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To the Editor: Cao et al. (Jan. 18 issue)1 evaluated changes in log10 copies of SARS-CoV-2 RNA per milliliter in adults with mild-to-moderate Covid-19 receiving simnotrelvir or placebo. However, only 611 of 1007 participants (61%) in the modified intention-to-treat–1 population were included in the analysis, and only 71% and 21% of this subgroup had measurements at days 9 and 14, respectively. Improved clarity about the analysis population and reasons for missing data are important in interpreting the results. Furthermore, analysis of changes in log10 copies per milliliter was performed after results below the lower limit of quantification (LLOQ) of the assay were set to the LLOQ, rather than being considered as left-censored values. Such imputation can lead to underestimation of virologic effects2; the decline in each randomly assigned group is at least as large as reported. In addition, the plateau of change at later times, which is inconsistent with the notion that persons might clear the virus completely, is an artifact of the imputation (the plateau is approximately LLOQ minus mean baseline log10 copies per milliliter).

Oral Simnotrelvir for Adult Patients with Mild-to-Moderate Covid-19. BACKGROUND: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial. METHODS: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed. RESULTS: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate. CONCLUSIONS: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.).

We initiated this trial on August 19, 2022, in China. To be eligible for participation, patients needed to be at least 18 years of age, to have onset of signs or symptoms of Covid-19 within 3 days before the first dose of trial drug or placebo, to have at least one sign or symptom of Covid-19 before the first dose of trial drug or placebo, and to have mild or moderate illness. Definitions of disease severity used in the trial were from the Food and Drug Administration and are provided in Table S1 in the Supplementary Appendix, available with the full text of this article at NEJM.org.10 Key exclusion criteria were an anticipated need for a high-flow nasal cannula, noninvasive ventilation, invasive ventilation, or extracorporeal membranous oxygenation within 48 hours; serious kidney, liver, or acute cardiovascular disease; and current or expected use of any medications or substances that have substantial drug interactions with cytochrome P-450 3A4 (Table S2). Detailed eligibility criteria are provided in the protocol, available at NEJM.org.

al membranous oxygenation within 48 hours; serious kidney, liver, or acute cardiovascular disease; and current or expected use of any medications or substances that have substantial drug interactions with cytochrome P-450 3A4 (Table S2). Detailed eligibility criteria are provided in the protocol, available at NEJM.org. The trial was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonisation Good Clinical Practice guidelines. The trial was approved by the ethics committee at each site. Written informed consent was obtained from all patients. Safety oversight was performed by the sponsor (Jiangsu Simcere Pharmaceutical) and an independent data and safety monitoring committee. The trial was designed in conjunction with representatives of the sponsor, and statisticians employed by the sponsor analyzed the data. The authors vouch for the completeness and accuracy of the data and for the adherence of the trial to the protocol. Two academic authors and two authors who are employees of the sponsor wrote the first draft. There was no agreement concerning confidentiality between the sponsor and the authors or the research institutions.

authors vouch for the completeness and accuracy of the data and for the adherence of the trial to the protocol. Two academic authors and two authors who are employees of the sponsor wrote the first draft. There was no agreement concerning confidentiality between the sponsor and the authors or the research institutions. Eligible patients were randomly assigned, in a 1:1 ratio through a centralized, interactive-response technology system, to receive either 750 mg of simnotrelvir (two tablets, 375 mg per tablet) plus 100 mg of ritonavir or matching placebo twice daily for 5 days. Randomization was stratified in blocks of six according to geographic region, age group (<65 years or ≥65 years), and Covid-19 vaccination status (not fully vaccinated, received primary vaccination, or received booster vaccination). Patients and investigators were unaware of the randomization assignments. The placebo tablets were composed of the same nonpharmacologic fillers and were visually identical to the active drugs. Patients were allowed to take relief medication (ibuprofen or acetaminophen). All the patients were quarantined and closely observed in designated hospitals in accordance with local policy during the trial. Adherence to the trial drug or placebo was assessed by nurses who were unaware of the randomization assignments.

