This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.The objective of this randomized, double-blind, placebo-controlled, parallel group designed Phase III clinical trial is to evaluate the safety and efficacy of simvastatin to slow the progression of Alzehimer's Disease (AD). There will be equal randomization to drug and placebo, with stratified, blocked randomization to insure balanced assignment within sites. The primary outcome is slowing the progression of AD, as measured by the cognitive portion of the AD Assessment Scale (ADAScog). Secondary outcomes include measures of clinical global change (ADCD-CGIC), mental status, functional ability, behavioral disturbances, quality of life and economic indicators. Four hundred subjects with mild to moderate AD who are free of life-threatening disease and who do not require lipid-lowering treatment (according to current guidelines) will be enrolled from approximately 40 sites, with a goal of 10-15 subjects enrolled at each site. Study medications will be prepared as follows: Simvastatin 20mg or matching placebo will be given for a period of 6 weeks, followed by simvastatin 40mg or matching placebo for the remainder of 18 months. Subjects who experience side effects will have medications adjusted as clinically warranted, at the discretion of the site PI. Efficacy Measures: The primary measure will be a change on the ADAS-cog over 18 months. Secondary measures include eighteen month changes on the ADCS Clinical Global Impression of Change (ADCS-CGIC), the Mini-Mental State Examination (MMSE), the Dependence Scale, the ADCS Activities of Daily Living (ADCS-ADL) scale, the Neuropsychiatric Inventory (NPI), and the Quality of Life and Pharmacoeconomic Measure. Biomarkers of amyloid, inflammation and oxidative stress will also be examined from stored samples in a subset of subjects, and apolipoprotein E and other markers will be collected for secondary analysis. Safety parameters include the reporting of adverse events, the recording of symptom checklists, and the performance of vital signs, physicals, neurological examinations and laboratory tests (including liver function and creatine kinase). As another contributing variable, DNA storage will permit examination of other potential predictors of response.
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