August 17, 2022

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Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

Patients

Randomization, Treatment Assignments, and Follow-up.

Patients were recruited through December 9, 2021, from the United States (105 sites), Bulgaria (30 sites), South Africa (28 sites), Brazil (26 sites), India (19 sites), Mexico (18 sites), Ukraine (17 sites), Turkey (16 sites), Japan and Spain (10 sites each), Russia (9 sites), Argentina and Colombia (8 sites each), Poland and South Korea (7 sites each), Hungary (6 sites), Taiwan (5 sites), Malaysia and Czech Republic (4 sites each), and Thailand and Puerto Rico (3 sites each).

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).

Demographic and Clinical Characteristics of the Patients (Full Analysis Population).

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).

Efficacy

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%.

Efficacy of Nirmatrelvir plus Ritonavir (NMV-r) in Preventing Covid-19–Related Hospitalization or Death from Any Cause through Day 28.

Panel A shows efficacy results among patients who were treated within 3 days and within 5 days after symptom onset and who did not receive or were not expected to receive Covid-19 therapeutic monoclonal antibodies at randomization. The average time at risk for an event was computed as the time to the first event or as the time to the last day of participation or day 28, whichever was earlier. The average study follow-up was computed as the time to the last day of participation or day 28, whichever was earlier. Panel B shows the cumulative percentage of patients with Covid-19–related hospitalization or death from any cause through day 28 among patients treated within 5 days after symptom onset. The cumulative percentage was estimated for each treatment group with use of the Kaplan–Meier method. The inset shows the same data on an expanded y axis. Panel C shows subgroup analysis of the differences of the proportions of patients treated within 5 days after symptom onset who had Covid-19–related hospitalization or death from any cause through day 28, estimated for each treatment group with use of the Kaplan–Meier method. P values are based on normal approximation of the data. Study populations are described in Table S2.

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.

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).

Viral Load

Change from Baseline in Log10-Transformed Viral Load over Time (Modified Intention-to-Treat Population).

Panel A shows the adjusted mean change in viral load from baseline among all the patients who received at least one dose of the drug or placebo, had at least one visit between day 1 and day 28, did not receive or were not expected at baseline to receive Covid-19 therapeutic monoclonal antibody treatment, and were treated within 3 days after the onset of Covid-19 (modified intention-to-treat population). Panel B shows findings for the subgroup of patients whose baseline SARS-CoV-2 serology status was negative, and Panel C shows findings for the subgroup of patients whose baseline SARS-CoV-2 serology status was positive. Panel D shows findings among patients whose baseline viral load was more than 104 copies per milliliter, and Panel E shows findings among patients whose baseline viral load was more than 107 copies per milliliter. Patients were excluded from the analysis if the viral load was not detected or if data on baseline viral load were missing. Results obtained with unvalidated swabs were also excluded. Results were obtained with the use of a mixed-effects repeated-measures analysis of covariance model. Treatment, visit, and visit-by-treatment interactions were fixed effects in the analysis. Geographic region, baseline SARS-CoV-2 serology status, baseline viral load, and nasopharyngeal sample site were covariates, and participant was a random effect.

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.

Safety

Summary of Adverse Events, Serious Adverse Events, and Adverse Events Leading to Discontinuation through Day 34 (Safety Analysis Population).

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%).

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.