3. Discussion
infection, taste disorder, smell disorder, illness
TASTE DISORDER, SARS-COV-2 INFECTION, DISEASE, RECRUITMENT, SEVERE ACUTE RESPIRATORY SYNDROME, INFECTIONS, INFECTION, OF SMELL DISORDERS, CORONAVIRUS, SMELL DISORDER
We described the protocol for a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial to assess the efficacy and safety of ensitrelvir, a novel oral SARS-CoV-2 3CL protease inhibitor, in expediting the resolution of symptoms in patients with mild-to-moderate COVID-19. We aimed to test the hypothesis that COVID-19 symptoms resolve sooner when patients are treated with ensitrelvir compared with placebo. Through this study, we sought to validate the potential antiviral efficacy of ensitrelvir observed in previous studies and to further establish its clinical efficacy and safety.Approximately 81% to 85% of patients with COVID-19 experience mild-to-moderate symptoms.To maximize patient recruitment during the SARS-CoV-2 epidemic, the phase 3 study aims for a seamless study design with continuous patient enrollment after the phase 2b study.Both the ensitrelvir 125 mg and 250 mg regimens demonstrated a potent antiviral efficacy against SARS-CoV-2 in the phase 2aTo evaluate the clinical efficacy of ensitrelvir against the SARS-CoV-2 infection, we will apply the primary endpoint focusing on the 5 major symptoms of the SARS-CoV-2 infection. In the post hoc analyses of the phase 2b study data, a trend toward a difference in the time to resolution of symptoms was observed between the ensitrelvir groups and placebo group; the time to resolution of symptoms was shorter in the ensitrelvir groups than in the placebo group. Additional analysis of the phase 2b study on smell and taste disorder revealed that compared with placebo, ensitrelvir reduced the number of patients experiencing both smell disorder (ensitrelvir 125 mg, Proportion of patients showing occurrence of smell disorder (A) and taste disorder (B) in the phase 2b study (ITT* population). *This population comprises all patients randomly assigned to the study intervention with SARS-CoV-2 viral titer detected at baseline. The detection of SARS-CoV-2 viral titer will be confirmed by viral titer assessment based on nasopharyngeal swab sample. Patients will be analyzed according to the assigned study intervention. ITT = intention-to-treat, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.Irrespective of risk factors and the severity of infection, symptoms of COVID-19 may persist for a prolonged duration. Therefore, a stringent endpoint such as the time to resolution of symptoms may be suitable for evaluating the clinical efficacy of ensitrelvir in mild-to-moderate infections. Moreover, this endpoint is also appropriate in light of disease modification due to vaccination and the emergence of new variants. Since there is no information on how symptoms in mild-to-moderate COVID-19 progress over time, the endpoint of time to resolution of COVID-19 symptoms will provide clarity on how symptoms resolve with or without an antiviral treatment.One of the strengths of this study is that it includes patients with COVID-19, irrespective of whether they are at a high-risk of developing severe illness, which broadens its relevance to the general adolescent and adult populations. Additionally, this study will enroll both vaccinated and unvaccinated individuals, unlike other studies assessing oral antivirals that mainly recruited unvaccinated patients. Since vaccination has a large impact on how the infection manifests in individuals, including vaccinated patients in the study will provide a comprehensive understanding of the antiviral treatment that reflects the current status of the SARS-CoV-2 pandemic.It is hoped that this phase 3 study will be able to confirm the clinical efficacy and safety of ensitrelvir in the treatment of mild-to-moderate COVID-19, and that the results will help provide evidence on symptom progression or improvement.