Prospective Study of Treatment with Ensitrelvir for COVID-19 in Patients Undergoing Hemodialysis (PROTECT-HD)

Abstract Introduction Patients on hemodialysis (HD) are vulnerable to COVID-19 and often excluded from pivotal antiviral trials. Ensitrelvir, an oral SARS-CoV-2 3C-like protease inhibitor approved in Japan, remains unevaluated in patients undergoing HD. This study assesses the pharmacokinetics, antiviral activity, safety, and clinical effectiveness of ensitrelvir in participants with mild COVID-19 undergoing HD. Methods In this prospective, single-arm, open-label study (December 2024–April 2025), participants with mild COVID-19 undergoing HD received ensitrelvir 375 mg on Day 1, followed by 125 mg once daily on Days 2–5. On Visit 2 (Day 3), plasma ensitrelvir concentrations were measured at three time points prior to ensitrelvir administration—before, during, and after dialysis. On Visit 3 (Day 5), blood samples were collected after dialysis and prior to ensitrelvir administration. Clinical outcomes, body temperature, SARS-CoV-2 viral load, and viral titers were monitored through Day 8. The primary endpoint was plasma concentration of ensitrelvir relative to dialysis; secondary endpoints included clinical outcomes, body temperature, and changes in viral load. Results Eight participants were evaluated: mean age, 68.1 years; mean body weight, 58.0 kg; and mean body mass index, 24.1 kg/m2. Plasma ensitrelvir concentrations (geometric mean) remained stable, with similar levels before (18.0 µg/mL) and after dialysis (16.4 µg/mL). All participants were judged clinically effective by the investigator by Day 8. Body temperature normalized within 16.6–48.0 h in four participants, and in one participant after 59.2 h. SARS-CoV-2 viral load (mean ± standard deviation) declined by 2.85 ± 1.52 log10 copies/mL from baseline to Day 8. No treatment-emergent adverse events, hospitalizations, or severe COVID-19-related complications occurred. Conclusion No dose adjustment was required regardless of HD. In participants with mild COVID-19 undergoing HD, plasma ensitrelvir concentrations were similar to those previously reported in healthy individuals. Ensitrelvir showed favorable antiviral and clinical responses, supporting its safe use without dose adjustments. Trial registration Japan Registry of Clinical Trials ID: jRCTs071240069.