Randomized, Double-Blind, Placebo-Controlled Study on the Efficacy of Caffeine in Cognitive Decline in Early to Moderate Alzheimer's Disease

The primary objective of this study is to evaluate the efficacy of a 30-week **caffeine** treatment compared to placebo on cognitive decline in patients with early to moderate stage **Alzheimer's disease** dementia, as measured by the Mini-Mental State Examination (MMSE) scores ranging from 16 to 26. This is clinically relevant as it aims to determine whether caffeine can slow cognitive deterioration in this patient population, potentially offering a novel therapeutic approach.

Secondary objectives include:

• Evaluating the effect of 30 weeks of caffeine treatment compared to placebo, and assessing the persistent effect 6 weeks post-discontinuation on cognitive and attentional functions, functional autonomy, quality of life, and caregiver burden.
• Assessing the heterogeneity of the caffeine treatment effect over 30 weeks across predefined subgroups, including iAChE treatment status, APOE4 genotype, caffeine metabolism rate, and gender.
• Evaluating the effect of caffeine treatment compared to placebo on the occurrence of adverse effects.
• Assessing the impact of caffeine treatment on the increase of caffeine and its three dimethylated metabolites (paraxanthine, theophylline, theobromine) when taken in the morning on an empty stomach.

The clinical trial focuses on evaluating the efficacy of caffeine over a 30-week treatment period compared to a placebo in individuals with beginning to moderate stage **Alzheimer's disease** dementia. The study population includes both men and women, aged over 50 years, who have been diagnosed with probable Alzheimer's disease, supported by brain imaging and routine blood tests. Participants are required to have a Mini-Mental State Examination (MMSE) score between 16 and 26. The trial includes individuals who are currently on stable doses of acetylcholine esterase inhibitors (AChEIs) and/or memantine, provided the treatment has been stable for at least two months prior to the screening and remains so throughout the study. Participants must have a partner who can provide support for more than 10 hours per week. The trial population is selected based on these criteria, and all participants must provide written consent and be socially insured. The sponsor has not provided information regarding the total number of participants in the study.

The clinical trial is designed as a **randomized**, **double-blind**, **placebo-controlled** study to evaluate the efficacy of **caffeine** treatment on cognitive decline in patients with early to moderate **Alzheimer's disease**. The trial will span a total duration of 30 weeks, with an additional 6-week follow-up period to assess the persistence of treatment effects. Participants will be randomly assigned to receive either caffeine capsules or placebo capsules, administered orally, with a maximum daily dose of 400 mg. The primary endpoint is the variation in the total Neuropsychological Test Battery (NTB) score at 30 weeks post-randomization. Secondary endpoints include changes in cognitive functions, functional autonomy, and the occurrence of adverse events.

The sequence of study visits includes an initial screening visit to confirm eligibility based on criteria such as age, diagnosis of Alzheimer's disease, and stable treatment with acetylcholine esterase inhibitors or memantine. Following randomization, participants will attend regular follow-up visits to monitor cognitive function, safety, and adherence to the study protocol. The end-of-study visit will occur at 36 weeks, 6 weeks after the cessation of treatment, to evaluate the lasting effects of caffeine. The expected length of participant involvement is approximately 36 weeks, with conditions for early termination including withdrawal of consent, significant protocol deviations, or adverse events that compromise participant safety.

The clinical trial involves the administration of **caffeine anhydrous** as the experimental medication. This compound is provided in the form of a **capsule** and is classified as a **neurostimulant**. The active substance, **caffeine**, is of chemical origin. Participants will receive a maximum daily dose of 400 mg, administered orally. The treatment period is set for a maximum of 30 days. The caffeine capsules are manufactured by the Centre Hospitalier Régional et Universitaire Lille. Compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the protocol.

In addition to the experimental treatment, the study includes a **placebo** group. The placebo is composed of **microcrystalline cellulose**, available in two dosages: 100 mg and 200 mg. These substances do not have a defined pharmaceutical form or active substance and are used to maintain the double-blind nature of the trial. The placebo is administered in a manner consistent with the experimental treatment to ensure blinding is maintained. The placebo serves as a comparator to evaluate the efficacy of caffeine on cognitive decline in patients with Alzheimer's disease.

The efficacy of caffeine treatment in the clinical trial will be assessed primarily through the variation in the total Neuropsychological Test Battery (NTB) score, expressed as a z-score, at 30 weeks post-randomization. This primary endpoint measures the difference between the baseline value at randomization and the value after 30 weeks of treatment. Secondary endpoints include the evaluation of cognitive functions, with specific attention to the Mini-Mental State Examination (MMSE) score, NTB executive functions sub-score, NTB memory sub-score, simple and complex reaction times in the TAP test, and the Epworth score. Functional autonomy will be assessed by the variation in the Disability Assessment for Dementia (DAD) score between baseline and 30 weeks post-randomization.

Additional assessments will evaluate the persistent effect of caffeine treatment six weeks after its interruption, with parameters measured at 36 weeks post-randomization. The Clinical Global Impression of Change (CGIC) score will also be evaluated at this time point. The trial will explore the heterogeneity of caffeine's effect on predefined subgroups, including those based on acetylcholine esterase inhibitor treatment, APOE4 genotype, caffeine metabolism, and gender, by analyzing the variation in the NTB score between baseline and 30 weeks. The occurrence of adverse events, as well as changes in Neuropsychiatric Inventory (NPI) scores, heart rate, and blood pressure, will be monitored throughout the follow-up period.

Biomarker analysis will include the evaluation of caffeine and its three dimethylated metabolites (paraxanthine, theophylline, theobromine) in the morning on an empty stomach. The evolution of these biomarkers will be tracked to assess the pharmacokinetic profile of caffeine during the study. These comprehensive assessments will provide a robust evaluation of caffeine's efficacy in managing cognitive decline in patients with beginning to moderate stage **Alzheimer's disease**.