly lower than that with placebo, regardless of age, sex, race, BMI, baseline serology status, viral load, coexisting conditions, or number of coexisting conditions at baseline. Treatment with nirmatrelvir plus ritonavir was also associated with an additional reduction in SARS-CoV-2 viral load at day 5, by a factor of 10, as compared with placebo.

ebo, regardless of age, sex, race, BMI, baseline serology status, viral load, coexisting conditions, or number of coexisting conditions at baseline. Treatment with nirmatrelvir plus ritonavir was also associated with an additional reduction in SARS-CoV-2 viral load at day 5, by a factor of 10, as compared with placebo. Nirmatrelvir plus ritonavir targets an essential protein that is conserved across coronaviruses.15,20,21 Given the well-conserved nature of the Mpro active site, inhibitors of Mpro may be more likely to retain activity against future variants.20,21 Fewer serious adverse events and adverse events leading to treatment discontinuation occurred with nirmatrelvir plus ritonavir than with placebo. The most frequent adverse events occurring more often in recipients of nirmatrelvir plus ritonavir were dysgeusia, diarrhea, and vomiting.

Nirmatrelvir plus ritonavir targets an essential protein that is conserved across coronaviruses.15,20,21 Given the well-conserved nature of the Mpro active site, inhibitors of Mpro may be more likely to retain activity against future variants.20,21 Fewer serious adverse events and adverse events leading to treatment discontinuation occurred with nirmatrelvir plus ritonavir than with placebo. The most frequent adverse events occurring more often in recipients of nirmatrelvir plus ritonavir were dysgeusia, diarrhea, and vomiting. The concomitant use of nirmatrelvir plus ritonavir and certain drugs may result in potentially important drug interactions. Such interactions need to be managed through dose reduction of the concomitant medication, use of an alternative concomitant medication, increased monitoring for adverse events or concomitant medication drug levels, temporary discontinuation of concomitant medications, or avoidance of coadministration. Drug interactions with low-dose ritonavir (100 mg) given over a short duration of 5 days for treatment of Covid-19 are likely to be of lesser clinical consequence than long-term use of low-dose or standard-dose (600 mg) ritonavir for patients with human immunodeficiency virus. Nirmatrelvir plus ritonavir is contraindicated with use of certain drugs because of the risk of serious adverse events.

n of 5 days for treatment of Covid-19 are likely to be of lesser clinical consequence than long-term use of low-dose or standard-dose (600 mg) ritonavir for patients with human immunodeficiency virus. Nirmatrelvir plus ritonavir is contraindicated with use of certain drugs because of the risk of serious adverse events. The trial has several strengths and limitations. Patients from diverse regions were included, enabling broad geographic generalizability. Although only persons at high risk for progression to severe Covid-19 were included, the corresponding demographic and clinical characteristics are relatively common: cardiovascular disease, obesity, and diabetes have been estimated at 7 to 14.9% worldwide prevalence in recent years,22-24 and approximately 12% of the world population in 2017 was 60 years of age or older.25 Of importance, this trial was restricted to unvaccinated persons, although a separate, ongoing trial of nirmatrelvir plus ritonavir (EPIC-Standard Risk [SR]; NCT05011513) includes vaccinated, high-risk persons.

e in recent years,22-24 and approximately 12% of the world population in 2017 was 60 years of age or older.25 Of importance, this trial was restricted to unvaccinated persons, although a separate, ongoing trial of nirmatrelvir plus ritonavir (EPIC-Standard Risk [SR]; NCT05011513) includes vaccinated, high-risk persons. Molnupiravir is an orally administered antiviral Covid-19 treatment that currently has emergency use authorization in the United States for use in the high-risk, nonhospitalized population,26 achieving a 30% reduction in Covid-19–related hospitalization or death through 29 days after randomization.27,28 Covid-19 therapeutic monoclonal antibodies are associated with relative risk reductions of approximately 70 to 85% against mild-to-moderate Covid-19 in outpatient settings11-13; however, monoclonal antibodies require intravenous or subcutaneous administration in a health care setting, and they may be less effective against emerging variants harboring mutations in the monoclonal antibody–targeted SARS-CoV-2 spike protein.7-9,29,30 Remdesivir, an agent administered intravenously that is approved for use in patients hospitalized for Covid-19, has shown an 87% reduction in the risk of progression to severe disease in the outpatient setting.31 Our data show that treatment with nirmatrelvir plus ritonavir early in Covid-19 illness can decrease progression to severe disease and quickly reduce SARS-CoV-2 viral load.