Evaluating Simvastatin's Potential Role in Therapy

Study Overview
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Brief Summary
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The purpose of this study is to see how simvastatin, a cholesterol-lowering drug, affects processes related to the development of Alzheimer's disease, including: 1) levels of a substance called beta-amyloid-42 found in the spinal fluid surrounding the brain, 2) blood flow in the brain, 3) inflammation in the brain, and 4) cognitive function.

Detailed Description
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Some studies suggest that statin medications, which are a group of cholesterol-lowering medicines, may help prevent Alzheimer's disease. However, this has not been proven in humans. The purpose of this study is to see how simvastatin affects a substance in the spinal fluid around the brain called beta-amyloid-42 which is thought to contribute to Alzheimer's disease. This study also evaluates whether simvastatin improves regional brain blood flow (on magnetic resonance imaging [MRI]), reduces inflammation, and improves cognitive function. The ESPRIT study was a 9-month randomized, controlled clinical trial that randomized 100 middle-aged adults with a parental history of Alzheimer's disease. Participants were randomized to simvastatin 40 mg for one month then 80 mg daily or matching placebo tablets. Fifty of the ESPRIT subjects participated in the MRI sub-study. Participants had the following data collected: fasting blood tests (baseline and months 3 and 9), medical history and medication questionnaires (each visit), study medication side effect review (all visits), lumbar puncture procedure (baseline and month 9), memory testing (baseline and months 3 and 9), and MRI (baseline and month 9 in 50 sub-study participants).

Official Title
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Effect of Statins on Pathobiology of Alzheimer's Disease

Conditions
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Alzheimer Disease

Intervention / Treatment
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* Drug: Simvastatin
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 35 to 69 Parent with Alzheimer's disease Exclusion Criteria: Current use of cholesterol-lowering medication Active liver disease History of adverse reaction to statins Contraindication to lumbar puncture Elevated lab values (creatine kinase and creatinine) Use of medications known to interact with statins History of dementia Currently pregnant or planning to become pregnant Use of large quantities of grapefruit juice (more than 1 quart per day) Current involvement in another investigational drug study Contraindications to MRI (for MRI sub-study) Ethical contraindication to placebo (persons with high vascular risk)

Ages Eligible for Study
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Minimum Age: 35 Years
Maximum Age: 69 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: simvastatin<br>simvastatin 40 mg nightly for 1 month then 80 mg nightly for 8 months | Drug: Simvastatin<br>* 40 mg tablet each night for one month, then 80 mg for 8 months<br>* Other names: Zocor;|
| Placebo Comparator: Placebo<br>Matching placebo tablet nightly for 9 months | Drug: Placebo<br>* Matching tablet each night for 9 months<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Cerebrospinal Fluid (CSF) Beta-amyloid-42 |  | baseline and 9 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Regional Cerebral Blood Flow on MRI | Mean changes noted in posterior cingulate cortex | baseline and 9 months | 
| Change in Inflammatory Markers | Change noted in serum high-sensitivity c-reactive protein | baseline and 9 months | 
| Changes in Cognitive Performance | Change in Hopkins Verbal Learning Test Delayed Recall The Hopkins Verbal Learning Test Delayed Recall score is the raw number of words recalled at Trial 4, adjusted for years of education and age. This is a 12-item word list test. | Baseline and 9 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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amyloid protein, apolipoprotein, cerebrospinal fluid, cerebrovascular circulation, inflammation, magnetic resonance imaging, prevention & control