Main menu

Pages

VV116 versus Nirmatrelvir-Ritonavir for oral treatment of Covid-19

featured image

Study design and randomization

In this multicenter, randomised, randomized controlled trial, symptomatic participants at high risk of progression to severe Covid-19 were randomly assigned in a 1:1 ratio to receive oral VV116 (600 mg every 12 hours on day 1 and 300 mg on day 1). every 12 hours on days 2 to 5) or oral nirmatrelvir-ritonavir (300 mg nirmatrelvir plus 100 mg ritonavir every 12 hours for 5 days) (Fig. S1 in the Supplementary Appendix, available with the full text of this article in NEJM. org). The VV116 was manufactured and supplied by Vigonvita Life Sciences. The selection of nirmatrelvir-ritonavir as an active control for comparison with VV116 was based on the established superiority of nirmatrelvir-ritonavir to placebo12 and its recommendation as standard care for our target population by the WHO guideline.11

Randomization was performed using a centralized, interactive web response system. All site investigators, site staff (except those who administered study medications), and those who were involved in endpoint assessments were unaware of study group assignments until disclosure on May 20, 2022. Participants remained aware of the study – group assignments throughout the trial. Additional details are provided in the Supplementary Appendix.

The data cut-off date for the primary analysis was May 13, 2022, when the target number of primary outcome events (>724 events) was reached in the full analysis population. The data cut-off date for the final analysis was August 18, 2022.

Judgment Supervision

The study was approved by the National Committee of Human Genetic Resources in China and the institutional review board or ethics committee at each study site prior to initiation 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 study 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 drafted the manuscript and the writing committee reviewed the manuscript and made the decision to submit it for publication. All authors signed data confidentiality agreements with Vigonvita Life Sciences and attest to the accuracy and completeness of the data and the study’s fidelity to the protocol, available at NEJM.org.

participants

After obtaining written informed consent, participants from seven hospitals in Shanghai, China, designated by the Chinese government for the treatment of Covid-19, were assessed for eligibility between April 4, 2022 and May 2, 2022. Age 18 and older were eligible if they had mild to moderate Covid-19 with a total symptom score of 2 or greater, as determined based on adapted definitions from the Food and Drug Administration.18 Symptom scores range from 0 to 3 (with higher scores indicating greater severity) for each of the 11 symptoms; total symptom scores range from 0 to 33 (Table S1). Other important inclusion criteria were a positive SARS-CoV-2 reverse polymerase chain reaction (RT-PCR) test with an additional finding indicating early infection or high viral activity (findings are listed in the Supplementary Appendix) and at least one risk factor for progression to severe Covid-19.

Main exclusion criteria were confirmed or suspected severe or critical Covid-19 or anticipated need for mechanical ventilation prior to randomization, alanine aminotransferase or aspartate aminotransferase level greater than 1.5 times the upper limit of the normal range, glomerular filtration rate (eGFR) less than 60 ml per minute, or the use of contraindicated drugs listed in the nirmatrelvir-ritonavir package insert. Although nirmatrelvir-ritonavir is not contraindicated in people with an eGFR of 30 to less than 60 ml per minute, we excluded these participants to avoid possible overdose in the updated protocol (version 3.0; 10 Apr 2022). Prior to that date, a total of 38 participants with an eGFR of 30 to less than 60 ml per minute had been enrolled in the study (16 in the VV116 group and 22 in the nirmatrelvir-ritonavir group). Complete eligibility criteria are provided in the Supplementary Appendix and in the protocol.

Evaluation

Covid-19-related symptom scores (described above) and WHO Clinical Progression Scale scores (range 0-10, with higher scores indicating a worse clinical condition) (Table S2) were determined by the investigators on the day 1 before the study. drug administration, followed by assessment at approximately the same time each day until resolution of target COVID-19-related symptoms or 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 available. More details on the assessment and data collection are provided in the protocol.

Endpoints

The primary efficacy endpoint was time from randomization to sustained clinical recovery by day 28. Sustained clinical recovery was defined as relief of all Covid-19-related target symptoms for 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 period of 2 consecutive days was considered the date of the event. Secondary efficacy endpoints included progression to severe or critical COVID-19 or death from any cause; the change in Covid-19-related symptom score and WHO Clinical Progression Scale score by day 28, the time to sustained resolution of all target symptoms and to a negative first SARS-CoV-2 test, and clinical recovery, resolution of symptoms, and a negative SARS-CoV-2 test on pre-specified days. Safety endpoints included adverse events and serious adverse events, with severity determined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Any adverse event arising or worsening from the time of informed consent through day 28 was actively recorded and reported to experimental regimen recipients. Endpoint details are provided in the Supplementary Appendix and Table S3. The primary endpoint was evaluated in the primary analysis (data cut-off date, May 13, 2022) and the data were updated in the final analysis (data cut-off date, August 18, 2022).

Statistical analysis

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 clinical recovery time in participants with omicron infection treated with nirmatrelvir-ritonavir, the baseline duration of 5.5 days was estimated based on the duration of acute symptoms in people infected with SARS-CoV-2 during the omicron wave19 and an overall vaccination rate of over 90% in the general population in Shanghai.20 To satisfy the noninferiority hypothesis, the lower bound of the 95% two-sided confidence interval for the primary endpoint hazard ratio had to be above 0.8. The non-inferiority margin corresponds to a sustained clinical recovery time of 6.875 days, 25% greater than 5.5 days. A minimum of 724 events were required to ensure a statistical power of 85%.

The non-inferiority hypothesis was tested in the full analysis population – that is, the modified intent-to-treat population (all participants who were randomized and received at least one dose of VV116 or nirmatrelvir-ritonavir). Sensitivity analyzes involved participants starting an experimental regimen within 5 days of symptom onset and the per-protocol population. The intention-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 on the full analysis population. The Kaplan-Meier method was used to estimate the mean time to sustained clinical recovery, with a 95% confidence interval estimated using the Brookmeyer-Crowley method with log-log transformation. The hazard ratio for sustained clinical recovery time and its 95% confidence interval were estimated using the Cox proportional hazards model. Data for participants without sustained clinical recovery were censored on the last day that Covid-19-related symptoms or signs were recorded. Participants with missing endpoint data were considered to have no clinical recovery on that day, and a sensitivity analysis was performed using the multiple imputation method. Subgroup analyzes of the primary outcome were prespecified to assess consistency of intervention effect. For efficacy outcomes other than the primary endpoint in the full analysis population, the 95% confidence intervals were not 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.

Comments