Patients were allowed to take relief medication (ibuprofen or acetaminophen). All the patients were quarantined and closely observed in designated hospitals in accordance with local policy during the trial. Adherence to the trial drug or placebo was assessed by nurses who were unaware of the randomization assignments. Patients assessed the severity of 11 Covid-19–associated signs and symptoms (listed in the protocol). The severity was scored on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms) twice daily from the time of the first dose (day 1) to day 14 and once daily on days 15 through 29 and was recorded in diaries (Table S3). For vomiting and diarrhea, the point scale was based on the symptom frequency. For other items, the point scale was based on the patient’s reply to the question, “What was the severity of your symptom during the previous 12 hours?” (days 1 through 14) or “What was the severity of your symptom during the previous 24 hours?” (days 15 through 29). On days 0, 1, 5, 14, and 29, safety laboratory tests (hematologic tests, blood chemical tests, and electrocardiography) were performed.

“What was the severity of your symptom during the previous 12 hours?” (days 1 through 14) or “What was the severity of your symptom during the previous 24 hours?” (days 15 through 29). On days 0, 1, 5, 14, and 29, safety laboratory tests (hematologic tests, blood chemical tests, and electrocardiography) were performed. Nasopharyngeal or oropharyngeal swab specimens were obtained on days 1, 3, 5 (end-of-treatment visit), 7, 9, and 14 for quantitation of SARS-CoV-2 RNA through reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay at a central laboratory. The type of sample collected (nasopharyngeal or oropharyngeal) was planned to be consistent across all sample points for each individual patient. Adverse events were assessed during the treatment period and for 29 days after the first dose. The modified intention-to-treat population was defined as all patients who received at least one dose of trial drug or placebo and had a diagnosis of SARS-CoV-2 infection confirmed by RT-PCR, no influenza virus infection, at least one Covid-19–related symptom at baseline, and at least one postbaseline visit (Table S4). Because it was determined that a number of the patients had received the first dose of trial drug or placebo between 72 and 96 hours after the onset of Covid-19 symptoms, patients in the modified intention-to-treat population who had received the first dose of trial drug or placebo within 72 hours were included in a separate analysis population (the modified intention-to-treat–1 population), which served as the main analysis population.

and 96 hours after the onset of Covid-19 symptoms, patients in the modified intention-to-treat population who had received the first dose of trial drug or placebo within 72 hours were included in a separate analysis population (the modified intention-to-treat–1 population), which served as the main analysis population. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the time from the first dose to the time when all 11 Covid-19–related symptoms were rated by the patients as absent (i.e., a score of 0) for 2 consecutive days. The primary efficacy end-point analysis was performed in the modified intention-to-treat–1 population as prespecified in the protocol. The validation of the primary end point is shown in Table S5. Secondary efficacy end points included the time to sustained alleviation of all 11 targeted Covid-19 symptoms (defined as a score of ≤1), the occurrence of severe Covid-19, and death. The time to patient-reported return to usual (pre–Covid-19) health status was also explored with the use of the Global Impression Questions (GIQ) scale.11 Post hoc efficacy analyses included the time to resolution of respiratory symptoms and the time to resolution of systemic symptoms.

ce of severe Covid-19, and death. The time to patient-reported return to usual (pre–Covid-19) health status was also explored with the use of the Global Impression Questions (GIQ) scale.11 Post hoc efficacy analyses included the time to resolution of respiratory symptoms and the time to resolution of systemic symptoms. Virologic end points included the changes from baseline in the SARS-CoV-2 RNA viral load (see Supplementary Methods). The analyses involved patients with available virologic data in the modified intention-to-treat–1 population. The safety end points included the frequency and severity of adverse events that occurred during the treatment period or the follow-up period (i.e., events that started on or before day 29), which were assessed in all patients who received at least one dose of trial drug or placebo. The safety events were coded according to the Medical Dictionary for Regulatory Activities, version 25.0. Exploratory analyses of viral rebound and symptom rebound in the full analysis population were conducted, as well as assessments of drug resistance (see Supplementary Methods).

st one dose of trial drug or placebo. The safety events were coded according to the Medical Dictionary for Regulatory Activities, version 25.0. Exploratory analyses of viral rebound and symptom rebound in the full analysis population were conducted, as well as assessments of drug resistance (see Supplementary Methods). Assuming that only 80% of 1200 patients enrolled in the trial would be included in the primary analysis, we calculated that a sample of 960 patients, with 949 of these patients having sustained resolution of symptoms, would provide at least 90% power to detect a 24-hour difference in the median time to sustained resolution of symptoms between the simnotrelvir group and the placebo group at a two-sided significance level of 0.05. Two efficacy interim analysis were planned for when 45% and 70% of the total predicted instances of resolution had occurred in this population.12 The second interim analysis of the primary end point met the prespecified efficacy criterion.

