THE AUTHORS REPLY: In response to Lin and Fleming: our trial reached the prespecified sample size needed to test the primary end point. It is true that the design of the trial, in which participants (but not investigators or assessors) were aware of trial-group assignments, could have introduced bias toward the active drug, which in our trial was nirmatrelvir-ritonavir rather than VV116. We concur that additional trials are required to establish the efficacy of VV116 in treating Covid-19. In response to Bergmann et al., Edwards, and Li: our trial faced challenges that included the shift of the dominant SARS-CoV-2 variants from delta to omicron, increased host immunity after infections and vaccinations, regional policy variation, and consequently, altered clinical outcomes. These factors led to a risk of disease progression in our target patients that was lower than our expectations from previous trials. As Li noted, the policy in China at the time of our trial required that all patients with a positive nucleic acid test be admitted to a hospital or a temporary isolation facility with early interventions and better outcomes. However, enforcement of the policy prevented us from using the incidence of hospitalization as a surrogate for disease progression, as was used in the pivotal trial of nir-matrelvir-ritonavir. Under these circumstances, we assessed the noninferiority of VV116 to nir-matrelvir-ritonavir in terms of symptom recovery, an important outcome indicating treatment benefits. Although the addition of a placebo group could have shown treatment efficacy, we did not establish this group for ethical reasons, given the established benefits of nirmatrelvir-ritonavir in patients with Covid-19 who had an increased risk of adverse outcomes. Consequently, it is difficult to interpret the efficacy of both drugs in the absence of a reference duration of sustained clinical recovery. The reference with
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