Evaluation of Donepezil Hydrochloride in Anorexia Nervosa: A Multicenter Double-Blind Randomized Controlled Trial Versus Placebo

The primary objective of this study is to evaluate the effect of oral administration of **donepezil**, an acetylcholinesterase inhibitor, compared with placebo, on the improvement of symptomatology in adult women with **anorexia nervosa**. This is clinically relevant as it aims to address the core symptoms of anorexia nervosa, potentially offering a novel therapeutic approach for this challenging condition.

Secondary objectives include:

• Evaluating the effect of acetylcholine esterase inhibitor administration on weight gain in adult women with anorexia nervosa compared to placebo.
• Assessing the impact on habit-forming learning in this population.
• Investigating the balance between goal-directed behaviors and habits in adult women with anorexia nervosa.

The clinical trial focuses on evaluating the effect of oral administration of donepezil, an **acetylcholinesterase inhibitor**, on the symptomatology of **anorexia nervosa**. The study population comprises exclusively female participants, aged between 18 and 65 years, who meet three DSM V criteria for anorexia nervosa, specifically the restrictive subtype. Participants are required to have a Body Mass Index (BMI) between 14 and 18.5 kg/m² and a resting heart rate of at least 40 bpm. The trial does not include a vulnerable population, and the sponsor has not provided information regarding the total number of participants. The selection criteria ensure that the study population is homogenous in terms of gender and specific health parameters, which are critical for assessing the treatment's efficacy in this demographic.

The clinical trial is designed to evaluate the effect of **donepezil hydrochloride**, an acetylcholinesterase inhibitor, on the symptomatology of **anorexia nervosa**. This study is a multicenter, double-blind, randomized, controlled trial comparing the investigational drug to a placebo. The trial is categorized as a Phase IIb study and is not considered low intervention. The trial is expected to commence recruitment on July 1, 2024, and is estimated to conclude by January 1, 2029.

Participants will be involved in the study for a maximum treatment period of three months. The study includes several key visits: an inclusion (screening) visit, follow-up visits, and an end-of-study visit. The inclusion visit will confirm eligibility based on criteria such as age, body mass index, and specific diagnostic criteria for anorexia nervosa. Follow-up visits will occur at specified intervals to monitor the primary and secondary endpoints, including changes in the Eating Disorder Examination Questionnaire (EDE-Q) scores, body mass index, and other neurocognitive and psychological assessments. The end-of-study visit will assess the overall outcomes and any adverse events experienced during the trial.

Participants are expected to adhere to the study protocol, with conditions for early termination including non-compliance, adverse events, or withdrawal of consent. The primary endpoint is the absolute intra-individual difference in the total EDE-Q score between the inclusion day (D0) and day 90 (D90). Secondary endpoints include changes in body mass index, neurocognitive test scores, and the occurrence of adverse events. The investigational product, donepezil, will be administered orally in capsule form, with a maximum daily dose of 5 mg. The placebo will have the same container composition as the investigational product, excluding the active substance.

The clinical trial involves the administration of **donepezil hydrochloride**, an acetylcholinesterase inhibitor, to evaluate its effect on the symptomatology of anorexia nervosa. The investigational medicinal product is available in two pharmaceutical forms: a capsule and a film-coated tablet. The capsule form, identified as "donépézil 2.5 mg gélules," contains 2.5 mg of donepezil hydrochloride per capsule. The maximum daily dose for this form is 2.5 mg, with a total maximum dose of 225 mg over a treatment period of 3 months. The route of administration is oral. The film-coated tablet, marketed as "DONEPEZIL ARROW 5 mg, comprimé pelliculé," contains 5 mg of donepezil hydrochloride per tablet. The maximum daily dose for this form is 5 mg, with a total maximum dose of 450 mg over the same treatment period. This form is also administered orally. Participant compliance with the dosing schedule will be monitored throughout the trial.

The trial also includes a **placebo** group to serve as a comparator. The placebo is designed to mimic the investigational medicinal product in terms of container composition and manufacturing process, with the exception of the active substance. The active substance in the placebo is lactose monohydrate. The placebo is administered orally, following the same dosing schedule as the investigational product, to ensure blinding and maintain the integrity of the trial. The placebo is manufactured by the same entity responsible for the investigational product, ensuring consistency in production standards.

Efficacy in this clinical trial will be assessed through a series of primary and secondary endpoints designed to evaluate the impact of **donepezil hydrochloride** on the symptomatology of anorexia nervosa. The primary endpoint is the absolute intra-individual difference in the total Eating Disorder Examination Questionnaire (EDE-Q) score between inclusion day 0 (D0) and day 90 (D90). This will provide a quantitative measure of symptom improvement over the treatment period.

Secondary endpoints include a variety of measures to capture different aspects of efficacy. These include intra-individual differences in body mass index (BMI) between D0 and D90, and between D0 and D180, as well as differences in response rates in the devalued condition of phase 3 "slip of action" of the HABITS neurocognitive test between D0 and D90. Additional assessments will be made using the Self-Report Habit Index (SRHI), Wisconsin Card Sorting Test (WSCT), Trail Making Test B-A, Brixton test, Yale-Brown Obsessive Compulsive Scale (Y-BOCS), and Hospital Anxiety and Depression Scale (HADS) scores, all measured at D0 and D90. The evolution of EDE-Q and Eating Disorder Inventory-3 (EDI-3) sub-dimensions scores will also be evaluated between D0 and D90.

Adverse events will be monitored according to a standard Common Terminology Criteria for Adverse Events (CTCAE), with specific attention to treatment discontinuations due to poor tolerance and changes in biological profiles, including transaminase levels, prothrombin time (PT), activated partial thromboplastin time (APTT), creatine phosphokinase (CPK), and blood count disturbances. These will be assessed at D3, D5, D30, and D90. Additionally, plasma and feces samples will be collected and stored at D1 and D90 for further analysis.