notrelvir group and the placebo group at a two-sided significance level of 0.05. Two efficacy interim analysis were planned for when 45% and 70% of the total predicted instances of resolution had occurred in this population.12 The second interim analysis of the primary end point met the prespecified efficacy criterion. In this trial, the time to resolution of symptoms was compared between the simnotrelvir group and the placebo group with the use of a Peto–Prentice generalized Wilcoxon test with geographic region, age group, and Covid-19 vaccination status used as stratifying variables (see the Supplementary Appendix). The Peto–Prentice generalized Wilcoxon test was also used for prespecified subgroup analyses of the primary efficacy end point and time to alleviation of 11 symptoms. Mixed models for repeated measures were used for log10 transformation of the changes from baseline in viral load. A post hoc comparison of the time to resolution of respiratory, fever, and systemic symptoms (excluding fever) between the simnotrelvir group and the placebo group was conducted. All P values are two-sided and were calculated with SAS software, version 9.4 (SAS Institute). Additional details of the statistical analyses, including the handling of missing data, are provided in the protocol.

Eligible patients were randomly assigned, in a 1:1 ratio through a centralized, interactive-response technology system, to receive either 750 mg of simnotrelvir (two tablets, 375 mg per tablet) plus 100 mg of ritonavir or matching placebo twice daily for 5 days. Randomization was stratified in blocks of six according to geographic region, age group (<65 years or ≥65 years), and Covid-19 vaccination status (not fully vaccinated, received primary vaccination, or received booster vaccination). Patients and investigators were unaware of the randomization assignments. The placebo tablets were composed of the same nonpharmacologic fillers and were visually identical to the active drugs. Patients were allowed to take relief medication (ibuprofen or acetaminophen). All the patients were quarantined and closely observed in designated hospitals in accordance with local policy during the trial. Adherence to the trial drug or placebo was assessed by nurses who were unaware of the randomization assignments.

Patients assessed the severity of 11 Covid-19–associated signs and symptoms (listed in the protocol). The severity was scored on a 4-point scale (with 0 indicating no symptoms, 1 mild symptoms, 2 moderate symptoms, and 3 severe symptoms) twice daily from the time of the first dose (day 1) to day 14 and once daily on days 15 through 29 and was recorded in diaries (Table S3). For vomiting and diarrhea, the point scale was based on the symptom frequency. For other items, the point scale was based on the patient’s reply to the question, “What was the severity of your symptom during the previous 12 hours?” (days 1 through 14) or “What was the severity of your symptom during the previous 24 hours?” (days 15 through 29). On days 0, 1, 5, 14, and 29, safety laboratory tests (hematologic tests, blood chemical tests, and electrocardiography) were performed. Nasopharyngeal or oropharyngeal swab specimens were obtained on days 1, 3, 5 (end-of-treatment visit), 7, 9, and 14 for quantitation of SARS-CoV-2 RNA through reverse-transcriptase–polymerase-chain-reaction (RT-PCR) assay at a central laboratory. The type of sample collected (nasopharyngeal or oropharyngeal) was planned to be consistent across all sample points for each individual patient. Adverse events were assessed during the treatment period and for 29 days after the first dose.

The modified intention-to-treat population was defined as all patients who received at least one dose of trial drug or placebo and had a diagnosis of SARS-CoV-2 infection confirmed by RT-PCR, no influenza virus infection, at least one Covid-19–related symptom at baseline, and at least one postbaseline visit (Table S4). Because it was determined that a number of the patients had received the first dose of trial drug or placebo between 72 and 96 hours after the onset of Covid-19 symptoms, patients in the modified intention-to-treat population who had received the first dose of trial drug or placebo within 72 hours were included in a separate analysis population (the modified intention-to-treat–1 population), which served as the main analysis population.

Assuming that only 80% of 1200 patients enrolled in the trial would be included in the primary analysis, we calculated that a sample of 960 patients, with 949 of these patients having sustained resolution of symptoms, would provide at least 90% power to detect a 24-hour difference in the median time to sustained resolution of symptoms between the simnotrelvir group and the placebo group at a two-sided significance level of 0.05. Two efficacy interim analysis were planned for when 45% and 70% of the total predicted instances of resolution had occurred in this population.12 The second interim analysis of the primary end point met the prespecified efficacy criterion.

