Clinical trial NCT00451828: Cholesterol and Pharmacogenetic Study
Official title: Cholesterol and Pharmacogenetic Study
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Hyperlipidemia
Hypercholesterolemia
Coronary Heart Disease
Cardiovascular Disease
Keywords: Statins
Cholesterol
Pharmacogenetics
Lead sponsor: UCSF Benioff Children's Hospital Oakland
Sponsor class: OTHER
Collaborators: name: National Heart, Lung, and Blood Institute (NHLBI)
name: San Francisco General Hospital
name: University of California, Los Angeles
name: Cedars-Sinai Medical Center
name: University of Washington
name: Duke University
First posted: 2007-03-26
Enrollment: 1000
Sex: ALL
Minimum age (years): 30
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: PREVENTION

Brief summary: The overall objective of the CAP study was to determine genetic influences on efficacy of simvastatin treatment with regard to LDL cholesterol reduction and changes in other markers of cardiovascular disease risk.

Detailed description: Despite widespread use of statin therapy for reducing risk of cardiovascular disease risk, there is considerable inter-individual variation in statin efficacy, and it would be desirable to identify markers that would be predictive of the magnitude of beneficial response. The effect of statin most strongly associated with improved clinical outcomes is reduction in LDL cholesterol. The CAP study was a six week non-randomized, open label study of simvastatin 40 mg/day in a group of 335 African-American and 609 Caucasian volunteer subjects. Measurements of plasma lipids and lipoproteins, as well as other markers of cardiovascular disease risk, were obtained at the screening and entry visits, and after four and six weeks of simvastatin treatment. Both baseline measurements and changes in response to simvastatin therapy are being used to test for associations with genetic polymorphisms. Significant findings are being replicated in other study cohorts.

Eligibility criteria: Inclusion Criteria:

* at least 30 years of age
* Total Cholesterol between 160 to 400 mg/dl
* \> 3 grandparents of African-American descent or \> 3 grandparents of Caucasian descent
* serum triglycerides \< 400 mg/dl
* fasting glucose \< 126 mg/dl

Exclusion Criteria:

* Use of lipid-lowering medication
* Use of over-the-counter products containing sterol or stanol esters or fish oil
* Recent or planned change in dietary intake or weight change of more than 4.5 kg
* Use of corticosteroids, immunosuppressive drugs or drugs affecting the CYP3A4 system
* Known liver disease or elevated transaminase levels
* Elevated creatine phosphokinase levels \> 10 times upper limits of normal
* Uncontrolled blood pressure, or diabetes mellitus
* Abnormal renal or thyroid function
* Current alcohol or drug abuse
* Major illness in the preceding three months
* Pregnancy
* Know intolerance to statins
* Racial ancestry other than African-American or Caucasian

Primary outcomes:
measure: Total Cholesterol
timeFrame: -2, 0, 4, 6 weeks
measure: LDL Cholesterol
timeFrame: -2, 0, 4, 6 weeks
measure: HDL Cholesterol
timeFrame: -2, 0, 4, 6 weeks
measure: Triglycerides
timeFrame: -2, 0, 4, 6 weeks
measure: C-reactive protein
timeFrame: -2, 0, 4, 6 weeks
Secondary outcomes:
measure: Total Cholesterol/HDL Cholesterol
timeFrame: -2, 0, 4, 6 weeks
measure: Apolipoprotein B
timeFrame: -2, 0, 4, 6 weeks
measure: Apolipoprotein AI
timeFrame: -2, 0, 4, 6 weeks
measure: Apolipoprotein CIII
timeFrame: -2, 0, 4, 6 weeks
measure: LDL Peak Particle size
timeFrame: -2, 0, 4, 6 weeks
measure: LDL Subfractions
timeFrame: -2, 0, 4, 6 weeks
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: San Francisco General Hospital
state: California
Study officials:
affiliation: UCSF Benioff Children's Hospital Oakland
name: Ronald M Krauss, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Simon JA, Lin F, Hulley SB, Blanche PJ, Waters D, Shiboski S, Rotter JI, Nickerson DA, Yang H, Saad M, Krauss RM. Phenotypic predictors of response to simvastatin therapy among African-Americans and Caucasians: the Cholesterol and Pharmacogenetics (CAP) Study. Am J Cardiol. 2006 Mar 15;97(6):843-50. doi: 10.1016/j.amjcard.2005.09.134. Epub 2006 Jan 27.
citation: Trupp M, Zhu H, Wikoff WR, Baillie RA, Zeng ZB, Karp PD, Fiehn O, Krauss RM, Kaddurah-Daouk R. Metabolomics reveals amino acids contribute to variation in response to simvastatin treatment. PLoS One. 2012;7(7):e38386. doi: 10.1371/journal.pone.0038386. Epub 2012 Jul 9.
citation: Mangravite LM, Medina MW, Cui J, Pressman S, Smith JD, Rieder MJ, Guo X, Nickerson DA, Rotter JI, Krauss RM. Combined influence of LDLR and HMGCR sequence variation on lipid-lowering response to simvastatin. Arterioscler Thromb Vasc Biol. 2010 Jul;30(7):1485-92. doi: 10.1161/ATVBAHA.110.203273. Epub 2010 Apr 22.
citation: Barber MJ, Mangravite LM, Hyde CL, Chasman DI, Smith JD, McCarty CA, Li X, Wilke RA, Rieder MJ, Williams PT, Ridker PM, Chatterjee A, Rotter JI, Nickerson DA, Stephens M, Krauss RM. Genome-wide association of lipid-lowering response to statins in combined study populations. PLoS One. 2010 Mar 22;5(3):e9763. doi: 10.1371/journal.pone.0009763.
citation: Medina MW, Gao F, Ruan W, Rotter JI, Krauss RM. Alternative splicing of 3-hydroxy-3-methylglutaryl coenzyme A reductase is associated with plasma low-density lipoprotein cholesterol response to simvastatin. Circulation. 2008 Jul 22;118(4):355-62. doi: 10.1161/CIRCULATIONAHA.108.773267. Epub 2008 Jun 16.
citation: Krauss RM, Mangravite LM, Smith JD, Medina MW, Wang D, Guo X, Rieder MJ, Simon JA, Hulley SB, Waters D, Saad M, Williams PT, Taylor KD, Yang H, Nickerson DA, Rotter JI. Variation in the 3-hydroxyl-3-methylglutaryl coenzyme a reductase gene is associated with racial differences in low-density lipoprotein cholesterol response to simvastatin treatment. Circulation. 2008 Mar 25;117(12):1537-44. doi: 10.1161/CIRCULATIONAHA.107.708388. Epub 2008 Mar 10.