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

• Sponsor: University of Wisconsin, Madison (Other)
• Overall Status: Completed
• CT.gov ID: NCT00939822
• Collaborator: National Institute on Aging (NIA) (NIH)
• Enrollment: 88
• Location: 1
• Arms: 2
• Actual Duration (Months): 54
• Patients Per Site Per Month: 1.6

Study Details

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
• 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: Mar 1, 2009
• Actual Primary Completion Date: Sep 1, 2013
• Actual Study Completion Date: Sep 1, 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 [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) ) [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 [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 [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

Criteria

• Ages Eligible for Study: 40 Years to 72 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

	Site	City	State	Country	Postal Code
1	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

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Related Info

Publications

None provided.

• Responsible Party: University of Wisconsin, Madison
• ClinicalTrials.gov Identifier: NCT00939822
• Other Study ID Numbers: 2015-0038; R01AG031790-01A1; H-2009-0030; H-2008-0275
• First Posted: Jul 15, 2009
• Last Update Posted: Aug 9, 2019
• Last Verified: Aug 1, 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; Simvastatin

Study Results

Participant Flow

Recruitment Details	Asymptomatic middle-aged adults (ages 40-72 years) with parental history of AD were recruited from the community through local memory clinics, newsletters, educational talks, booths at health fairs, and newspaper and magazine advertisements.
Pre-assignment Detail	Screened individuals were not randomized to drug or placebo if they withdrew consent, were unable to complete baseline procedures or no longer met inclusion criteria.

Arm/Group Title	Simvastatin	Placebo
Arm/Group Description	40 mg. Simvastatin/day Simvastatin: 40 mg Simvastatin/day	Matching Placebo Placebo: Matching Placebo
Period Title: Overall Study
STARTED	44	44
COMPLETED	42	41
NOT COMPLETED	2	3

Baseline Characteristics

Arm/Group Title	Simvastatin	Placebo	Total
Arm/Group Description	40 mg. Simvastatin/day Simvastatin: 40 mg Simvastatin/day	Matching Placebo Placebo: Matching Placebo	Total of all reporting groups
Overall Participants	44	44	88
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	41 93.2%	38 86.4%	79 89.8%
>=65 years	3 6.8%	6 13.6%	9 10.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.95 (6.2)	54.4 (7.8)	55.21 (6.99)
Sex: Female, Male (Count of Participants)
Female	31 70.5%	32 72.7%	63 71.6%
Male	13 29.5%	12 27.3%	25 28.4%
Region of Enrollment (participants) [Number]
United States	44 100%	44 100%	88 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin	Placebo
Arm/Group Description	40 mg. Simvastatin/day Simvastatin: 40 mg Simvastatin/day	Matching Placebo Placebo: Matching Placebo
Measure Participants	39	40
Mean (95% Confidence Interval) [ratio]	1.01	0.98

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin	Placebo
Arm/Group Description	40 mg. Simvastatin/day Simvastatin: 40 mg Simvastatin/day	Matching Placebo Placebo: Matching Placebo
Measure Participants	39	40
Mean (95% Confidence Interval) [ratio]	1.03	0.98

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin	Placebo
Arm/Group Description	40 mg. Simvastatin/day Simvastatin: 40 mg Simvastatin/day	Matching Placebo Placebo: Matching Placebo
Measure Participants	39	40
sAPP-alpha	0.96	1.03
sAPP-beta	0.98	1.00

4. Secondary Outcome

Title	Changes in CSF Total Tau (T-tau) and Phosphorylated Tau (P-tau) as Measured by xMAP
Description	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.
Time Frame	Baseline and 18 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Simvastatin	Placebo
Arm/Group Description	40 mg. Simvastatin/day Simvastatin: 40 mg Simvastatin/day	Matching Placebo Placebo: Matching Placebo
Measure Participants	39	40
Total tau	1.01	1.01
Phosphorylated tau	1.16	1.15

Adverse Events

Arm/Group Title	Simvastatin		Placebo
Arm/Group Description	40 mg. Simvastatin/day Simvastatin: 40 mg Simvastatin/day		Matching Placebo Placebo: Matching Placebo
All Cause Mortality
	Simvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/44 (0%)
Serious Adverse Events
	Simvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/44 (0%)
Other (Not Including Serious) Adverse Events
	Simvastatin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/44 (0%)		0/44 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.