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

March 14, 2006
April 12, 2010
August 2002
April 2005   (final data collection date for primary outcome measure)
CSF abeta levels [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
CSF abeta levels
Complete list of historical versions of study NCT00303277 on ClinicalTrials.gov Archive Site
CSF biomarkers [ Time Frame: baseline and 12 weeks ] [ Designated as safety issue: No ]
  • CSF biomarkers
  • plasma biomarkers
Not Provided
Not Provided
 
Do HMG CoA Reductase Inhibitors Affect Abeta Levels?
Do HMG CoA Reductase Inhibitors Affect Abeta Levels?

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.

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.

Interventional
Phase 4
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
  • Alzheimer's Disease
  • Aging
  • Drug: simvastatin
    simvastatin 40 mg tablets once per day for 12 weeks
    Other Names:
    • simvastatin
    • Zocor
  • Drug: pravastatin
    pravastatin 80 mg tablets once per day for 12 weeks
    Other Names:
    • pravastatin
    • Lipitor
  • Active Comparator: 1
    simvastatin
    Intervention: Drug: simvastatin
  • Active Comparator: 2
    pravastatin
    Intervention: Drug: pravastatin

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Completed
35
April 2005
April 2005   (final data collection date for primary outcome measure)

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
Both
18 Years to 90 Years
No
Contact information is only displayed when the study is recruiting subjects
United States
 
NCT00303277
21974
Yes
Elaine R. Peskind, MD, Professor, Director of Clinical Research, Mental Health Service, VA Puget Sound Health Care System/University of Washington School of Medicine
Seattle Institute for Biomedical and Clinical Research
Not Provided
Principal Investigator: Elaine R Peskind, MD University of Washington
Seattle Institute for Biomedical and Clinical Research
April 2010

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP