Do HMG CoA Reductase Inhibitors Affect Abeta Levels?

This study has been completed.
Sponsor:
Information provided by:
Seattle Institute for Biomedical and Clinical Research
ClinicalTrials.gov Identifier:
NCT00303277
First received: March 14, 2006
Last updated: April 12, 2010
Last verified: April 2010
  Purpose

Recent evidence suggests that there is a significant overlap between AD and cerebrovascular disease. In fact, AD and cerebrovascular disease may share some of the same risk factors, including hypercholesterolemia. In addition, studies have suggested that the HMG Co-A reductase inhibitor lipid-lowering agents, known as "statins," decrease the risk of AD by up to 70%; however, effects differed by specific statin use. This study will compare two statins, simvastatin (which crosses the blood brain barrier) and pravastatin (which does not), with respect to their ability to alter blood and cerebrospinal fluid (CSF) levels of AD and inflammatory markers. The primary aim of the proposed study is to determine whether there is a reduction in Abeta with statins and whether the ability of the statin to cross the blood-brain barrier will affect its ability to decrease Abeta. If it can be demonstrated that statins alter AD-associated biomarkers, this would have broad implications for the treatment and prevention of AD.


Condition Intervention Phase
Alzheimer's Disease
Aging
Drug: simvastatin
Drug: pravastatin
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Do HMG CoA Reductase Inhibitors Affect Abeta Levels?

Resource links provided by NLM:


Further study details as provided by Seattle Institute for Biomedical and Clinical Research:

Primary Outcome Measures:
  • CSF abeta levels [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • CSF biomarkers [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]

Enrollment: 35
Study Start Date: August 2002
Study Completion Date: April 2005
Primary Completion Date: April 2005 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: 1
simvastatin
Drug: simvastatin
simvastatin 40 mg tablets once per day for 12 weeks
Other Names:
  • simvastatin
  • Zocor
Active Comparator: 2
pravastatin
Drug: pravastatin
pravastatin 80 mg tablets once per day for 12 weeks
Other Names:
  • pravastatin
  • Lipitor

Detailed Description:

Recent evidence suggests that there is a significant overlap between AD and cerebrovascular disease. In fact, AD and cerebrovascular disease may share some of the same risk factors, including hypercholesterolemia. In addition, studies have suggested that the HMG Co-A reductase inhibitor lipid-lowering agents, known as "statins," decrease the risk of AD by up to 70%; however, effects differed by specific statin use. This study will compare two statins, simvastatin (which crosses the blood brain barrier) and pravastatin (which does not), with respect to their ability to alter blood and cerebrospinal fluid (CSF) levels of AD and inflammatory markers. The primary aim of the proposed study is to determine whether there is a reduction in Abeta with statins and whether the lipophilicity of the statin will affect its ability to decrease Abeta. In addition, the proposal will determine statin effects on both peripheral and central inflammation and whether the lipophilicity of the statin will affect its ability to decrease inflammation. If it can be demonstrated that statins alter AD-associated biomarkers, this would have broad implications for the treatment and prevention of AD.

This study will be performed in 60 cognitively normal middle-aged and older persons with hypercholesterolemia (total cholesterol >200 and/or LDL>130), presumably persons that have a lipid-related increased risk of AD and in whom alterations of CSF Abeta can be interpreted.The differential effects of the two statins will be evaluated in a 12-week randomized treatment trial with 30 subjects in each group.

Prior to randomization and following 12 weeks of treatment with simvastatin or pravastatin, subjects will undergo CSF and blood collection. In the CSF, concentrations of Abeta 1-40, Abeta 1-42, soluble APP, tau, 24S-hydroxycholesterol, apoE, total cholesterol, F2-isoprostanes, glucose, protein, and cell count will be measured. In the blood, concentrations of total cholesterol, HDL, LDL, triglyceride, phospholipids, fatty acids, 24S-hydroxycholesterol, apoE, apoB, apoA1, Abeta 1-40, Abeta 1-42, F2-isoprostanes, C-reactive protein, fibrinogen, iron, homocysteine, and albumin will be measured. Plasma simvastatin and pravastatin concentrations will be measured at study completion. APOE genotyping will be performed.

  Eligibility

Ages Eligible for Study:   18 Years to 90 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Total cholesterol > 200, and/or LDL > 130
  • No cognitive impairment
  • Statin-naive for at least one year
  • Women must not be pregnant, nursing, or planning to become pregnant

Exclusion Criteria:

  • Back ailments which would hinder LP procedure
  • Neurological disease, including stroke, Parkinson's disease, Multiple Sclerosis, uncontrolled epilepsy, history of severe head trauma
  • Hepatic disease
  • Renal insufficiency
  • Unstable medical disease
  • Severe pulmonary disease
  • Severe cardiac disease
  • Uncontrolled hypertension (greater than 160/90)
  • Uncontrolled hyper/hypothyroidism
  • History of blood clotting abnormalities or platelet abnormalities
  • History of chronic major psychiatric disorders or presence of current major depressive disorder (by DSM-IV criteria)
  • History of substance abuse within the past year
  • Taking exclusionary medications
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00303277

Locations
United States, Washington
VA Puget Sound Health Care System
Seattle, Washington, United States, 98108
Sponsors and Collaborators
Seattle Institute for Biomedical and Clinical Research
Investigators
Principal Investigator: Elaine R Peskind, MD University of Washington
  More Information

Publications:
Responsible Party: Elaine R. Peskind, MD, Professor, Director of Clinical Research, Mental Health Service, VA Puget Sound Health Care System/University of Washington School of Medicine
ClinicalTrials.gov Identifier: NCT00303277     History of Changes
Other Study ID Numbers: 21974
Study First Received: March 14, 2006
Last Updated: April 12, 2010
Health Authority: United States: Institutional Review Board

Keywords provided by Seattle Institute for Biomedical and Clinical Research:
Alzheimer's disease
beta-amyloid
statins

Additional relevant MeSH terms:
Alzheimer Disease
Dementia
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Tauopathies
Neurodegenerative Diseases
Delirium, Dementia, Amnestic, Cognitive Disorders
Mental Disorders
Simvastatin
Pravastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Lipid Regulating Agents
Therapeutic Uses
Anticholesteremic Agents
Enzyme Inhibitors

ClinicalTrials.gov processed this record on July 29, 2014