Effect of CAFfeine on Cognition in Alzheimer's Disease

Study Overview
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Brief Summary
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Sporadic Alzheimer's disease is a multifactorial illness arising a major medico-economic stakes for our aging societies. There is currently no curative treatment available. Coffee is a complex beverage with psychostimulant properties whose main effective element, caffeine, has a pleiotropic effect on the central nervous system. Caffeine pharmacological properties enable its use like an Alzheimer's disease symptomatic treatment. Its supposed benefits mustn't obscure anxiety and insomnia caffeine effect at large dose, which Alzheimer's patients might be more vulnerable. The main study objective is to evaluate placebo-controlled caffeine efficacy (30 treatments weeks) on cognitive decline in Alzheimer's disease dementia at beginning to moderate stage (MMSE 16-24).

Official Title
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Multicentre, Randomized, Double-blind, Placebo-controlled Trial Evaluating the Effect of a 30-week Caffeine Treatment on Cognition in Alzheimer's Disease at Beginning to Moderate Stages

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Caffeine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥ 50 at screening Probable Alzheimer dementia according to the criteria of the National Institute on Aging-Alzheimer's Association; diagnosis must be supported by brain imaging (CT or MRI) and blood test (including ionogram, kidney and liver function, calcemia, CRP, TSH, B12 vitamins and folates) performed in routine care MMSE score ≥16 Presence of an informant and caregiver, living with the patient IAChE and/or Memantine treatment non-compulsory ; If implemented it must be effective and stable for 2 months before the selection visit and must remain stable for the duration of the study Exclusion Criteria: Patients who refuse to adopt a low caffeine diet (eviction of tea, caffeinated sodas, chocolate in large quantities) Current major depressive episode according to DSM-5 criteria Another chronic pathology of the central nervous system Major anxiety according to the clinician (consistent with the corresponding nPI-R items that must indicate a severity >2 and an impact >3) Sleep disorders defined by severity and an impact on NPI-R; a patient fitted for OSA may be included if the device has been in use for 3 months and well tolerated (stable) Decompensated heart disease or severe rhythm disorder (excluding slow, treated and stable chronic atrial fibrillation) Active smoking For childbearing women : pregnancy in progress or planned (A pregnancy test will be performed) Patients who take forbidden treatment : Psychotropic treatments introduced or modified < 2 months before inclusion Chronic use of CYP1A2 inducing or inhibiting drugs All caffeine-containing specialties Drugs that influence caffeine metabolism Drugs that may interact with caffeine

Ages Eligible for Study
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Minimum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Caffeine<br>after a 3 weeks up titration period, 1 capsule of 200 mg twice a day during 27 weeks (ie 400mg/day) | Drug: Caffeine<br>* 100mg caffeine capsule treatment, beginning after caffeine diet during 6 weeks, titrate in 3 weeks (by 100mg stages) until 400mg aim dose per day in 2 doses during 27 weeks, and finally interrupt according to the same negative titration.<br>|
| Placebo Comparator: placebo<br>after a 3 weeks up titration period, 2 capsules per day during 27 weeks | Drug: Placebo<br>* Placebo capsule treatment, beginning after caffeine diet during 6 weeks, titrate in 3 weeks until 2 doses aim dose per day during 27 weeks, and finally interrupt according to the same negative titration.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in NTB scores | difference between randomized value and value after 30 weeks of treatment | 30 weeks after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Caffeine treatment effect on MMSE score | difference between randomized value and value after 30 weeks of treatment on MMSE score | 30 weeks after randomization | 
| Caffeine treatment effect on NTB subscores | difference between randomized value and value after 30 weeks of treatment on NTB subscores | 30 weeks after randomization | 
| Caffeine treatment effect on TAP scores | difference between randomized value and value after 30 weeks of treatment on TAP scores | 30 weeks after randomization | 
| Caffeine treatment effect on Epworth score | difference between randomized value and value after 30 weeks of treatment on Epworth score | 30 weeks after randomization | 
| Caffeine treatment effect on DAD-6 score | difference between randomized value and value after 30 weeks of treatment on DAD-6 score | 30 weeks after randomization | 
| Caffeine treatment effect on QoL-AD score | difference between randomized value and value after 30 weeks of treatment on QoL-AD score | 30 weeks after randomization | 
| Caffeine treatment effect on CGIC score | difference between randomized value and value after 30 weeks of treatment on CGIC score | 30 weeks after randomization | 
| Caffeine treatment effect on Zarit score | difference between randomized value and value after 30 weeks of treatment on Zarit score | 30 weeks after randomization | 
| persistent effect of caffeine treatment on MMSE score after a 6 weeks wash out period | difference between value after 30 weeks of treatment and value after a 6 weeks wash out period (from Week 30 to Week 36) on MMSE score | 36 weeks after randomization | 
| persistent effect of caffeine treatment on NTB subscores after a 6 weeks wash out period | difference between value after 30 weeks of treatment and value after a 6 weeks wash out period (from Week 30 to Week 36) on NTB subscores | 36 weeks after randomization | 
| persistent effect of caffeine treatment on TAP scores after a 6 weeks wash out period | difference between value after 30 weeks of treatment and value after a 6 weeks wash out period (from Week 30 to Week 36) on TAP scores | 36 weeks after randomization | 
| persistent effect of caffeine treatment on Epworth score after a 6 weeks wash out period | difference between value after 30 weeks of treatment and value after a 6 weeks wash out period (from Week 30 to Week 36) on Epworth score | 36 weeks after randomization | 
| persistent effect of caffeine treatment on DAD-6 score after a 6 weeks wash out period | difference between value after 30 weeks of treatment and value after a 6 weeks wash out period (from Week 30 to Week 36) on DAD-6 score | 36 weeks after randomization | 
| persistent effect of caffeine treatment on QoL-AD score after a 6 weeks wash out period | difference between value after 30 weeks of treatment and value after a 6 weeks wash out period (from Week 30 to Week 36) on QoL-AD score | 36 weeks after randomization | 
| persistent effect of caffeine treatment on Zarit score after a 6 weeks wash out period | difference between value after 30 weeks of treatment and value after a 6 weeks wash out period (from Week 30 to Week 36) on Zarit score | 36 weeks after randomization | 
| Caffeine effect heterogeneity: impact of AD treatment | impact of AD treatment on caffeine effect | 30 weeks after randomization | 
| Caffeine effect heterogeneity: impact of ApoE4 status | impact of ApoE4 status on caffeine effect | 30 weeks after randomization | 
| Caffeine effect heterogeneity: impact of caffeine metabolism speed | impact of caffeine metabolism on caffeine effect | 30 weeks after randomization | 
| Caffeine effect heterogeneity: impact of gender | impact of gender on caffeine effect | 30 weeks after randomization | 
| Caffeine safety profile: NPI scores | changes in NPI scores and subscores between caffeine and placebo arms | 30 weeks after randomization | 
| Caffeine safety profile: heart beat | changes in heart beat between caffeine and placebo arms | 30 weeks after randomization | 
| Caffeine safety profile: blood pressure | changes in blood pressure between caffeine and placebo arms | 30 weeks after randomization | 
| Caffeine and its derivatives concentrations in blood samples | increase in caffeinemia and its derivatives in the morning (fasting samples) | 30 weeks after randomization | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Alzheimer's disease, caffeine, cognitive impairment