Effect of Atorvastatin (Lipitor) on Gene Expression in People With Vascular Disease
| Status: | Completed |
|---|---|
| Conditions: | Peripheral Vascular Disease, Cardiology |
| Therapuetic Areas: | Cardiology / Vascular Diseases |
| Healthy: | No |
| Age Range: | 21 - Any |
| Updated: | 4/21/2016 |
| Start Date: | February 2006 |
| End Date: | December 2008 |
Dose-Response Study of Modulation of Gene Expression in Peripheral Blood Mononuclear Cells by Atorvastatin
This study will determine if the drug Atorvastatin (Lipitor) changes the genetic material
found in blood cells of people with vascular (blood vessel) disease. Vascular diseases
affect the blood flow in the body and can lead to a heart attack or stroke. Information
gained from this study could be used to develop a more reliable blood test that predicts the
risk of heart attack or stroke.
People 21 and older who have two or more risk factors for developing vascular disease are
eligible for this study. Candidates are screened with a medical history, physical
examination, electrocardiogram, ultrasound of the carotid (neck) arteries, blood tests, and
check of blood pressure and heart rate.
Participants are randomly assigned to one of four treatment groups. Three groups receive
Lipitor in a dose of either 10, 20 or 40 milligrams; the fourth group receives a placebo.
All take the study drug for 3 months. In addition, they undergo the following tests and
procedures:
Study Phase I (Months 2-4)
Participants in all groups are seen once a month at the NIH Clinical Center for blood tests
and monitoring of drug side effects.
Study Phase 2 (Months 5-10)
- Placebo group: Participants are given 40 mg of Lipitor for 3 months (months 5-7) and
seen by a physician once a month during that time. Blood is drawn at the 7-month visit
and then participants are referred back to their physicians. During months 8, 9 and 10,
participants are called once a month to check on their health. Participation ends after
the tenth month.
- Lipitor group: Participants are referred back to their physicians for months 5 and 6
and are called once a month. During month 7, they return to the clinic for a follow-up
evaluation and blood test. Participation ends after the seventh month.
found in blood cells of people with vascular (blood vessel) disease. Vascular diseases
affect the blood flow in the body and can lead to a heart attack or stroke. Information
gained from this study could be used to develop a more reliable blood test that predicts the
risk of heart attack or stroke.
People 21 and older who have two or more risk factors for developing vascular disease are
eligible for this study. Candidates are screened with a medical history, physical
examination, electrocardiogram, ultrasound of the carotid (neck) arteries, blood tests, and
check of blood pressure and heart rate.
Participants are randomly assigned to one of four treatment groups. Three groups receive
Lipitor in a dose of either 10, 20 or 40 milligrams; the fourth group receives a placebo.
All take the study drug for 3 months. In addition, they undergo the following tests and
procedures:
Study Phase I (Months 2-4)
Participants in all groups are seen once a month at the NIH Clinical Center for blood tests
and monitoring of drug side effects.
Study Phase 2 (Months 5-10)
- Placebo group: Participants are given 40 mg of Lipitor for 3 months (months 5-7) and
seen by a physician once a month during that time. Blood is drawn at the 7-month visit
and then participants are referred back to their physicians. During months 8, 9 and 10,
participants are called once a month to check on their health. Participation ends after
the tenth month.
- Lipitor group: Participants are referred back to their physicians for months 5 and 6
and are called once a month. During month 7, they return to the clinic for a follow-up
evaluation and blood test. Participation ends after the seventh month.
Background: Atherosclerosis and its consequences - coronary heart disease and stroke - are
principal causes of mortality in developed countries. Being able to accurately predict an
individual's risk of vascular disease is needed for preventive strategies and measuring the
effectiveness thereof. Current risk assessment tools are imperfect at best. It is possible
that information from gene expression profiling of peripheral white blood cells may add
predictive information about vascular risk. We previously identified a panel of 78 genes in
the peripheral blood that correlated with an individual's future risk of stroke. We
hypothesize that gene expression in white blood cells will be modified by an intervention
that has been shown to reduce vascular risk via anti-inflammatory mechanisms: the
3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor class of lipid lowering
drugs, known as "statins". The vascular protective effects of statins appear to be due in
part to immune modulation and to be dose-dependent. Statin administration has been shown to
modulate gene expression in peripheral blood mononuclear cells in vitro.
Objectives: Overall: To determine if atorvastatin modulates gene expression in peripheral
blood mononuclear cells in a dose dependent manner in a cohort of subjects at risk of
vascular disease. Specific: To determine if: (1) Inflammatory genes are specifically and
temporarily modified by atrovastatin in a dose dependent manner; (2) A previously defined
panel of 78 genes is included among the genes modified by atorvastatin; and (3) Gene
expression changes correlate the degree of gene expression modulation by atorvastatin with
the degree of lipid lowering and other inflammatory parameters such as high sensitivity
C-reactive protein.