From August 19, 2022, to December 16, 2022, a total of 1208 patients were enrolled at 35 research sites in China; 603 were assigned to receive simnotrelvir plus ritonavir, and 605 were assigned to receive placebo (Figure 1). After randomization, 1139 patients received trial drug or placebo and were included in the full analysis population. Of the 1139 patients in the full analysis population, 95.5% of those in the simnotrelvir group and 97.0% of those in the placebo group had good adherence (i.e., they took >80% of the intended doses); the mean (±SD) number of doses taken was 9.7±1.4 (9.7±1.5 in the simnotrelvir group and 9.8±1.3 in the placebo group).

. Of the 1139 patients in the full analysis population, 95.5% of those in the simnotrelvir group and 97.0% of those in the placebo group had good adherence (i.e., they took >80% of the intended doses); the mean (±SD) number of doses taken was 9.7±1.4 (9.7±1.5 in the simnotrelvir group and 9.8±1.3 in the placebo group). The characteristics of the patients were generally similar in the two groups (Table 1). The median age was 35 years. Overall, the trial recruited a fully vaccinated and relatively young population, with approximately half the patients (609 [53.5%]) having at least one risk factor for severe Covid-19 (Table S6). The most common risk factors were overweight or obesity (35.7%), current or former smoking (22.7%), and cardiovascular disease (4.5%). The percentage of the patients with moderate disease was higher in the simnotrelvir group than in the placebo group (67.5% vs. 61.3%). Almost all the patients (1092 [95.9%]) had completed primary vaccination, and 874 patients (76.7%) had received a booster dose. A total of 1007 patients received trial drug or placebo within 72 hours after symptom onset and were included in the modified intention-to-treat–1 population (Figure 1). Approximately half the patients (49.6%) received trial drug or placebo within 48 hours after symptom onset. The most frequent Covid-19 symptoms at baseline were sore or dry throat (76.2%), cough (73.4%), stuffy or runny nose (55.9%), headache (52.9%), and fever (52.9%) (Table S7). The percentage of patients who used treatment for symptoms was similar in the two groups (Table S8).

placebo within 48 hours after symptom onset. The most frequent Covid-19 symptoms at baseline were sore or dry throat (76.2%), cough (73.4%), stuffy or runny nose (55.9%), headache (52.9%), and fever (52.9%) (Table S7). The percentage of patients who used treatment for symptoms was similar in the two groups (Table S8). In the modified intention-to-treat–1 population, the median time to sustained resolution of Covid-19 symptoms (i.e., symptom scores of 0) was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, −35.8 hours [95% CI, −60.1 to −12.4]; P=0.006 by Peto–Prentice test) (Figure 2A). The results were similar in the sensitivity analysis in which baseline disease severity was added as a covariate in the model (P=0.005 by Peto–Prentice test). In the subgroup of patients with risk factors for severe Covid-19, the median difference in the time to sustained resolution was −60.4 hours (95% CI, −84.3 to −23.2) (Figure 2B). The efficacy in the modified intention-to-treat and per-protocol populations was similar to that in the modified intention-to-treat–1 population (Fig. S1).

p of patients with risk factors for severe Covid-19, the median difference in the time to sustained resolution was −60.4 hours (95% CI, −84.3 to −23.2) (Figure 2B). The efficacy in the modified intention-to-treat and per-protocol populations was similar to that in the modified intention-to-treat–1 population (Fig. S1). The median time to sustained alleviation of symptoms (i.e., symptom scores of ≤1) was also significantly shorter in the simnotrelvir group than in the placebo group in the modified intention-to-treat–1 population (120.4 hours [95% CI, 119.4 to 132.8] vs. 168.3 hours [95% CI, 155.0 to 191.2]; median difference, −47.9 hours [95% CI, −69.8 to −24.0]) (Fig. S2). In addition, simnotrelvir significantly accelerated the resolution of respiratory symptoms (median between-group difference, −41.4 hours; 95% CI, −70.7 to −13.3) (Fig. S3A). The time to resolution of systemic symptoms and fever was similar in the two groups (Fig. S3B and S3C). According to the daily score for each of the 11 Covid-19 symptoms and signs, resolution of cough, stuffy or runny nose, and sore or dry throat was the main contributor to the resolution of Covid-19 symptoms. In addition, fever, chill, headache, stuffy or runny nose, shortness of breath, and muscle or body aches showed substantially greater abatement on the first day of treatment in the simnotrelvir group than in the placebo group (Fig. S4). The GIQ results also showed a shorter time to usual health status in the simnotrelvir group than in the placebo group (Table S9). At day 29, severe Covid-19 had not developed in any patient. No patient in either group died.

