Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: A protocol for a multicenter, randomized, double-blind, placebo-controlled, phase 3 study (the SCORPIO-SR trial)

BackgroundMost antiviral treatments are targeted toward patients with severe or moderate-to-severe illness or those at high risk of developing severe Coronavirus disease 2019 (COVID-19). Limited options exist for patients with mild-to-moderate COVID-19, irrespective of vaccination history or risk status. Ensitrelvir is a novel oral SARS-CoV-2 3C-like protease inhibitor. The phase 2 studies of ensitrelvir have demonstrated promising results in mild-to-moderate COVID-19, whereas the challenge to evaluate the clinical efficacy due to shifting vaccinated status and the emergence of the Omicron variant has been suggested. 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. MethodsThis 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 as loading dose on Day 1), ensitrelvir 250 mg (750 mg as loading dose on Day 1), or placebo. The study interventions will be administered orally once daily for 5 days. The primary endpoint will be the time to resolution of the 5 symptoms of COVID-19 (stuffy or runny nose, sore throat, cough, feeling hot or feverish, low energy or tiredness), and the primary population will be patients with <72 hours from COVID-19 onset to randomization in ensitrelvir 125 mg group. The key secondary endpoints include the change from baseline on Day 4 in the amount of SARS-CoV-2 viral RNA and the time to the first negative SARS-CoV-2 viral titer. Closed testing procedure will be used for the primary and key secondary endpoints in both the primary and entire patient population. All safety assessments and adverse events will be reported. DiscussionTime to resolution of the 5 COVID-19 symptoms is a suitable endpoint to assess antiviral treatment in patients infected with the Omicron variant. In the phase 2 studies, ensitrelvir has demonstrated antiviral efficacy against SARS-CoV-2 and a trend toward reducing time to resolution of symptoms in patients with mild-to-moderate COVID-19. Through this study, we will seek to validate and establish the clinical efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19. Trial registrationJapan Registry of Clinical Trials (https://jrct.niph.go.jp): jRCT2031210350.

Efficacy and safety of ensitrelvir in patients with mild-to-moderate COVID-19: the phase 2b part of a randomized, placebo-controlled, phase 2/3 study

This phase 2b part of a randomized phase 2/3 study assessed the efficacy and safety of ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19). Patients were randomized (1:1:1) to orally receive ensitrelvir fumaric acid 125 mg (375 mg on day 1; n=140) or 250 mg (750 mg on day 1; n=140) or placebo (n=141) once daily for 5 days. Compared with placebo, the change from baseline in severe acute respiratory syndrome coronavirus 2 titer (measured as log10 50% tissue-culture infectious dose) on day 4 was significantly greater with ensitrelvir 125 mg and 250 mg (differences from placebo: -0.41, P<0.0001 for both). The total score of predefined 12 COVID-19 symptoms showed an improving trend with ensitrelvir treatment without a significant intergroup difference. Most adverse events were mild in severity. Ensitrelvir treatment demonstrated a favorable antiviral efficacy and potential clinical benefit with an acceptable safety profile. (Japan Registry of Clinical Trials identifier: jRCT2031210350)

A Randomized Phase 2/3 Study of Ensitrelvir, a Novel Oral SARS-CoV-2 3C-like Protease Inhibitor, in Japanese Patients With Mild-to-Moderate COVID-19 or Asymptomatic SARS-CoV-2 Infection: Results of the Phase 2a Part

For the treatment of coronavirus disease 2019 (COVID-19), antiviral agents that can achieve rapid severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) reduction are warranted. This double-blind, phase 2a part of a phase 2/3 study assessed the efficacy and safety of ensitrelvir, a novel oral SARS-CoV-2 3C-like protease inhibitor, in Japanese patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection. Sixty-nine patients enrolled from 56 sites were randomized (1:1:1) to orally receive 5-day ensitrelvir fumaric acid (375 mg on day 1 followed by 125 mg daily or 750 mg on day 1 followed by 250 mg daily) or placebo and followed up until day 28. The primary outcome was change from baseline in SARS-CoV-2 viral titer. A total of 16, 14, and 17 patients in the ensitrelvir 125 mg, ensitrelvir 250 mg, and placebo groups, respectively, were included in the intention-to-treat population (mean age: 38.8, 40.4, and 38.0 years, respectively). On day 4, the change from baseline in SARS-CoV-2 viral titer (log10 50% tissue culture infectious dose/mL) in patients with positive viral titer and viral RNA at baseline was greater with ensitrelvir 125 mg (mean [standard deviation], -2.42 [1.42]; P = 0.0712) and 250 mg (-2.81 [1.21]; P = 0.0083) versus placebo (-1.54 [0.74]), and ensitrelvir treatment reduced SARS-CoV-2 RNA by -1.4 to -1.5 log10 copies/mL versus placebo. All adverse events were mild to moderate. Ensitrelvir treatment demonstrated rapid SARS-CoV-2 clearance and was well tolerated in patients with mild-to-moderate COVID-19 or asymptomatic SARS-CoV-2 infection (Japan Registry of Clinical Trials identifier: jRCT2031210350).