Pharmacoepidemiology and Pharmacogenetics of a Statin Adverse Event

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
Bruce Psaty, University of Washington
ClinicalTrials.gov Identifier:
NCT00241748
First received: October 17, 2005
Last updated: January 4, 2012
Last verified: January 2012
  Purpose

To conduct a case-control study of factors that increased the risk of rhabdomyolysis, an adverse drug reaction in cerivastatin users


Condition
Rhabdomyolysis

Study Type: Observational
Study Design: Observational Model: Case Control
Time Perspective: Retrospective
Official Title: Pharmacoepidemiology and Pharmacogenetics of a Statin Adverse Event

Resource links provided by NLM:


Further study details as provided by University of Washington:

Biospecimen Retention:   Samples With DNA

DNA is extracted from swish and spit samples. DNA is retained.


Enrollment: 187
Study Start Date: September 2005
Study Completion Date: December 2011
Primary Completion Date: December 2011 (Final data collection date for primary outcome measure)
Groups/Cohorts
1
Rhabdomyolysis Case Subjects
2
Heart and Vascular Health Study statin users - control group 1
3
Cardiovascular Health Study statin users - control group 2

Detailed Description:

BACKGROUND:

Cerivastatin (Baycol), an HMG-CoA reductase inhibitor (statin), was approved and marketed in early 1998 for the treatment of dyslipidemias. Soon afterwards, suspected adverse drug reaction (SADR) reports in cerivastatin users often cited rhabdomyolysis, an uncommon condition in which the breakdown of skeletal muscle cells causes pain, weakness and, in-some cases, renal failure or death. By the time that cerivastatin was withdrawn from the market in 2001, the FDA had received 1,899 SADRs for rhabdomyolysis associated with cerivastatin compared to 1,440 for all other statins combined. In an analysis conducted by FDA scientists, the relative reporting rate (RRR) of fatal rhabdomyolysis was 40 times higher among users of cerivastatin than among users of other statins. For the outcome of all fatal and non-fatal rhabdomyolysis, the RRR was 54 times higher. About half of the rhabdomyolysis cases occurred in subjects who had taken both cerivastatin and gemfibrozil. Subsequently, pharmacokinetic studies demonstrated that gemfibrozil inhibits both major metabolic pathways for cerivastatin-not only the Cytochrome P-450 (CYP) 2C8-mediated oxidation, but also the glucuronidation by uridine diphosphate glucuronysyltransferases (UGT). The investigators hypothesize that rhabdomyolysis cases who were taking cerivastatin but not gemfibrozil had one or both of two types of risk factors: (1) medications that are known inhibitors of these enzymes; or (2) functional genetic variants in one or more of the CYP or UGT enzymes.

Coronary heart disease (CHD) is the leading cause of morbidity and mortality in the U.S. and statin agents are commonly employed for the treatment of hyperlipidemia, one of the principal risk factors for CHD. Given the hundreds of thousands to millions of Americans presently on statin therapy, and the potentially serious (though relatively rare) complication of rhabdomyolysis, this is a significant topic to study.

DESIGN NARRATIVE:

The investigators hypothesize that rhabdomyolysis cases who were taking cerivastatin but not gemfibrozil had one or both of two types of risk factors: (1) medications that are known inhibitors of these enzymes; or (2) functional genetic variants in one or more of the CYP or UGT enzymes. This project is a case-control study of factors that increased the risk of rhabdomyolysis in cerivastatin users. Cases will be cerivastatin users who had rhabdomyolysis, and statin users from two on-going epidemiologic studies will serve as two complementary control groups. "For cases, identified with the assistance of attorneys, a review of medical records and telephone interview will verify the diagnosis and provide information on medication use. Subjects will also return a mouthwash buccal sample for DNA extraction. All subjects will be genotyped for known functional variants in CYP2C8, UGT1A1 and UGT1A3. In the hypothesis-testing part of this case-control study, medications known to be inhibitors of these enzymes and functional variants in their genes will be evaluated as risk factors for rhabdomyolysis in cerivastatin users. Additionally, pharmacoepidemiologic analyses of the FDA AERS data will be conducted to identify other potential new drug-drug interactions. Power to detect expected effect sizes is 80% or greater. In the discovery phase of the project, the DNA of rhabdomyolysis cases who did not take gemfibrozil will be sequenced to identify new single nucleotide polymorphisms (SNPs) in CYP2C8, UGT1 Al and UGT1 A3. The functional significance of new pharmacoepidemiologic associations will be evaluated in in vitro pharmacokinetic inhibition studies. Additionally, newly discovered SNPs in CYP2C8 will be expressed in E. coli and evaluated for their functional significance.

  Eligibility

Ages Eligible for Study:   30 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population

Cases: persons suffering cervistatin-associated rhabdomyolysis who sued the manufactorer and settled their case Control 1: statin users participating in the Heart and Vascular Health Study Control 2: statin users participating in the Cardiovascular Health Study

Criteria

Inclusion Criteria:

  • Older than 30 years old

Exclusion Criteria:

  • Recent history of trauma
  Contacts and Locations
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Please refer to this study by its ClinicalTrials.gov identifier: NCT00241748

Locations
United States, Washington
University of Washington
Seattle, Washington, United States, 98101
Sponsors and Collaborators
University of Washington
Investigators
Principal Investigator: Bruce M Psaty, MD, PhD University of Washington
  More Information

No publications provided

Responsible Party: Bruce Psaty, Professor, University of Washington
ClinicalTrials.gov Identifier: NCT00241748     History of Changes
Other Study ID Numbers: 1310, R01HL078888
Study First Received: October 17, 2005
Last Updated: January 4, 2012
Health Authority: United States: Federal Government

Additional relevant MeSH terms:
Rhabdomyolysis
Muscular Diseases
Musculoskeletal Diseases

ClinicalTrials.gov processed this record on October 23, 2014