Statin Effects on Beta-Amyloid and Cerebral Perfusion in Adults at Risk for Alzheimer's Disease (SHARP)

• ClinicalTrials.gov Identifier: NCT00939822
• Recruitment Status: Completed
• First Posted: July 15, 2009
• Results First Posted: August 9, 2019
• Last Update Posted: August 9, 2019
• Sponsor: University of Wisconsin, Madison
• Collaborator: National Institute on Aging (NIA)
• Information provided by (Responsible Party): University of Wisconsin, Madison

Study Description

Brief Summary:

The purpose of the research is to see how simvastatin affects a substance in the body called beta-amyloid. Beta-amyloid is found in the brain and in the liquid around the brain and spinal cord. High amounts of beta-amyloid may be associated with a greater risk of getting Alzheimer's disease. This study will see if simvastatin can lower the amount of beta-amyloid in the spinal fluid. This study will also see if simvastatin affects memory and thinking, blood flow in the brain, and blood vessel function. The investigators hope that future studies show whether simvastatin might prevent memory loss and decrease the chance of developing Alzheimer's disease.

Condition or disease	Intervention/treatment	Phase
Alzheimer's Disease	Drug: Simvastatin; Drug: Placebo	Phase 2

Detailed Description:

Studies show that some medicines that lower cholesterol may reduce the risk of developing Alzheimer's disease, but this has not yet been proven in humans. We are looking for individuals to participate in this study to see if a cholesterol-lowering medication, called simvastatin affects blood flow to the brain, blood vessel function and a substance in the spinal fluid related to the changes in Alzheimer's disease.

The SHARP study included 88 adults ages 40-72 with parental history of documented Alzheimer's disease. The study had 9 visits over the course of 18 months. Participants had fasting blood tests collected, completed a medical history questionnaire and medication side effect review, underwent lumbar puncture procedure, completed memory testing, and had ultrasound and MRI procedures. Participants were randomly assigned to receive either simvastatin or a placebo each night for 18 months.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 88 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Statin Effects on Beta-Amyloid and Cerebral Perfusion in Adults at Risk for AD: "Statins in Healthy, At-Risk Adults: Impact on Amyloid and Regional Perfusion (SHARP)" Study
• Actual Study Start Date: March 2009
• Actual Primary Completion Date: September 2013
• Actual Study Completion Date: September 2013

Arms and Interventions

Arm	Intervention/treatment
Experimental: Simvastatin; 40 mg. Simvastatin/day	Drug: Simvastatin; 40 mg Simvastatin/day
Placebo Comparator: Placebo; Matching Placebo	Drug: Placebo; Matching Placebo

Outcome Measures

Primary Outcome Measures :

1. Changes in Cerebrospinal Fluid (CSF) Beta-amyloid-42 Levels Compared to Baseline as Measured by xMAP [ Time Frame: Baseline and 18 months ]

   Change in CSF beta-amyloid-42 was defined as the ratio of 18-month levels to baseline levels.

   Beta-amyloid-42 is a substance found in the plaques in the brain of people with Alzheimer's disease and can be detected in CSF. There is no defined normal range yet for middle-aged adults.

Secondary Outcome Measures :

1. Changes in CSF Beta-amyloid-40 Levels as Measured by xMAP (Multi-Analyte Profiling) ) [ Time Frame: Baseline and 18 months ]

   Change in CSF beta-amyloid-40 was defined as the ratio of 18-month levels to baseline levels.

   Beta amyloid-40 is a substance found in the brain vessels of individuals with Alzheimer's disease and has more potent cerebrovascular effects on individuals with Alzheimer's disease than any other form of beta amyloid.

2. Changes in CSF Soluble Alpha Precursor Proteins (sAPP-alpha) and Soluble Beta Precursor Proteins (sAPP-beta) as Measured by Duplex [ Time Frame: Baseline and 18 months ]

   Changes in CSF sAPP-alpha and sAPP-beta were defined as the ratio of 18-month levels to baseline levels.

   sAPP-alpha and sAPP-beta are components of beta-amyloid that provide information on beta-amyloid breakdown.

3. Changes in CSF Total Tau (T-tau) and Phosphorylated Tau (P-tau) as Measured by xMAP [ Time Frame: Baseline and 18 months ]

   Changes in CSF t-tau and p-tau were defined as the ratio of 18-month levels to baseline levels.

   T-tau and p-tau are substances found in the brain that can provide information on nerve cell health in the brain and tangle formation in nerve cells.

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 72 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• Parent diagnosed with Alzheimer's disease
• Age 40-72

Exclusion Criteria:

• Active liver disease
• History of adverse reaction to statins
• Contraindication to lumbar puncture
• Elevated creatine kinase and creatinine lab values
• Use of medications known to interact with statins
• History of dementia or mild cognitive impairment
• Currently pregnant or planning to become pregnant
• Use of large quantities of grapefruit juice (more than 1 quart per day)
• Contraindications to MRI (for MRI sub-study)
• Currently on cholesterol-lowering medication or use in past 4 months
• History of heart attack, heart problems, stroke and/or diabetes
• Drinking more than a quart of grapefruit juice per day
• Metal implants, or metal debris in body (MRI)
• List of medications that interact with simvastatin

Contacts and Locations

Locations

United States, Wisconsin

Karen Lazar

Fitchburg, Wisconsin, United States, 53711

Sponsors and Collaborators

University of Wisconsin, Madison

National Institute on Aging (NIA)

Investigators

• Principal Investigator: Cynthia M. Carlsson, MD, MS; UW Madison School of Medicine and Public Health

More Information

Additional Information:

Related Info 

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Vogt NM, Hunt JFV, Ma Y, Van Hulle CA, Adluru N, Chappell RJ, Lazar KK, Jacobson LE, Austin BP, Asthana S, Johnson SC, Bendlin BB, Carlsson CM. Effects of simvastatin on white matter integrity in healthy middle-aged adults. Ann Clin Transl Neurol. 2021 Aug;8(8):1656-1667. doi: 10.1002/acn3.51421. Epub 2021 Jul 18.

Gepner AD, Lazar K, Hulle CV, Korcarz CE, Asthana S, Carlsson CM. Effects of Simvastatin on Augmentation Index Are Transient: Outcomes From a Randomized Controlled Trial. J Am Heart Assoc. 2019 Oct 15;8(20):e009792. doi: 10.1161/JAHA.118.009792. Epub 2019 Oct 12.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT00939822
• Other Study ID Numbers: 2015-0038; R01AG031790-01A1 ( U.S. NIH Grant/Contract ); H-2009-0030 ( Other Identifier: Old IRB Number ); H-2008-0275 ( Other Identifier: Old IRB Number )
• First Posted: July 15, 2009
• Results First Posted: August 9, 2019
• Last Update Posted: August 9, 2019
• Last Verified: August 2019

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Alzheimer Disease; Dementia; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Tauopathies; Neurodegenerative Diseases; Neurocognitive Disorders; Mental Disorders; Simvastatin; Anticholesteremic Agents; Hypolipidemic Agents; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Enzyme Inhibitors