A Clinical Study Evaluating the Effects of Memantine on Brain Atrophy in Patients With Alzheimer's Disease

Study Overview
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Brief Summary
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Pre-clinical studies have demonstrated that memantine can decrease the neuronal toxicity associated with excessive glutamate release and calcium overload in neurons. Previous studies have shown that memantine helps to treat the symptoms of Alzheimer's Disease (AD). In AD, the rate of brain tissue loss, or atrophy, is faster than in normal aging and this seems to go hand in hand with some of the symptoms of the disease. This suggests that memantine treatment in AD could provide both symptomatic improvement and neuro-protective effects. The purpose of this study was to show whether memantine, in addition to providing symptomatic benefits, can slow the rate of brain atrophy as assessed using magnetic resonance imaging (MRI) technology.

Detailed Description
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The primary objective of this study was to evaluate the effects of memantine on the rate of brain atrophy compared to placebo in patients with AD (moderate severity) over a 1-year period. This was a multinational, randomised, double-blind, parallel-group, placebo-controlled, fixed-dose study (20 mg memantine). The study also included secondary imaging, cognitive and behavioural measures.

Official Title
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A 1-year Randomised, Double-blind Placebo-controlled Study to Evaluate the Effects of Memantine on Rate of Brain Atrophy in Patients With Alzheimer's Disease

Conditions
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Alzheimer's Disease

Intervention / Treatment
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* Drug: Memantine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Outpatients at least 50 years of age with a current diagnosis of probable AD of moderate severity (MMSE score between 12 and 20, inclusive) consistent with NINCDS-ADRDA criteria and MRI scans Patients must have had a knowledgeable and reliable caregiver to accompany them to all clinic visits during the study Patients were either on or off existing acetylcholinesterase inhibitor (AChEI) treatment provided that the treatment had been initiated >6 months prior to screening, had stabilised with respect to dose for >3 months, and remained fixed during the entire study. AChEI treatment could not be initiated or modified during the study Exclusion Criteria: The patient had evidence of clinically significant active disease (including recent myocardial infarction and uncompensated congestive heart failure [NYHA II-IV]) The patient had evidence of any clinically significant neurodegenerative disease or neurological disorder other than AD The patient was contraindicated for MRI Other protocol-defined inclusion and exclusion criteria applied.

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: Memantine<br> | Drug: Memantine<br>* 10 mg tablets twice daily<br>* Other names: Ebixa®;|
| Placebo Comparator: Placebo<br> | Drug: Placebo<br>* Tablets twice daily<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total Brain Atrophy Rate Estimated Using Brain Boundary Shift Integral (BBSI) | Measures direct changes in total brain volume per visit interval (screening to Week 4, 42, or 52 or from Week 4 to Week 42 or 52) | Baseline to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Total Hippocampal Volume (HCV) | Estimated mean changes in total HCV | Baseline to 1 year | 
| Cognitive and Behavioural Outcomes: Controlled Oral Word Association Test (COWAT) Total Score | Adjusted mean change from baseline on cognitive and behavioural scores. COWAT: Verbal fluency test. The patient was asked to, during 1 minute, generate as many words as possible beginning with three pre-specified letters. The total score was calculated as the sum of acceptable words generated, with higher scores indicating lower cognitive impairment | Baseline to 1 year | 
| Cognitive and Behavioural Outcomes: Mini Mental State Examination (MMSE) Total Score | Adjusted mean change from baseline on cognitive and behavioural scores. MMSE: Brief, structured examination of mental status that assesses orientation, memory, attention, naming, comprehension, and praxis. The range is 0 to 30, with a lower score indicating a worse mental state | Baseline to 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Memantine, Neuroimaging, MRI, Brain atrophy