A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part)

Abstract

Background: Limited treatment options exist for patients with mild-to-moderate coronavirus disease 2019 (COVID-19), irrespective of vaccination history or risk status. Ensitrelvir is a novel oral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 3C-like (3CL) protease inhibitor. While phase 2 studies of ensitrelvir have demonstrated promising results in treating mild-to-moderate COVID-19, evaluation of its clinical efficacy due to shifting vaccination status and emergence of the Omicron variant represents significant challenges. Here, we describe the protocol for a phase 3 study designed to evaluate the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19, regardless of risk status or vaccination history.

Methods: This is a multicenter, randomized, double-blind, placebo-controlled, phase 3 study. Patients with mild-to-moderate COVID-19 within 120 hours from onset will be randomized in a 1:1:1 ratio into 3 treatment arms-ensitrelvir 125 mg (375 mg loading dose on Day 1), ensitrelvir 250 mg (750 mg loading dose on Day 1), and placebo. The study interventions will be administered orally, once-daily, for 5 days. The primary endpoint will be the time to resolution of 5 symptoms of COVID-19 (stuffy or runny nose, sore throat, cough, feeling hot or feverish, and low energy or tiredness), and the key secondary endpoints will include the change from baseline on Day 4 in the amount of SARS-CoV-2 viral ribonucleic acid (RNA) and the time to first negative SARS-CoV-2 viral titer. The primary population for the primary and key secondary endpoints will be patients with <72 hours from COVID-19 onset to randomization and, subsequently, patients in entire patient population (<120 hours) in the ensitrelvir 125 mg group. Closed testing procedure will be used for the primary and key secondary endpoints in both the primary and entire patient populations. All safety assessments and adverse events (AE) will be reported.

Discussion: In a post hoc analysis of the phase 2b study, compared with placebo, ensitrelvir demonstrated a reduced time to resolution of 5 symptoms in patients with mild-to-moderate COVID-19. Through this study, we intend to validate and establish the efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19.

Figure 1.

Study design. ^aOptional visit. However, administration of study intervention and entry of patient diary should continue. ^bAssessments will be performed only for patients providing consent/assent to participate in the exploratory period. Op = optional, V = visit.

Figure 2.

Kaplan–Meier plot of the time to resolution of the 5 COVID-19 symptoms in the patient group with <72 h from the onset to randomization 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 was confirmed by viral titer assessment based on nasopharyngeal swab samples. Patients were analyzed according to the assigned study intervention. COVID-19 = coronavirus disease 2019, ITT = intention-to-treat, SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Table 2

Schedule of activities.

Figure 3.

Weibull distribution (A) and corresponding hazard ratio curve (B) assumed when calculating the required number of patients for the phase 3 study for the time to resolution of the 5 symptoms of COVID-19. COVID-19 = coronavirus disease 2019.

Figure 4.

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.