Alzheimer's Disease
Conditions
Keywords
Alzheimer's Disease, Prevention, Spinal Fluid, Biomarkers, Simvastatin
Brief summary
A year-long randomized, double-blind, placebo-controlled trial of simvastatin to see if it produces beneficial changes in cerebral spinal fluid proteins associated with Alzheimer's disease.
Detailed description
The purpose of this study is to see if a drug called simvastatin (brand name Zocor) beneficially affects the level of certain molecules (such as proteins) in the spinal fluid of people. The molecules the investigators are measuring are thought to be important in the development of Alzheimer's disease (AD), and the investigators are testing whether simvastatin can change proteins to a level that is associated with a reduced risk for AD. Simvastatin has been approved by the United States Food and Drug Administration (FDA) for the treatment of high cholesterol and to reduce the risk of coronary artery disease. It is an investigational drug in this study. Participants will be randomly assigned to Placebo or Simvastatin. The investigators and the participant will be blinded. Randomization will be stratified by age and gender. This study is being funded by the National Institute on Aging. The investigators will take part in this study at the VA Puget Sound Health Care System. This study will last up to 1 year. Participants will be asked to come to the VA in Seattle a total of 9 times, 2 of those times will be for lumbar punctures (also known as a spinal tap). The investigators would also like to ask a person who knows the participant well (such as a spouse, child, sibling, or good friend) some questions about the participant's health, memory, mood and behavior, and abilities to do daily tasks at the beginning and the end of the study. Participants must be cognitively normal, healthy, willing to have a lumbar puncture, and not need or take any medications to control cholesterol.
Interventions
DRUGSimvastatin
Simvastatin 40mg qHS for 1 year
DRUGPlacebo
Placebo 1 tablet qHS for 1 year
Sponsors
Seattle Institute for Biomedical and Clinical Research
VA Puget Sound Health Care System
University of Washington
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
45 Years to 64 Years
Healthy volunteers
Yes
Inclusion criteria
(participants must meet the following criteria) * If female of childbearing potential, must have negative pregnancy test at baseline, and all subsequent visits. * Age 45 to 64 years inclusive. * Considered cognitively normal with no evidence of memory or other cognitive impairments (MMSE \>26, Logical Memory delayed recall \> 6, CDR score of 0). * Normal or only mildly elevated cholesterol which does not require drug therapy based on National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP-III) guidelines. * An LDL level above 70mg/dL. * Hamilton Depression Scale (HAM-D) score \< 12. * BMI between 18 - 34 (or exception made by MD). * In good recent general health (i.e., no trauma or infection in the 4 weeks before LP). * On stable dose of non-exclusionary medications for the 4 weeks preceding the LP. * Platelet count \>100,000.
Exclusion criteria
(participants must NOT satisfy any of the following conditions) * Any contraindications to LP, such as spinal deformity, severe disease or infection in the LP region, bleeding tendency, anticoagulant or blood-thinning medications. * Taken a statin medication in the past 12 months. * Any clinically significant laboratory abnormalities. * Any neurological disorders: multiple sclerosis, epilepsy, stroke, Parkinson's, other degenerative CNS disorders, or neuropathy with radicular involvement. * Acute or chronic major psychiatric disorders: schizophrenia, affective disorders, or severe anxiety disorders. (Dysthymia allowed, history of MDD allowed if currently in remission) * Unstable or poorly controlled medical problems such as: heart failure, diabetes (poorly controlled or insulin dependent), hypertension (BP \>160/100), pulmonary disease with hypoxia or hypercapnia, significant liver disease or known hepatitis C seropositivity, renal failure, treatment for cancer in the past 2 years (other than non-melanoma skin cancer) or known HIV positive status. * Use of illegal drugs or alcohol abuse (\>2 drinks/day or 10/week) within the past year. * Concurrent participation in another investigational drug study. * Use of any exclusionary medications in the 4 weeks prior to screening: * Drugs which could interact with statins: itraconazole, ketoconazole, erythromycin, clarithromycin, HIV protease inhibitors, nefazodone, amiodarone, cyclosporine, isoniazid, quinidine, or large quantities of grapefruit juice (\>1 quart daily) * Central nervous system acting medications: antipsychotics, anti-Parkinson's disease medications, anti convulsants, or CNS stimulants * Chronic use of benzodiazepines, sedating antihistamines, or other sedative-hypnotic agents (prn use is allowed as long as it is not within 72 hours of LP or cognitive testing) * Medications affecting coagulation and/or inflammation: coumadin, potent anti-inflammatory medications (hydrocortisone, methotrexate or other potent immune-modulating medications), and anti-HIV medications (Aspirin up to 325 mg/day is allowed.) * Lipid-lowering drugs: fibrates or niacin \>500mg/day (stable dose of omega-3 is allowed) * Does the subject's family history meet any of the following criteria? * Both parents had/have dementia * On one side of the family, over two consecutive generations three relatives had/have dementia? * One parent had an onset of dementia before age 60? * Does the subject have a major active autoimmune or immunological disorder?
