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| ID | Type | Description | Link |
|---|---|---|---|
| 1K23AG026752-01 | U.S. NIH Grant/Contract | View source |
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| Name | Class |
|---|---|
| National Institute on Aging (NIA) | NIH |
| Paul Beeson Faculty Scholars Program | OTHER |
| The John A. Hartford Foundation | OTHER |
| The Atlantic Philanthropies |
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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.
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).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| simvastatin | Experimental | simvastatin 40 mg nightly for 1 month then 80 mg nightly for 8 months |
|
| Placebo | Placebo Comparator | Matching placebo tablet nightly for 9 months |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Simvastatin | Drug | 40 mg tablet each night for one month, then 80 mg for 8 months |
|
| Measure | Description | Time Frame |
|---|---|---|
| Change in Cerebrospinal Fluid (CSF) Beta-amyloid-42 | baseline and 9 months |
| 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 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Cynthia M. Carlsson, MD, MS | University of Wisconsin, Madison | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of Wisconsin | Madison | Wisconsin | 53705 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 11296263 | Background | Fassbender K, Simons M, Bergmann C, Stroick M, Lutjohann D, Keller P, Runz H, Kuhl S, Bertsch T, von Bergmann K, Hennerici M, Beyreuther K, Hartmann T. Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5856-61. doi: 10.1073/pnas.081620098. Epub 2001 Apr 10. | |
| 11344276 | Background | Wolozin B. A fluid connection: cholesterol and Abeta. Proc Natl Acad Sci U S A. 2001 May 8;98(10):5371-3. doi: 10.1073/pnas.101123198. No abstract available. |
| Label | URL |
|---|---|
| Wisconsin Alzheimer's Disease Research Center | View source |
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103 participants enrolled in the trial and 100 were randomized to treatment (1 no longer met inclusion criteria, 2 declined participation).
Middle-aged adults with parental history of Alzheimer's disease were recruited for this single-site trial (Madison, Wisconsin) from the Wisconsin Registry for Alzheimer's Prevention (WRAP) or the community through newsletters, websites, educational talks, health fairs, local clinics, and newspaper and magazine advertisements.
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| ID | Title | Description |
|---|---|---|
| FG000 | Simvastatin | Simvastatin 40 mg tablet nightly for 1 month then 80 mg tablet nightly for 8 months |
| FG001 | Placebo | Matching placebo tablet nightly for 9 months |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Simvastatin | Simvastatin 40 mg tablet nightly for 1 month then 80 mg tablet nightly for 8 months |
| BG001 | Placebo | Matching placebo tablet nightly for 9 months |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Change in Cerebrospinal Fluid (CSF) Beta-amyloid-42 | 1 participant declined follow up CSF collection in simvastatin arm; CSF could not be accessed at month 9 in 1 participant in placebo arm | Posted | Mean | Standard Deviation | ng/L | baseline and 9 months |
|
|
9 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Simvastatin | Simvastatin 40 mg tablet nightly for 1 month then 80 mg tablet nightly for 8 months |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Elevated creatine kinase (CK) (> 2 times upper limit of normal) | Musculoskeletal and connective tissue disorders | Systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Cynthia M. Carlsson, MD, MS | University of Wisconsin School of Medicine and Public Health | 608-280-7000 | cmc@medicine.wisc.edu |
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| ID | Term |
|---|---|
| D000544 | Alzheimer Disease |
| D000686 | Amyloidosis |
| D007249 | Inflammation |
| ID | Term |
|---|---|
| D003704 | Dementia |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D019821 | Simvastatin |
| ID | Term |
|---|---|
| D008148 | Lovastatin |
| D009281 | Naphthalenes |
| D011084 | Polycyclic Aromatic Hydrocarbons |
| D006841 | Hydrocarbons, Aromatic |
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| OTHER |
| Starr Foundation | OTHER |
| American Federation for Aging Research | OTHER |
| Merck Sharp & Dohme LLC | INDUSTRY |
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| Placebo | Drug | Matching tablet each night for 9 months |
|
| 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 |
| 15734937 | Background | Johnson NA, Jahng GH, Weiner MW, Miller BL, Chui HC, Jagust WJ, Gorno-Tempini ML, Schuff N. Pattern of cerebral hypoperfusion in Alzheimer disease and mild cognitive impairment measured with arterial spin-labeling MR imaging: initial experience. Radiology. 2005 Mar;234(3):851-9. doi: 10.1148/radiol.2343040197. |
| Lost to Follow-up |
|
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Education | Mean | Standard Deviation | years |
|
| Cognitive Function | Measured by Mini Mental State Exam (MMSE), a cognitive battery scored on a 0-30 point range where >24 points indiacte better outcomes; <24 points indicates cognitive dysfunction. | Mean | Standard Deviation | points |
|
| Apolipoprotein E4 carrier | Apolipoprotein E4 (APOE4) carrier status was determined by genotyping whole blood from subjects. | Number | participants |
|
| Total cholesterol | Measured by nuclear magnetic resonance (NMR) spectroscopy | Mean | Standard Deviation | mg/dL |
|
| High-sensitivity c-reactive protein | Mean | Standard Deviation | mg/L |
|
| Cerebrospinal fluid beta-amyloid-42 | Cerebrospinal fluid beta amyloid 42 was measured by XMAP. | Mean | Standard Deviation | ng/L |
|
| Counts |
|---|
| Participants |
|
|
|
| Secondary | Changes in Regional Cerebral Blood Flow on MRI | Mean changes noted in posterior cingulate cortex | Number of participants analyzed represent participants in MRI substudy with readable MRI scans at both baseline and 9 months; 24 and 17 readable MRI scans in simvastatin and placebo arms, respectively. Unusable MRI scans resulted from poor quality images due to technical problems. | Posted | Mean | Standard Deviation | mL/100 g/min | baseline and 9 months |
|
|
|
|
| Secondary | Change in Inflammatory Markers | Change noted in serum high-sensitivity c-reactive protein | 2 participants in the simvastatin arm and 3 participants in the placebo arm had incomplete hs-CRP results | Posted | Mean | Standard Deviation | mg/L | baseline and 9 months |
|
|
|
|
| Secondary | 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. | 1 participant in simvastatin arm with missing data | Posted | Mean | Standard Deviation | adjusted words recalled | Baseline and 9 months |
|
|
|
|
| 0 |
| 51 |
| 4 |
| 51 |
| EG001 | Placebo | Matching placebo tablet nightly for 9 months | 0 | 49 | 1 | 49 |
| Elevated liver transaminases (>2 times upper limit of normal) | Hepatobiliary disorders | Systematic Assessment |
|
| Anxiety/depression | Psychiatric disorders | Systematic Assessment |
|
| Gastrointestinal discomfort | Gastrointestinal disorders | Systematic Assessment |
|
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| D024801 |
| Tauopathies |
| D019636 | Neurodegenerative Diseases |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |
| D057165 | Proteostasis Deficiencies |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D010335 | Pathologic Processes |
| D013568 | Pathological Conditions, Signs and Symptoms |
| D006844 |
| Hydrocarbons, Cyclic |
| D006838 | Hydrocarbons |
| D009930 | Organic Chemicals |
| D011083 | Polycyclic Compounds |