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Muscle Characteristics Associated With Statin Therapy

This study has been withdrawn prior to enrollment.
(Unable to recruit subjects.)
Sponsor:
ClinicalTrials.gov Identifier:
NCT00990834
First Posted: October 7, 2009
Last Update Posted: May 22, 2015
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Information provided by:
Scripps Health
  Purpose
The purpose of this study is to investigate the mechanism of statin-related myopathy by evaluating muscle samples before and after statin exposure.

Condition Intervention
Hydroxymethylglutaryl-CoA Reductase Inhibitors Myopathy Drug: simvastatin

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Muscle Characteristics Associated With Statin Therapy

Resource links provided by NLM:


Further study details as provided by Scripps Health:

Primary Outcome Measures:
  • Atrogin-1 expression. [ Time Frame: One to eight months. ]
  • Intramuscular Ras level. [ Time Frame: One to eight months. ]

Secondary Outcome Measures:
  • Intramuscular Coenzyme Q10 level. [ Time Frame: One to eight months. ]
  • Intramuscular mitochondrial to nuclear DNA ratio. [ Time Frame: One to eight months. ]
  • Intramuscular geranylgeranylpyrophosphate. [ Time Frame: One to eight months. ]
  • PPAR-gamma coactivator-1-alpha expression. [ Time Frame: One to eight months. ]

Enrollment: 0
Study Start Date: November 2009
Estimated Study Completion Date: June 2011
Estimated Primary Completion Date: June 2011 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Statin exposure
Subjects' endpoints will be measured before and after one to eight months of statin exposure.
Drug: simvastatin
simvastatin 80 mg PO daily for one to eight months.
Other Name: Zocor

Detailed Description:
Statins have been proven to reduce cardiovascular events and mortality in large clinical trials but remain underutilized partly due to the associated myopathy. Severe reactions manifested as rhabdomyolysis are rare but myalgia is commonly noted in clinical practice. The pathophysiology of these events remains obscure. Previous studies suggest that statins block the downstream products (such as cellular signaling molecules) of the mevalonate pathway needed for normal muscle function. Other studies show that statins are associated with gene expressions involved in muscle damage such as atrogin-1. We will quantify these entities pre and post statin therapy to better understand these reactions.
  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   21 Years to 90 Years   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Primary surgeon's permission.
  • Patient is > 21 years of age.
  • Patient will go through a two phase surgery with the two procedures one to eight months apart.
  • Patient or representative understands the nature of the study.
  • Normal thyroid stimulating hormone (TSH).
  • LDL-cholesterol > 100 mg/dL or highly sensitive C-reactive protein (hsCRP) > 2.0.
  • One of the following risk factors: male > 45 year old or female > 55 year old, smoker, hypertension, first degree family history of coronary artery disease < 55 year old, HDL <40 mg/dL, chronic kidney disease, diabetes mellitus, previous TIA or stroke, previous coronary artery disease.

Exclusion Criteria:

  • Has been on a lipid-lowering medication previously.
  • Severe illness (e.g. trauma or sepsis) more than 24 hours before obtaining the first biopsy.
  • Less than a 10% reduction of LDL after 3 months of therapy (indicative of non-adherence).
  • Contraindications to statins such as liver failure.
  • History of underlying muscle disorder.
  • Taking amiodarone.
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT00990834


Locations
United States, California
Scripps-Mercy Hospital
San Diego, California, United States, 92103
Sponsors and Collaborators
Scripps Health
Investigators
Principal Investigator: Tam H Truong, MD Scripps Health
Principal Investigator: Paul S Phillips, MD Scripps Health
  More Information

Publications:
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med. 1995 Nov 16;333(20):1301-7.
Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998 Nov 5;339(19):1349-57.
Kashani A, Phillips CO, Foody JM, Wang Y, Mangalmurti S, Ko DT, Krumholz HM. Risks associated with statin therapy: a systematic overview of randomized clinical trials. Circulation. 2006 Dec 19;114(25):2788-97. Epub 2006 Dec 11. Review.
Bruckert E, Hayem G, Dejager S, Yau C, Bégaud B. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients--the PRIMO study. Cardiovasc Drugs Ther. 2005 Dec;19(6):403-14.
Flint OP, Masters BA, Gregg RE, Durham SK. Inhibition of cholesterol synthesis by squalene synthase inhibitors does not induce myotoxicity in vitro. Toxicol Appl Pharmacol. 1997 Jul;145(1):91-8.
Nishimoto T, Ishikawa E, Anayama H, Hamajyo H, Nagai H, Hirakata M, Tozawa R. Protective effects of a squalene synthase inhibitor, lapaquistat acetate (TAK-475), on statin-induced myotoxicity in guinea pigs. Toxicol Appl Pharmacol. 2007 Aug 15;223(1):39-45. Epub 2007 May 24.
Matzno S, Yasuda S, Juman S, Yamamoto Y, Nagareya-Ishida N, Tazuya-Murayama K, Nakabayashi T, Matsuyama K. Statin-induced apoptosis linked with membrane farnesylated Ras small G protein depletion, rather than geranylated Rho protein. J Pharm Pharmacol. 2005 Nov;57(11):1475-84.
Young JM, Florkowski CM, Molyneux SL, McEwan RG, Frampton CM, George PM, Scott RS. Effect of coenzyme Q(10) supplementation on simvastatin-induced myalgia. Am J Cardiol. 2007 Nov 1;100(9):1400-3. Epub 2007 Aug 16.
Draeger A, Monastyrskaya K, Mohaupt M, Hoppeler H, Savolainen H, Allemann C, Babiychuk EB. Statin therapy induces ultrastructural damage in skeletal muscle in patients without myalgia. J Pathol. 2006 Sep;210(1):94-102.
Grundy SM, Cleeman JI, Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, Pasternak RC, Smith SC Jr, Stone NJ; National Heart, Lung, and Blood Institute; American College of Cardiology Foundation; American Heart Association. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004 Jul 13;110(2):227-39. Review. Erratum in: Circulation. 2004 Aug 10;110(6):763.
Sever PS, Dahlöf B, Poulter NR, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O'Brien E, Ostergren J; ASCOT investigators. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet. 2003 Apr 5;361(9364):1149-58.
Cohen JC, Boerwinkle E, Mosley TH Jr, Hobbs HH. Sequence variations in PCSK9, low LDL, and protection against coronary heart disease. N Engl J Med. 2006 Mar 23;354(12):1264-72.
Hanai J, Cao P, Tanksale P, Imamura S, Koshimizu E, Zhao J, Kishi S, Yamashita M, Phillips PS, Sukhatme VP, Lecker SH. The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity. J Clin Invest. 2007 Dec;117(12):3940-51.
Shishehbor MH, Patel T, Bhatt DL. Using statins to treat inflammation in acute coronary syndromes: Are we there yet? Cleve Clin J Med. 2006 Aug;73(8):760-6. Review.

Responsible Party: Truong, H. Tam, MD, Scripps Mercy Hospital
ClinicalTrials.gov Identifier: NCT00990834     History of Changes
Other Study ID Numbers: MCAST
First Submitted: October 5, 2009
First Posted: October 7, 2009
Last Update Posted: May 22, 2015
Last Verified: May 2015

Keywords provided by Scripps Health:
Statin
Myopathy
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Atrogin-1

Additional relevant MeSH terms:
Muscular Diseases
Musculoskeletal Diseases
Neuromuscular Diseases
Nervous System Diseases
Simvastatin
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Anticholesteremic Agents
Hypolipidemic Agents
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Lipid Regulating Agents
Enzyme Inhibitors


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