Design and randomization of trials
In this multicenter, controlled, randomized, observer-blinded trial, symptomatic participants at high risk of progression to severe Covid-19 were randomized in a 1:1 ratio to receive either oral VV116 (600 mg every 12 hours on Day 1 and 300 mg every 12 hours on Days 2-5) or oral nirmatrelvir–ritonavir (300 mg nirmatrelvir plus 100 mg ritonavir every 12 hours for 5 days) (Fig .S1 in the Additional appendix, available with the full text of this article at NEJM.org). VV116 was manufactured and supplied by Vigonvita Life Sciences. Selection of nirmatrelvir-ritonavir as active control for comparison with VV116 was based on established superiority of nirmatrelvir-ritonavir over placebo1 2 and on its recommendation as standard treatment for our target population by WHO guidelines.11
Randomization was performed using a centralized, interactive web response system. All site investigators, site personnel (except those who administered the test drugs), and those who participated in the endpoint assessments were unaware of the group assignments. trial until the blinding was lifted on May 20, 2022. Participants remained up to date with group homework throughout the trial. Further details are provided in the Additional appendix.
The data cut-off date for the primary analysis was May 13, 2022, when the target number of primary endpoint events (>724 events) was reached in the full analysis population. The data deadline for the final analysis was August 18, 2022.
Supervision of trials
The trial was approved by the National Committee of Human Genetic Resources in China and the Institutional Review Board or Ethics Committee of each trial site before the start of recruitment and was conducted in accordance with the Declaration of Helsinki and good clinical practice guidelines. One of the sponsors, Vigonvita Life Sciences, designed and monitored the trial and collected and analyzed data in collaboration with site investigators. Safety oversight was performed by Vigonvita Life Sciences and the Institutional Review Board or Ethics Committee at each site. The first author wrote the manuscript, and the editorial board reviewed the manuscript and made the decision to submit it for publication. All authors had data confidentiality agreements with Vigonvita Life Sciences and vouch for the accuracy and completeness of the data and the reliability of the trial to the protocolavailable at NEJM.org.
Speakers
After obtaining written informed consent, participants from seven hospitals in Shanghai, China, who were designated by the Chinese government for the treatment of Covid-19 were assessed for eligibility between April 4, 2022 and the May 2, 2022. Adults 18 years of age or older were eligible if they had mild to moderate Covid-19 with a total symptom score of 2 or greater, as determined based on definitions adapted from the Food and Drug Administration.18 Symptom scores range from 0 to 3 (higher scores indicating greater severity) for each of the 11 symptoms; Total symptom scores range from 0 to 33 (Table S1). Other key inclusion criteria were a positive SARS-CoV-2 reverse transcriptase-polymerase chain reaction (RT-PCR) test with an additional result indicating early infection or high viral activity (results are listed in the Additional appendix), and at least one risk factor for progression to severe Covid-19.
The main exclusion criteria were confirmed or suspected severe or critical Covid-19 or an anticipated need for mechanical ventilation before randomisation, an alanine aminotransferase or aspartate aminotransferase level greater than 1.5 times the upper limit of the normal, an estimated glomerular filtration rate (eGFR) of less than 60 ml per minute, or the use of contraindicated drugs listed in the nirmatrelvir-ritonavir package insert. Although nirmatrelvir-ritonavir is not contradicted in people with an eGFR of 30 to less than 60 ml per minute, we excluded these participants to avoid potential overdose in the updated protocol (version 3.0; April 10, 2022) . Before this date, a total of 38 participants with an eGFR of 30 to less than 60 ml per minute had been included in the trial (16 in the VV116 group and 22 in the nirmatrelvir-ritonavir group). Full eligibility criteria are provided in the Additional appendix and protocol.
Evaluation
Covid-19 symptom scores (described above) and WHO Clinical Progression Scale scores (range 0-10, with higher scores indicating worse clinical status) (Table S2 ) were determined by the investigators on day 1 before the trial. drug administration, followed by assessment at approximately the same time each day until target Covid-19 symptoms resolve or by day 28, whichever comes first. SARS-CoV-2 RNA from nasopharyngeal swabs was measured by RT-PCR assay at each site, with qualitative data (positive or negative) and quantitative data (cycle threshold value) obtained if they are available. More details on the assessment and data collection are provided in the protocol.
Endpoints
The primary efficacy endpoint was the time from randomization to sustained clinical recovery through day 28. Sustained clinical recovery was defined as alleviation of all target Covid-19-related symptoms at a total symptom score of 0 or 1 (range 0 to 33), with higher scores indicating greater severity) for 2 consecutive days. The first day of the 2 consecutive day period was considered the date of the event. Secondary efficacy endpoints included progression to severe or critical Covid-19 or death from any cause; change in Covid-19 symptom score and WHO Clinical Progression Scale score through day 28, time to sustained resolution of all target symptoms and a first SARS- test CoV-2 negative, and clinical recovery, resolution of symptoms, and a negative SARS-CoV-2 test on predefined days. Safety endpoints included adverse events and serious adverse events, with severity determined using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Any adverse event that occurred or worsened from the time of informed consent through Day 28 was actively recorded and reported for trial regimen recipients. Endpoint details are provided in the Additional appendix and Table S3. The primary endpoint was assessed in the primary analysis (data cut-off, May 13, 2022) and data were updated in the final analysis (data cut-off, August 18, 2022).
Statistical analyzes
The primary efficacy hypothesis was that VV116 would be non-inferior to nirmatrelvir-ritonavir with respect to sustained clinical recovery. Due to lack of data on time to clinical recovery in participants with omicron infection treated with nirmatrelvir-ritonavir, the baseline duration of 5.5 days was estimated based on duration of symptoms acute in people infected with SARS-CoV-2 during the omicron wave19 and an overall vaccination rate of more than 90% in the general population of Shanghai.20 To satisfy the non-inferiority hypothesis, the lower limit of the two-sided 95% confidence interval of the hazard ratio for the primary endpoint had to be greater than 0.8. The non-inferiority margin corresponds to a duration of 6.875 days of sustained clinical recovery, or 25% more than 5.5 days. A minimum of 724 events was required to ensure statistical power of 85%.
The non-inferiority hypothesis was tested in the full analysis population, i.e. the modified intention-to-treat population (all participants who were randomized and received at least one dose of VV116 or nirmatrelvir-ritonavir). Sensitivity analyzes involved participants who started a trial diet within 5 days of symptom onset and the per-protocol population. The intent-to-treat population (all participants who were randomized) was analyzed post hoc. Details of the analysis populations are provided in Tables S4 and S5.
For all other efficacy analyses, data were analyzed in the full population analysis. The Kaplan-Meier method was used to estimate the median time to sustained clinical recovery, with the 95% confidence interval estimated using the Brookmeyer-Crowley method with log-log transformation. The hazard ratio for time to sustained clinical recovery and its 95% confidence interval were estimated using the Cox proportional hazards model. Data from participants without sustained clinical recovery were censored on the last day that symptoms or signs related to Covid-19 were recorded. Participants with missing endpoint data were considered to have had no clinical recovery that day, and a sensitivity analysis was performed using the multiple imputation method. Subgroup analyzes of the primary endpoint were prespecified to assess the consistency of the intervention effect. For efficacy outcomes other than the primary endpoint in the full population analysis, 95% confidence intervals have not been adjusted for multiplicity and should not be used to infer treatment effects. Additional details are provided in the statistical analysis plan, available with the protocol.
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