DNA Diagnostic System for Statin Safety and Efficacy (SIM)

Lipitor®, Zocor®, and Crestor® are statin drugs commonly taken to lower cholesterol and prevent heart disease. Statins lower cholesterol by different amounts in different patients and sometimes statins cause muscle pain, cramps, or weakness. This study will examine genetic differences in the blood of patients taking statins to predict both how well the statins lower cholesterol, and whether muscle discomfort occurs. Finding such genetic connections is the key to developing genetic tests that might eventually help determine which statin is best for a patient. About 1000 people will be in the study.

Study Overview

• Status: Unknown
• Conditions: Hypercholesterolemia; Myopathy

Detailed Description

Statin efficacy in primary and secondary prevention of cardiovascular disease has led to increasingly aggressive usage and dosage of statins. Their main clinically relevant safety risk is statin-induced myopathy (SIM) evidenced as a constellation of neuromuscular side effects (NMSE) that include myalgias (muscle aches, cramps, weakness) and myositis (monitored by elevation of serum creatine kinase [CK] activity). NMSEs are disabling to 3-20% of patients on statins, require alteration of therapy, and reduce compliance. NMSEs vary in extent between drugs and from patient to patient. We will develop a novel product termed SIM PhyzioType™ system to provide clinicians with individualized information for each patient on the safest statin drug among atorvastatin, simvastatin, and rosuvastatin, the 3 most prescribed statins. The PhyzioType consists of a multi-SNP (single nucleotide polymorphism) ensemble that, interpreted with a biomathematical algorithm, predicts drug response. We have developed a prototype PhyzioType system incorporating predictive models for myalgia, serum CK activity, and LDLc reduction for atorvastatin and simvastatin patients. We will recruit to obtain 250 patients treated with each drug and use existing clinical records to characterize their NMSE and LDLc responses. We will use physiogenomic analysis to identify those SNPs that differentiate the risk of NMSEs among the 3 statins and combine them into the SIM PhyzioType system. This work will also contribute to the pharmacology of SIM and unravel new pharmaceutical targets. We will create and validate the SIM PhyzioType system with clinically useful prediction of NMSEs and potency for each of the 3 statins. In Phase III a prospective trial is planned for FDA approval of the SIM PhyzioType product.

• Study Type: Observational
• Enrollment (Anticipated): 750

Contacts and Locations

• Study Contact: Name: Richard L. Seip, PhD; Phone Number: 860-545-5005; Email: rseip@harthosp.org

Study Locations

• United States
  • California
    • San Francisco, California, United States, 94110
      • Recruiting
      • University of California-San Francisco
      • Contact: Alan H.B. Wu, PhD; Phone Number: (415) 206-3540; Email: wualan@labmed2.ucsf.edu
      • Principal Investigator: Alan H.B. Wu, PhD
  • Connecticut
    • Hartford, Connecticut, United States, 06102
      • Recruiting
      • Hartford Hospital
      • Contact: Richard L. Seip, PhD; Phone Number: 860-545-5005; Email: rseip@harthosp.org
      • Principal Investigator: Paul D. Thompson, M.D.
  • New York
    • New York, New York, United States, 10021
      • Recruiting
      • Rogosin Institute, New York Presbyterian Hospital
      • Contact: Chioma Okoro; Phone Number: 105 212-702-9600; Email: cokoro@mail.rockefeller.edu
      • Contact: Bruce Gordon, M.D.
      • Principal Investigator: Bruce Gordon, M.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients treated for hypercholesterolemia at Hartford Hospital, University of California-San Francisco, or the Rogosin Clinic at New York Presbyterian Hospital

Description

Inclusion Criteria:

• receiving, or documented to have received in the past, any of the statins including atorvastatin, simvastatin, rosuvastatin treatment for hypercholesterolemia
• chart-documented clinical record of having had, never having had, or possibly having had, statin-associated myopathy

Exclusion Criteria:

• never having taken any statin medication

Study Plan

How is the study designed?

Number of groups / cohorts

3

Cohorts and Interventions

Group / Cohort
1; receiving atorvastatin
2; receiving simvastatin
3; receiving rosuvastatin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
myopathy	in response to statin therapy
serum creatine kinase activity	in response to statin therapy

Secondary Outcome Measures

Outcome Measure	Time Frame
LDL cholesterol	in response to statin therapy

Collaborators and Investigators

• Sponsor: Genomas, Inc
• Collaborators: University of California, San Francisco; Hartford Hospital; Cornell University

Publications and helpful links

General Publications

• Ruano G, Thompson PD, Windemuth A, Seip RL, Dande A, Sorokin A, Kocherla M, Smith A, Holford TR, Wu AH. Physiogenomic association of statin-related myalgia to serotonin receptors. Muscle Nerve. 2007 Sep;36(3):329-35. doi: 10.1002/mus.20871.
• Ruano G, Thompson PD, Windemuth A, Smith A, Kocherla M, Holford TR, Seip R, Wu AH. Physiogenomic analysis links serum creatine kinase activities during statin therapy to vascular smooth muscle homeostasis. Pharmacogenomics. 2005 Dec;6(8):865-72. doi: 10.2217/14622416.6.8.865.
• Ruano G, Seip R, Windemuth A, Wu AH, Thompson PD. Laboratory Medicine in the Clinical Decision Support for Treatment of Hypercholesterolemia: Pharmacogenetics of Statins. Clin Lab Med. 2016 Sep;36(3):473-91. doi: 10.1016/j.cll.2016.05.010. Epub 2016 Jun 24.
• Ruano G, Windemuth A, Wu AH, Kane JP, Malloy MJ, Pullinger CR, Kocherla M, Bogaard K, Gordon BR, Holford TR, Gupta A, Seip RL, Thompson PD. Mechanisms of statin-induced myalgia assessed by physiogenomic associations. Atherosclerosis. 2011 Oct;218(2):451-6. doi: 10.1016/j.atherosclerosis.2011.07.007. Epub 2011 Jul 20.

Helpful Links

• Hartford Hospital & the Henry Low Heart Center
• Rogosin Institute, affiliated with NY Presbyterian Hospital and Weill Cornell School of Medicine

Study record dates

Study Major Dates

• Study Start: January 1, 2007
• Primary Completion (Anticipated): December 1, 2009
• Study Completion (Anticipated): December 1, 2009

Study Registration Dates

• First Submitted: October 2, 2008
• First Submitted That Met QC Criteria: October 3, 2008
• First Posted (Estimate): October 6, 2008

Study Record Updates

• Last Update Posted (Estimate): October 6, 2008
• Last Update Submitted That Met QC Criteria: October 3, 2008
• Last Verified: October 1, 2008

More Information

Terms related to this study

• Keywords: single nucleotide polymorphisms, SNP, LDL cholesterol, statin myopathy, atorvastatin, simvastatin, rosuvastatin
• Additional Relevant MeSH Terms: Metabolic Diseases; Nervous System Diseases; Musculoskeletal Diseases; Neuromuscular Diseases; Lipid Metabolism Disorders; Hyperlipidemias; Dyslipidemias; Hypercholesterolemia; Muscular Diseases
• Other Study ID Numbers: 1 R44 HL091697-01