ent on the first day of treatment in the simnotrelvir group than in the placebo group (Fig. S4). The GIQ results also showed a shorter time to usual health status in the simnotrelvir group than in the placebo group (Table S9). At day 29, severe Covid-19 had not developed in any patient. No patient in either group died. The baseline viral load was similar in the two groups (Table 1 and Figure 3). On day 3, the mean (±SE) additional change in viral load from baseline in the simnotrelvir group as compared with the placebo group was −1.10±0.13 log10 copies per milliliter (95% CI, −1.36 to −0.84) (Figure 3). On day 5, the additional change in viral load with simnotrelvir as compared with placebo was −1.51±0.14 log10 copies per milliliter (95% CI, −1.79 to −1.24) (Figure 3). The viral load changes at day 7 and day 9 were also greater with simnotrelvir than with placebo. Among the patients in the modified intention-to-treat–1 population who received trial drug or placebo within 48 hours after symptom onset, simnotrelvir also led to greater reductions in viral load than placebo until day 9, with the largest between-group difference observed on day 5 (−1.74±0.18 log10 copies per milliliter; 95% CI, −2.10 to −1.38) (Fig. S5A). Among the patients in the modified intention-to-treat–1 population who received trial drug or placebo between 48 and 72 hours after symptom onset, differences in the decrease in viral load were also maintained until day 9 (Fig. S5B). In the modified intention-to-treat population, differences in the decrease in viral load were similar to those in the modified intention-to-treat–1 population (Fig. S5C).

l drug or placebo between 48 and 72 hours after symptom onset, differences in the decrease in viral load were also maintained until day 9 (Fig. S5B). In the modified intention-to-treat population, differences in the decrease in viral load were similar to those in the modified intention-to-treat–1 population (Fig. S5C). Among the patients in the modified intention-to-treat–1 population who had available respiratory samples, more than 99% (607 of 611) had the same type of sample obtained at every time point. At baseline, 273 had nasopharyngeal swab specimens, and 338 had oropharyngeal swab specimens. The change from baseline in viral load in the simnotrelvir group as compared with the placebo group was similar for nasopharyngeal and oropharyngeal swabs (Fig. S5D and S5E). After the exclusion of the 4 patients from the modified intention-to-treat–1 population who had both types of swab specimens obtained, the results of viral load analysis remained consistent (Fig. S5F).

ir group as compared with the placebo group was similar for nasopharyngeal and oropharyngeal swabs (Fig. S5D and S5E). After the exclusion of the 4 patients from the modified intention-to-treat–1 population who had both types of swab specimens obtained, the results of viral load analysis remained consistent (Fig. S5F). All 750 patients in the full analysis population who had respiratory samples available (379 in the simnotrelvir group and 371 in the placebo group) were included in the assessment of viral and symptom rebound. Viral rebound occurred in 18 of the 379 patients (4.7%) in the simnotrelvir group and 18 of the 371 patients (4.9%) in the placebo group. Among the patients who had sustained resolution of symptoms by day 14, symptom rebound occurred in 1 of 425 patients (0.2%) in the simnotrelvir group and 2 of 420 patients (0.5%) in the placebo group. No patient had both viral and symptom rebound. Additional details of the results for viral and symptom rebound are provided in Table S10. We did not identify any evidence of drug resistance (see Supplementary Results).

1 of 425 patients (0.2%) in the simnotrelvir group and 2 of 420 patients (0.5%) in the placebo group. No patient had both viral and symptom rebound. Additional details of the results for viral and symptom rebound are provided in Table S10. We did not identify any evidence of drug resistance (see Supplementary Results). During the period from the first dose through day 29, the incidence of adverse events was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%) (Table 2 and Table S11). These adverse events were mostly of grade 1 or 2. No serious adverse event occurred in the simnotrelvir group, whereas two serious adverse events occurred in two patients in the placebo group. One 28-year-old woman had abdominal pain that was diagnosed as acute appendicitis, and a 46-year-old woman had vaginal bleeding that was diagnosed as adenomyosis. Adverse events during treatment that were considered by the site investigator to be related to trial drug or placebo occurred more frequently in the simnotrelvir group than in the placebo group (17.5% vs. 10.2%). The top three adverse events that were reported as being related to simnotrelvir were an increase in blood triglyceride levels (in 4.3% of the patients in the simnotrelvir group and 2.1% in the placebo group), a decrease in neutrophil count (1.9% and 0.2%), and diarrhea (1.7% and 1.1%).