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Aβ42 in Cerebrospinal Fluid (CSF) at 1 Year | 1-year change of CSF Aβ42 from baseline | CSF Aβ42 concentration were measured at baseline and after 1-year intervention. |
| Change From Baseline in CSF Total Tau at 1 Year | 1-yr change | CSF total tau was measured at baseline and after 1-year of intervention |
| Change From Baseline in CSF ptau181 at 1 Year | 1-year change from baseline | ptau 181 measured in CSF at baseline and after 1-year intervention |
Countries
United States
Participant flow
Recruitment details
Statin-naïve middle-aged adults were recruited for this single-site trial (Seattle, WA) from the University of Washington Alzheimer's Disease Research Center Registry or the community through newsletters, websites, educational talks, health fairs, local clinics, and newspaper and magazine advertisements.
Pre-assignment details
917 people were pre-screened by phone for eligibility, 400 did not respond or declined, 457 did not meet inclusion/exclusion criteria. 60 completed a full screen visit. Of these 60 potential participants, 2 were lost to follow-up after screen, 2 withdrew, 7 screen failed and 49 were enrolled and randomized.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo 1 tablet qHS for 1 year | 23 |
| Simvastatin Simvastatin 40mg qHS for 1 year | 26 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
Baseline characteristics
| Characteristic | Simvastatin | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 55.7 years STANDARD_DEVIATION 4.5 | 55.9 years STANDARD_DEVIATION 4.7 | 56.1 years STANDARD_DEVIATION 4.9 |
| CSF Aβ42 level | 520 pg/ml STANDARD_DEVIATION 114 | 517 pg/ml STANDARD_DEVIATION 113 | 515 pg/ml STANDARD_DEVIATION 113 |
| CSF ptau level | 27 pg/ml STANDARD_DEVIATION 10 | 29 pg/ml STANDARD_DEVIATION 12 | 31 pg/ml STANDARD_DEVIATION 15 |
| CSF total tau level | 38 pg/ml STANDARD_DEVIATION 16 | 41 pg/ml STANDARD_DEVIATION 16 | 43 pg/ml STANDARD_DEVIATION 17 |
| Region of Enrollment United States | 26 participants | 49 participants | 23 participants |
| Sex: Female, Male Female | 19 Participants | 37 Participants | 18 Participants |
| Sex: Female, Male Male | 7 Participants | 12 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 23 |
| other Total, other adverse events | 26 / 26 | 22 / 23 |
| serious Total, serious adverse events | 0 / 26 | 0 / 23 |
Outcome results
Primary
Change From Baseline in Aβ42 in Cerebrospinal Fluid (CSF) at 1 Year
CSF Aβ42 concentration were measured at baseline and after 1-year intervention.
Time frame: 1-year change of CSF Aβ42 from baseline
Population: In the Placebo group, 1 participant was dropped due to AE and 1 was lost to follow-up.~In the Simvastatin group, 1 participant was dropped due to AE. These 3 participants were not included in the primary analysis per analysis plan.~All these 3 subjects were not included in the primary analysis based on our per protocol analysis plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in Aβ42 in Cerebrospinal Fluid (CSF) at 1 Year | 5.3 1-yr change, pg/ml | Standard Deviation 31 |
| Simvastatin | Change From Baseline in Aβ42 in Cerebrospinal Fluid (CSF) at 1 Year | 0.5 1-yr change, pg/ml | Standard Deviation 42 |
p-value: 0.53ANCOVA
Primary
Change From Baseline in CSF ptau181 at 1 Year
ptau 181 measured in CSF at baseline and after 1-year intervention
Time frame: 1-year change from baseline
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in CSF ptau181 at 1 Year | -2.9 1-yr change (final - baseline), pg/ml | Standard Deviation 12.9 |
| Simvastatin | Change From Baseline in CSF ptau181 at 1 Year | 1.7 1-yr change (final - baseline), pg/ml | Standard Deviation 6.3 |
p-value: 0.25ANCOVA
Primary
Change From Baseline in CSF Total Tau at 1 Year
CSF total tau was measured at baseline and after 1-year of intervention
Time frame: 1-yr change
Population: In the Placebo group, 1 participant was dropped due to AE and 1 was lost to follow-up.~In the Simvastatin group, 1 participant was dropped due to AE. These 3 participants were not included in the primary analysis per analysis plan.~All these 3 subjects were not included in the primary analysis based on our per protocol analysis plan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Change From Baseline in CSF Total Tau at 1 Year | -0.1 pg/ml | Standard Deviation 3.9 |
| Simvastatin | Change From Baseline in CSF Total Tau at 1 Year | 1.6 pg/ml | Standard Deviation 4.7 |
p-value: 0.36ANCOVA