Evaluation of Donepezil Versus Non-Pharmacological Management in Patients with Alzheimer's Disease: A Randomized Controlled Trial

Trial ID: 2024-515038-34-00
Protocol: APHP201183
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Dementia Alzheimer's type

Objectives

The primary objective of the study is to evaluate the **cognitive efficiency** at 6 months of daily intake of donepezil compared to the usual non-drug management in patients with Alzheimer's disease. This assessment is clinically relevant as it aims to determine the potential benefits of donepezil, a cholinesterase inhibitor, in enhancing cognitive function, which is a critical aspect of managing Alzheimer's disease.

Secondary objectives include assessing the efficacy at 6 months on various clinical scales: ADAS-Cog, CDR, ADCS-ADL, quality of life, and ZARIT. These measures provide a comprehensive evaluation of the treatment's impact on cognitive abilities, daily living activities, caregiver burden, and overall quality of life, offering a broader understanding of the therapeutic benefits and challenges associated with donepezil treatment in Alzheimer's disease.

Participants

The clinical trial involves participants diagnosed with **Alzheimer's disease** according to the 2014 IWG-2 criteria. The study population includes both male and female subjects aged 50 years and older. Participants are required to have a **Mini-Mental State Examination (MMSE)** score of 10 or higher at inclusion. The trial does not involve a vulnerable population. Participants must be covered by social security and should not be under any legal protection measures such as guardianship or curatorship. Additionally, they must have sufficient command of the French language to undertake neuropsychological tests. The presence of a family companion or a person at home is necessary to ensure treatment compliance if the MMSE score is below 20. The sponsor has not provided information regarding the total number of participants. Selection criteria include abnormal levels of Aβ42 or an abnormal Aβ40/Aβ42 ratio, and phosphorylated tau in the cerebrospinal fluid, according to local cut-offs. The trial does not specify any particular lifestyle considerations such as diet or physical activity.

Plans and Procedures

The clinical trial is designed to evaluate the cognitive efficiency of **donepezil** in comparison to non-drug management in patients with **Alzheimer's disease**. This study is a randomized, double-blind, controlled trial with an estimated duration from February 2022 to August 2026. Participants will be randomly assigned to receive either donepezil or standard non-drug care. The trial will involve a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a diagnosis of Alzheimer's disease according to the 2014 IWG-2 criteria, age of 50 years or older, and an MMSE score of 10 or higher. Participants must also have a family companion or caregiver to ensure treatment compliance if the MMSE score is below 20.

Following the inclusion visit, participants will undergo regular follow-up visits to monitor cognitive function and overall health. The primary endpoint is the difference in MMSE scores between the inclusion visit and the 6-month mark, comparing the donepezil group to the non-drug management group. Secondary endpoints include changes in ADAS-Cog, CDR, ADCS-ADL, quality of life, and ZARIT scores at 6 months. The end-of-study visit will occur at the conclusion of the 6-month treatment period, where final assessments will be conducted.

Participant involvement is expected to last for 6 months, with the possibility of early termination if adverse effects occur or if the participant withdraws consent. The trial aims to provide valuable insights into the efficacy of donepezil as an adjunct to non-drug treatment pathways in Alzheimer's disease management.

Treatment

The clinical trial involves the administration of **DONEPEZIL**, an experimental medication, in the form of a **film-coated tablet**. The active substance in this medication is **donepezil**, which is classified as a chemical compound. The medication is administered **orally**. The dosing regimen for this trial specifies a **maximum daily dose** of 5 mg, with a **maximum total dose** of 10 mg. The treatment period is set for a duration of **6 months**. Participants are required to adhere to the prescribed dosing schedule, and compliance will be monitored throughout the study to ensure accurate assessment of the medication's efficacy.

In addition to the experimental treatment, the study includes a comparator group receiving **non-drug treatment** as part of the usual management for Alzheimer's disease. This non-drug treatment serves as the standard-of-care therapy against which the effects of donepezil will be evaluated. The objective of the trial is to assess the cognitive efficiency of donepezil over a 6-month period compared to this non-drug management approach. Participants in both groups will be monitored for adherence to their respective treatment protocols to ensure the integrity of the trial data.

Efficacy

The efficacy of the clinical trial titled "CHOLINE-2 - Donepezil Versus Non-drug Treatment in Alzheimer's Disease" will be assessed by evaluating cognitive efficiency over a period of six months. The primary endpoint for efficacy assessment is the difference in the **Mini-Mental State Examination (MMSE)** score between the inclusion and six-month timepoints, comparing the arm treated with **donepezil** to the usual non-drug management arm. Secondary endpoints include differences at six months in scores from the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), Clinical Dementia Rating (CDR), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), quality of life assessments, and the Zarit Burden Interview (ZARIT).

These efficacy parameters will be measured using validated scales and patient-reported outcomes. The MMSE, ADAS-Cog, CDR, and ADCS-ADL are standardized tools commonly used in clinical trials to assess cognitive function and daily living activities in patients with Alzheimer's disease. The quality of life and caregiver burden will be evaluated using appropriate questionnaires. Data collection will occur at baseline and at the six-month mark to determine the efficacy of donepezil compared to non-drug treatment. The analysis will focus on the changes in these scores to assess the cognitive benefits of the treatment regimen.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Diagnosis of Alzheimer's disease according to the 2014 IWG-2 criteria.
Covered by social security.
Age ≥ 50 years old.
Lack of legal protection measure (guardianship, curatorship).
MMSE score ≥ 10 on inclusion.
Aβ42 in the CSF or abnormal Aβ40 / Aβ42 ratio according to the local cut-offs of the different centers.
Phosphorylated tau in the CSF abnormal according to the local cut-offs of the different centers.
Presence of a family companion or a person at home who can ensure compliance with treatment in the event of an MMSE score <20.
Sufficient command of the French language for the taking of neuropsychological tests.

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Exclusion Criteria

Other cause of major neurocognitive impairment.
Previous symptomatic treatment of Alzheimer's disease
Known hypersensitivity to donepezil hydrochloride or to any of the excipients listed in the SPC.
Cardiological contraindication after possible advice from a cardiologist, at the initiative of the investigator, including bradycardia, sinus disease or other supraventricular conduction abnormalities such as sinoauricular or atrioventricular block.
Family or personal history of QTc prolongation, or a Fridericiacorrected QT interval (QTcF) > 450 msec for men and > 470 msec for women.
Use of concomitant medications known to prolong the QTc interval,
History of relevant pre-existing cardiac pathology (e.g. uncompensated heart failure, recent myocardial infarction, bradyarrhythmias) or electrolyte disorders (hypokalaemia, hypomagnesaemia).
Patients at particular risk of ulceration, history of ulcer disease, or receiving concomitant treatment with non-steroidal anti-inflammatory drugs.
Patients at risk of urinary retention.
History of epileptic disease.
History of neuroleptic malignant syndrome
History of asthma or obstructive bronchopulmonary disease.
Severe hepatic impairment
Taking any of the following medications: > CYP3A4 inhibitors, such as ketonozale. > 2D6 inhibitors, such as quinidine. > CYP3A4 inhibitors such as itraconazole and erythromycin. > CYP2D6 inhibitors, such as fluoxetine. > Enzyme inducers such as rifampin, phenytoin, carbamazepine. > Class IA antiarrhythmics (e.g. quinidine); > Class III antiarrhythmics (e.g. amiodarone, sotalol). > Other antipsychotics (e.g. phenothiazine derivatives, sertindole, pimozide, ziprasidone). > Certain antibiotics (e.g. clarithromycin, erythromycin, levofloxacin, moxifloxacin).
Participation in other interventional research