Study Design: Dose-response randomized, blinded study of atorvastatin treatment of 120
volunteer subjects with at least two conventional vascular risk factors who are not
currently taking a statin. In the first and primary phase of the study, subjects will be
administered atorvastatin in a blinded fashion in one of four doses (0mg, 10mg, 20mg or
40mg) for a period of three months. Block randomization will stratify on age and risk factor
status. In the second and validation phase of the study, the subjects randomized to 0mg of
atorvastatin in phase 1 will receive 40mg of atorvastatin for a further 3 month period. The
remaining subjects will not be randomized to study drug in phase II of the study. Lipid
profiles, liver function tests and muscle enzymes will be measured prior to enrollment, and
during the treatment phases of the study. Gene expression profiles in the peripheral blood
will be measured using Affymetrix microarrays pre treatment and at the end of phases I and
II.
Outcome measures: (1) Gene changes induced by statin treatment by dosage and over time; (2)
Accuracy of vascular gene panel for defining gene expression changes induced by statin
treatment; and (3) Correlations of gene expression changes with conventional vascular risk
factors, changes in lipid and inflammatory markers and determination of best vascular risk
prediction paradigm.
principal causes of mortality in developed countries. Being able to accurately predict an
individual's risk of vascular disease is needed for preventive strategies and measuring the
effectiveness thereof. Current risk assessment tools are imperfect at best. It is possible
that information from gene expression profiling of peripheral white blood cells may add
predictive information about vascular risk. We previously identified a panel of 78 genes in
the peripheral blood that correlated with an individual's future risk of stroke. We
hypothesize that gene expression in white blood cells will be modified by an intervention
that has been shown to reduce vascular risk via anti-inflammatory mechanisms: the
3-hydroxy-3-methylglutaryl coenzyme A (HMGCoA) reductase inhibitor class of lipid lowering
drugs, known as "statins". The vascular protective effects of statins appear to be due in
part to immune modulation and to be dose-dependent. Statin administration has been shown to
modulate gene expression in peripheral blood mononuclear cells in vitro.
Objectives: Overall: To determine if atorvastatin modulates gene expression in peripheral
blood mononuclear cells in a dose dependent manner in a cohort of subjects at risk of
vascular disease. Specific: To determine if: (1) Inflammatory genes are specifically and
temporarily modified by atrovastatin in a dose dependent manner; (2) A previously defined
panel of 78 genes is included among the genes modified by atorvastatin; and (3) Gene
expression changes correlate the degree of gene expression modulation by atorvastatin with
the degree of lipid lowering and other inflammatory parameters such as high sensitivity
C-reactive protein.
Study Design: Dose-response randomized, blinded study of atorvastatin treatment of 120
volunteer subjects with at least two conventional vascular risk factors who are not
currently taking a statin. In the first and primary phase of the study, subjects will be
administered atorvastatin in a blinded fashion in one of four doses (0mg, 10mg, 20mg or
40mg) for a period of three months. Block randomization will stratify on age and risk factor
status. In the second and validation phase of the study, the subjects randomized to 0mg of
atorvastatin in phase 1 will receive 40mg of atorvastatin for a further 3 month period. The
remaining subjects will not be randomized to study drug in phase II of the study. Lipid
profiles, liver function tests and muscle enzymes will be measured prior to enrollment, and
during the treatment phases of the study. Gene expression profiles in the peripheral blood
will be measured using Affymetrix microarrays pre treatment and at the end of phases I and
II.
Outcome measures: (1) Gene changes induced by statin treatment by dosage and over time; (2)
Accuracy of vascular gene panel for defining gene expression changes induced by statin
treatment; and (3) Correlations of gene expression changes with conventional vascular risk
factors, changes in lipid and inflammatory markers and determination of best vascular risk
prediction paradigm.
- INCLUSION CRITERIA:
- Age 21 or older
- Not taking a statin or other lipid-lowering drug and no history of statin use
- Two or more risk factors as listed below:
- Age (men greater than or equal to 45 years, women greater than or equal to 55 years)
- Hypertension (BP greater than or equal to 140/90 or on antihypertensive medication)
- Cigarette smoking
- Coronary heart disease equivalents (includes diabetes mellitus, abdominal aortic
aneurysm, peripheral vascular disease, carotid artery disease)
- Prior stroke or transient ischemic attack
- Family history of premature coronary heart disease (CHD): CHD in male first degree
relative less than 55 years or CHD in female first degree relative less than 65 years
- Total cholesterol greater than or equal to 240mg/dL and/or LDL cholesterol greater
than or equal to 160 mg/dL
- Low HDL cholesterol (less than 40 mg/dL)
Note: A high HDL cholesterol (greater than 60 mg/dL) counts as a negative risk factor: its
presence removes one risk factor from the total counts.
EXCLUSION CRITERIA
- Current or past history of statin use
- Assessed need for immediate statin treatment by subject's primary care physician
- Current use of an investigational drug as part of another research protocol
- Chronic or active liver disease
- Chronic or active muscle disease
- Alcohol abuse
- Prior myocardial infarct
- Heart failure
- Uncontrolled arrhythmias
- Any clinically important hematological or biochemical abnormality on routine
screening
- Recent history of cancer
- Pregnant women or breast-feeding women
- Concomitant use of the following medications, including drugs that strongly inhibit
CYP3A54: nicotinic acid, gemfibrozil, clofibrate, fenofibrate, verapamil, mibefradil,
cyclcosporin, nefazodone, fluoxetine, paroxetine, ketoconazole, itraconazole,
cimetadine, clarithromycin, erythromycin, protease inhibitors, NSAIDs, celebrex
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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