Efficacy of Donepezil for Fatigue and Psychological Symptoms in Post-COVID-19 Condition: Study Protocol for a Multicenter Randomized, Placebo-controlled, Double-blind Trial

Background: Approximately 30% of coronavirus disease 2019 COVID-19 patients develop fatigue and psychological symptoms. We previously demonstrated the efficacy of donepezil, an acetylcholinesterase inhibitor that is widely used to treat dementia, in basic research.

Methods: This is a multicenter, double-blind, randomized, controlled, phase II clinical trial in which 120 patients with COVID-19 will be randomized in a 1:1 ratio to a donepezil or placebo group. Inclusion criteria are as follows: (1) Adult. (2) With COVID-19 infection who had an upper respiratory tract infection, fever, or cough in the acute phase. (3) With a global binary fatigue score ≥4 on the Chalder Fatigue Scale assessment (4) Within 52 weeks of the onset of COVID-19. (5) Patients who provide consent themselves. In the donepezil group, a low dose (3 mg/day) is administered for the first week and is increased to 5 mg/day for 2 weeks. The control group receives placebo for 3 weeks. The primary endpoint is a change in and the absolute value of the Chalder Fatigue Scale score after 3 weeks of treatment. Secondary endpoints are a change in and the absolute value of the Chalder Fatigue Scale score after 8 weeks of treatment, the other mental scores after 3 and 8 weeks of treatment, a symptom survey, adverse events, and medication compliance rate.

Results: This study protocol is ongoing and the results will be analyzed in April 2024.

Conclusions: The off-label use of donepezil at the default dose for dementia has potential for the treatment of post-COVID-19 condition.