In the modified intention-to-treat–1 population, the median time to sustained resolution of Covid-19 symptoms (i.e., symptom scores of 0) was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, −35.8 hours [95% CI, −60.1 to −12.4]; P=0.006 by Peto–Prentice test) (Figure 2A). The results were similar in the sensitivity analysis in which baseline disease severity was added as a covariate in the model (P=0.005 by Peto–Prentice test). In the subgroup of patients with risk factors for severe Covid-19, the median difference in the time to sustained resolution was −60.4 hours (95% CI, −84.3 to −23.2) (Figure 2B). The efficacy in the modified intention-to-treat and per-protocol populations was similar to that in the modified intention-to-treat–1 population (Fig. S1).

The baseline viral load was similar in the two groups (Table 1 and Figure 3). On day 3, the mean (±SE) additional change in viral load from baseline in the simnotrelvir group as compared with the placebo group was −1.10±0.13 log10 copies per milliliter (95% CI, −1.36 to −0.84) (Figure 3). On day 5, the additional change in viral load with simnotrelvir as compared with placebo was −1.51±0.14 log10 copies per milliliter (95% CI, −1.79 to −1.24) (Figure 3). The viral load changes at day 7 and day 9 were also greater with simnotrelvir than with placebo. Among the patients in the modified intention-to-treat–1 population who received trial drug or placebo within 48 hours after symptom onset, simnotrelvir also led to greater reductions in viral load than placebo until day 9, with the largest between-group difference observed on day 5 (−1.74±0.18 log10 copies per milliliter; 95% CI, −2.10 to −1.38) (Fig. S5A). Among the patients in the modified intention-to-treat–1 population who received trial drug or placebo between 48 and 72 hours after symptom onset, differences in the decrease in viral load were also maintained until day 9 (Fig. S5B). In the modified intention-to-treat population, differences in the decrease in viral load were similar to those in the modified intention-to-treat–1 population (Fig. S5C).

All 750 patients in the full analysis population who had respiratory samples available (379 in the simnotrelvir group and 371 in the placebo group) were included in the assessment of viral and symptom rebound. Viral rebound occurred in 18 of the 379 patients (4.7%) in the simnotrelvir group and 18 of the 371 patients (4.9%) in the placebo group. Among the patients who had sustained resolution of symptoms by day 14, symptom rebound occurred in 1 of 425 patients (0.2%) in the simnotrelvir group and 2 of 420 patients (0.5%) in the placebo group. No patient had both viral and symptom rebound. Additional details of the results for viral and symptom rebound are provided in Table S10. We did not identify any evidence of drug resistance (see Supplementary Results).

During the period from the first dose through day 29, the incidence of adverse events was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%) (Table 2 and Table S11). These adverse events were mostly of grade 1 or 2. No serious adverse event occurred in the simnotrelvir group, whereas two serious adverse events occurred in two patients in the placebo group. One 28-year-old woman had abdominal pain that was diagnosed as acute appendicitis, and a 46-year-old woman had vaginal bleeding that was diagnosed as adenomyosis. Adverse events during treatment that were considered by the site investigator to be related to trial drug or placebo occurred more frequently in the simnotrelvir group than in the placebo group (17.5% vs. 10.2%). The top three adverse events that were reported as being related to simnotrelvir were an increase in blood triglyceride levels (in 4.3% of the patients in the simnotrelvir group and 2.1% in the placebo group), a decrease in neutrophil count (1.9% and 0.2%), and diarrhea (1.7% and 1.1%).

