Effects of Simvastatin on Biomarkers (SimBio)

Effects of Simvastatin on CSF AD Biomarkers in Cognitively Normal Subjects

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.

Study Overview

• Status: Completed
• Conditions: Alzheimer's Disease
• Intervention / Treatment: Drug: Simvastatin; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 49
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98108
      • VA Puget Sound Health Care System

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 45 years to 64 years (Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

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?

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Simvastatin; Simvastatin 40mg qHS for 1 year	Drug: Simvastatin; Simvastatin 40mg qHS for 1 year; Other Names: Zocor
Placebo Comparator: Placebo; Placebo 1 tablet qHS for 1 year	Drug: Placebo; Placebo 1 tablet qHS for 1 year; Other Names: Sugar Pill

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Aβ42 in Cerebrospinal Fluid (CSF) at 1 Year	CSF Aβ42 concentration were measured at baseline and after 1-year intervention.	1-year change of CSF Aβ42 from baseline
Change From Baseline in CSF Total Tau at 1 Year	CSF total tau was measured at baseline and after 1-year of intervention	1-yr change
Change From Baseline in CSF ptau181 at 1 Year	ptau 181 measured in CSF at baseline and after 1-year intervention	1-year change from baseline

Collaborators and Investigators

• Sponsor: University of Washington
• Collaborators: VA Puget Sound Health Care System; Seattle Institute for Biomedical and Clinical Research
• Investigators: Principal Investigator: Gail Li, MD, PhD, University of Washington

Study record dates

Study Major Dates

• Study Start: June 1, 2010
• Primary Completion (Actual): October 1, 2015
• Study Completion (Actual): October 1, 2015

Study Registration Dates

• First Submitted: June 9, 2010
• First Submitted That Met QC Criteria: June 9, 2010
• First Posted (Estimate): June 11, 2010

Study Record Updates

• Last Update Posted (Actual): July 28, 2017
• Last Update Submitted That Met QC Criteria: June 30, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: Alzheimer's Disease; Prevention; Biomarkers; Simvastatin; Spinal Fluid
• Additional Relevant MeSH Terms: Mental Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurocognitive Disorders; Neurodegenerative Diseases; Dementia; Tauopathies; Alzheimer Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Simvastatin
• Other Study ID Numbers: 37373; 00183 (Other Identifier: VA Puget Sound Health System MIRB#)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes