Summary of COVID-19 ensitrelvir studies

1. Mukae et al., 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

69 patient ensitrelvir early treatment RCT: 45% improved viral clearance (p=0.002).
RCT 69 patients in in Japan, showing faster viral clearance with ensitrelvir. 5-day ensitrelvir (375mg on day 1 followed by 125 mg daily or 750mg on day 1 followed by 250mg daily).
May 2022, medRxiv, https://www.medrxiv.org/content/early/2022/05/17/2022.05.17.22275027, https://c19p.org/mukae

2. Schilling et al., Antiviral efficacy of oral ensitrelvir versus oral ritonavir-boosted nirmatrelvir in COVID-19

392 patient ensitrelvir early treatment RCT: 8% faster recovery (p=0.006) and 49% improved viral clearance (p<0.0001).
RCT 604 low-risk adults with early COVID-19 symptoms showing significantly improved SARS-CoV-2 viral clearance with both ensitrelvir and paxlovid. Inclusion criteria selected for low-risk patients with high viral loads which may not generalize to high-risk patients or patients treated prior to having high viral load. Authors indicate that "between March 2023 and April 2024 the three study arms randomised 604 patients", however figure S7 shows paxlovid patients starting before July 2022. 120 day long COVID results in the protocol are not reported. The protocol was modified mid-trial in October 2024: the number of patients was increased, the swabbing schedule was changed, and patient self-swabbing was added. Results appear to be improved in the post-change period. The swabbing schedule in the paper conflicts with the October 2024 change reported in the protocol ("now swabbing day 0 to day 5 once or twice per day to characterise viral clearance").
May 2025, medRxiv, https://www.medrxiv.org/content/10.1101/2025.05.18.25327861, https://c19p.org/schilling4

3. Mukae et al., 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

227 patient ensitrelvir early treatment RCT: 9% improved recovery (p=0.28) and 32% faster viral clearance (p=0.0001).
RCT 428 COVID-19 patients in Japan showing faster viral clearance and improved recovery with ensitrelvir.
Dec 2022, Clinical Infectious Diseases, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciac933/6881001, https://c19p.org/mukae3

4. Yotsuyanagi et al., Efficacy and Safety of 5-Day Oral Ensitrelvir for Patients With Mild to Moderate COVID-19: The SCORPIO-SR Randomized Clinical Trial

1,821 patient ensitrelvir early treatment RCT: 11% faster recovery (p=0.3) and 49% improved viral clearance (p=0.001).
RCT 1,821 COVID-19 outpatients in Japan, Vietnam, and South Korea, showing improved viral clearance and improved recovery (significant for patients treated within 3 days of onset) with ensitrelvir. Only 2 hospitalizations were reported, with no deaths.
Jul 2023, JAMA Network Open, https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2814871, https://c19p.org/yotsuyanagi

5. Katsuta et al., The time to return-to-work in healthcare workers with COVID-19 treated with ensitrelvir, a novel oral inhibitor of 3C-like protease of SARS-CoV-2: An observational study utilizing pre-existing data from a single hospital

102 patient ensitrelvir early treatment study: 10% faster recovery (p=0.02).
Retrospective 102 healthcare workers in Japan showing shorter time to return-to-work with ensitrelvir treatment for COVID-19.
Apr 2025, J. Infection and Chemotherapy, https://www.sciencedirect.com/science/article/pii/S1341321X25000662, https://c19p.org/katsuta

6. Takazono et al., Real-World Effectiveness of Ensitrelvir in Reducing Severe Outcomes in Outpatients at High Risk for COVID-19

167,310 patient ensitrelvir early treatment study: 24% higher mortality (p=0.84), 158% higher ventilation (p=0.2), 36% lower need for oxygen therapy (p=0.33), and 37% lower hospitalization (p=0.02).
Retrospective 167,310 high-risk COVID-19 outpatients in Japan showing significantly lower hospitalization with ensitrelvir treatment.
Jun 2024, Infectious Diseases and Therapy, https://link.springer.com/10.1007/s40121-024-01010-4, https://c19p.org/takazono

7. Luetkemeyer et al., Ensitrelvir for the Treatment of Nonhospitalized Adults with COVID-19: Results from the SCORPIO-HR, Phase 3, Randomized, Double-blind, Placebo-Controlled Trial

2,085 patient ensitrelvir early treatment RCT: 203% higher hospitalization (p=0.37), 5% faster recovery (p=0.14), and 19% improved viral clearance (p=0.02).
RCT 2,093 outpatients with mild-to-moderate COVID-19 showing improved viral clearance but no significant difference in time to symptom resolution with ensitrelvir. Participants were randomized to receive ensitrelvir or placebo within five days of symptom onset, with the primary analysis focusing on those treated within three days. A mid-trial protocol change excluded participants treated more than three days post-symptom onset from the primary analysis.
Feb 2025, Clinical Infectious Diseases, https://academic.oup.com/cid/advance-article/doi/10.1093/cid/ciaf029/8017725, https://c19p.org/luetkemeyer

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