In this phase 2–3 trial of treatment for mild-to-moderate Covid-19, simnotrelvir plus ritonavir shortened the time to sustained symptom resolution by approximately 1.5 days among patients who received treatment within 3 days after symptom onset. Simnotrelvir had more benefits for the alleviation of respiratory symptoms than placebo. In addition, simnotrelvir was associated with an additional decrease in viral load until day 9. The most pronounced antiviral effect occurred on day 5, when the decrease in viral load in the simnotrelvir group was 1.51 log10 copies per milliliter greater than that in the placebo group. Most adverse events were mild or moderate.

on, simnotrelvir was associated with an additional decrease in viral load until day 9. The most pronounced antiviral effect occurred on day 5, when the decrease in viral load in the simnotrelvir group was 1.51 log10 copies per milliliter greater than that in the placebo group. Most adverse events were mild or moderate. For patients with mild-to-moderate Covid-19, viral replication and direct viral damage are important drivers of disease.13 Persistent Covid-19 symptoms have been found to be associated with poor quality of life.14,15 However, the benefits of antiviral medications in shortening the disease course have still not been fully determined. In the Evaluation of Protease Inhibition for COVID-19 in Standard-Risk Patients (EPIC-SR) trial, nirmatrelvir plus ritonavir did not accelerate sustained alleviation of 11 symptoms.16,17 However, data from the Stopping COVID-19 Progression with Early Protease Inhibitor Treatment in Standard-Risk Patients (SCORPIO-SR) trial and the Platform Adaptive Trial of Novel Antivirals for Early Treatment of COVID-19 in the Community (PANORAMIC) suggested that oral small-molecule antiviral drugs could provide clinical benefits in shortening the duration of symptoms.18,19 Nirmatrelvir, ensitrelvir, and simnotrelvir were associated with a maximum difference from placebo of approximately 1, 1.4, and 1.5 log10 copies per milliliter, respectively, in viral-load decrease.16,18 Various factors may contribute to the disparity in the aforementioned clinical and antiviral effects, including research settings, blinding status, definitions of outcomes, patient characteristics, dose of the medications, and techniques used in obtaining and testing the respiratory samples. A direct comparison in the same trial will be necessary to infer the actual differences in efficacy among these antiviral agents.

including research settings, blinding status, definitions of outcomes, patient characteristics, dose of the medications, and techniques used in obtaining and testing the respiratory samples. A direct comparison in the same trial will be necessary to infer the actual differences in efficacy among these antiviral agents. Observational studies have indicated that even in the vaccinated population, nirmatrelvir use is associated with lower mortality among older persons or persons at increased risk for disease progression.20,21 Because of the absence of events, we cannot assess the effect of simnotrelvir on reducing the risk of disease progression in this trial. Because the subgroup analyses in the trial were not adequately powered and were not corrected for type I error, they should not be used to draw definitive conclusions about efficacy, and the apparent difference in the point estimates in different subgroups should be interpreted with caution. We plan to undertake real-world observational studies as well as phase 4 trials to further evaluate end points such as death and disease progression, as well as to determine the efficacy in different subgroups.

and the apparent difference in the point estimates in different subgroups should be interpreted with caution. We plan to undertake real-world observational studies as well as phase 4 trials to further evaluate end points such as death and disease progression, as well as to determine the efficacy in different subgroups. The most frequent adverse event that occurred at a higher incidence in the simnotrelvir group than in the placebo group was an increase in the blood triglyceride level. This adverse event is also common in association with other 3CLpro inhibitors, including nirmatrelvir22 and ensitrelvir.18 Postauthorization pharmacovigilance is important, as is close monitoring of the safety profile of the drug in larger populations in real-world clinical settings.

se in the blood triglyceride level. This adverse event is also common in association with other 3CLpro inhibitors, including nirmatrelvir22 and ensitrelvir.18 Postauthorization pharmacovigilance is important, as is close monitoring of the safety profile of the drug in larger populations in real-world clinical settings. The trial has strengths and limitations. First, we recruited vaccinated people, approximately half of whom had risk factors for severe Covid-19. The trial population is similar to the general population in terms of immunity against SARS-CoV-2 and risk-factor status. Second, although the double-blind design of the trial decreases the placebo effect in symptom evaluation, the placebo contained only excipients; therefore, unblinding may have occurred in some patients, given the unique taste of ritonavir. Third, the recruited population was relatively young. The efficacy and safety among older patients still warrants investigations in future research. Finally, both nasopharyngeal and oropharyngeal swabs were used in this trial. However, the sampling method was consistent in nearly all patients (excluding four) across the trial visits. The sensitivity analysis showed a limited effect on the virologic analysis. In this trial, early administration of simnotrelvir plus ritonavir was effective in shortening the time to symptom resolution among adult patients with Covid-19, without evident safety concerns.