VV116 versus Nirmatrelvir-Ritonavir for Oral Treatment of Covid-19

Abstract

Background: Nirmatrelvir-ritonavir has been authorized for emergency use by many countries for the treatment of coronavirus disease 2019 (Covid-19). However, the supply falls short of the global demand, which creates a need for more options. VV116 is an oral antiviral agent with potent activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Methods: We conducted a phase 3, noninferiority, observer-blinded, randomized trial during the outbreak caused by the B.1.1.529 (omicron) variant of SARS-CoV-2. Symptomatic adults with mild-to-moderate Covid-19 with a high risk of progression were assigned to receive a 5-day course of either VV116 or nirmatrelvir-ritonavir. The primary end point was the time to sustained clinical recovery through day 28. Sustained clinical recovery was defined as the alleviation of all Covid-19-related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 indicating a shorter time to sustained clinical recovery with VV116 than with nirmatrelvir-ritonavir).

Results: A total of 822 participants underwent randomization, and 771 received VV116 (384 participants) or nirmatrelvir-ritonavir (387 participants). The noninferiority of VV116 to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery was established in the primary analysis (hazard ratio, 1.17; 95% confidence interval [CI], 1.01 to 1.35) and was maintained in the final analysis (median, 4 days with VV116 and 5 days with nirmatrelvir-ritonavir; hazard ratio, 1.17; 95% CI, 1.02 to 1.36). In the final analysis, the time to sustained symptom resolution (score of 0 for each of the 11 Covid-19-related target symptoms for 2 consecutive days) and to a first negative SARS-CoV-2 test did not differ substantially between the two groups. No participants in either group had died or had had progression to severe Covid-19 by day 28. The incidence of adverse events was lower in the VV116 group than in the nirmatrelvir-ritonavir group (67.4% vs. 77.3%).

Conclusions: Among adults with mild-to-moderate Covid-19 who were at risk for progression, VV116 was noninferior to nirmatrelvir-ritonavir with respect to the time to sustained clinical recovery, with fewer safety concerns. (Funded by Vigonvita Life Sciences and others; ClinicalTrials.gov number, NCT05341609; Chinese Clinical Trial Registry number, ChiCTR2200057856.).

Figure 1. Screening, Randomization, and Follow-up.

Participants were recruited between April 4 and May 2, 2022, from seven sites in Shanghai, China, during the outbreak of coronavirus disease 2019 (Covid-19) dominated by the B.1.1.529 (omicron) variant. The data-cutoff date for the final analysis was August 18, 2022.

Figure 2. Time to Sustained Clinical Recovery.

Shown are the results of the final analysis (data-cutoff date, August 18, 2022) of the time to sustained clinical recovery, estimated by means of the Kaplan–Meier method, in the full analysis population (771 participants) (Panel A), per-protocol population (729 participants) (Panel B), and participants who started a trial regimen within 5 days after symptom onset (596 participants) (Panel C). Sustained clinical recovery was defined as the alleviation of all Covid-19–related target symptoms to a total score of 0 or 1 for the sum of each symptom (on a scale from 0 to 3, with higher scores indicating greater severity; total scores on the 11-item scale range from 0 to 33) for 2 consecutive days. The first day of the 2-consecutive-day period was considered to be the event date. The 95% confidence intervals were estimated with the use of normal approximation (Brookmeyer–Crowley method) on the basis of log–log transformation. Hazard ratios were calculated with the use of the Cox proportional-hazards model. A lower boundary of the two-sided 95% confidence interval for the hazard ratio of more than 0.8 was considered to indicate noninferiority (with a hazard ratio of >1 suggesting that participants receiving VV116 had a shorter time to sustained clinical recovery than those receiving nirmatrelvir–ritonavir).