Muscle Characteristics Associated With Statin Therapy

NCT00990834 | Withdrawn DMC

• 1 other identifier: MCAST
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The purpose of this study is to investigate the mechanism of statin-related myopathy by evaluating muscle samples before and after statin exposure.

Conditions

Hydroxymethylglutaryl-CoA Reductase Inhibitors; Myopathy

Keywords

Statin; Myopathy; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Atrogin-1

Outcome Measures

Primary Outcomes (2)

• Atrogin-1 expression.

  One to eight months.

• Intramuscular Ras level.

  One to eight months.

Secondary Outcomes (4)

• Intramuscular Coenzyme Q10 level.

  One to eight months.

• Intramuscular mitochondrial to nuclear DNA ratio.

  One to eight months.

• Intramuscular geranylgeranylpyrophosphate.

  One to eight months.

• PPAR-gamma coactivator-1-alpha expression.

  One to eight months.

Study Arms (1)

Statin exposure

EXPERIMENTAL

Subjects' endpoints will be measured before and after one to eight months of statin exposure.

Drug: simvastatin

Interventions

simvastatin DRUG

simvastatin 80 mg PO daily for one to eight months.

Also known as: Zocor

Statin exposure

Eligibility Criteria

• Age: 21 Years - 90 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Scripps Health: lead

Study Sites (1)

Scripps-Mercy Hospital

San Diego, California, 92103, United States

Location

Related Publications (14)

• 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. doi: 10.1056/NEJM199511163332001.

  PMID: 7566020 BACKGROUND

• 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. doi: 10.1056/NEJM199811053391902.

  PMID: 9841303 BACKGROUND

• 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. doi: 10.1161/CIRCULATIONAHA.106.624890. Epub 2006 Dec 11.

  PMID: 17159064 BACKGROUND

• Bruckert E, Hayem G, Dejager S, Yau C, Begaud 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. doi: 10.1007/s10557-005-5686-z.

  PMID: 16453090 BACKGROUND

• 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. doi: 10.1006/taap.1997.8131.

  PMID: 9221828 BACKGROUND

• 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. doi: 10.1016/j.taap.2007.05.005. Epub 2007 May 24.

  PMID: 17599378 BACKGROUND

• 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. doi: 10.1211/jpp.57.11.0014.

  PMID: 16259781 BACKGROUND

• 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. doi: 10.1016/j.amjcard.2007.06.030. Epub 2007 Aug 16.

  PMID: 17950797 BACKGROUND

• 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. doi: 10.1002/path.2018.

  PMID: 16799920 BACKGROUND

• 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. doi: 10.1161/01.CIR.0000133317.49796.0E.

  PMID: 15249516 BACKGROUND

• Sever PS, Dahlof 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. doi: 10.1016/S0140-6736(03)12948-0.

  PMID: 12686036 BACKGROUND

• 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. doi: 10.1056/NEJMoa054013.

  PMID: 16554528 BACKGROUND

• 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. doi: 10.1172/JCI32741.

  PMID: 17992259 BACKGROUND

• 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. doi: 10.3949/ccjm.73.8.760.

  PMID: 16913201 BACKGROUND

MeSH Terms

Conditions

Muscular Diseases

Interventions

Simvastatin

Condition Hierarchy (Ancestors)

Musculoskeletal Diseases; Neuromuscular Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Lovastatin; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds

Study Officials

• Tam H Truong, MD

  Scripps Health

  PRINCIPAL INVESTIGATOR

• Paul S Phillips, MD

  Scripps Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: BASIC SCIENCE
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: October 5, 2009
• First Posted: October 7, 2009
• Study Start: November 1, 2009
• Primary Completion: June 1, 2011
• Study Completion: June 1, 2011
• Last Updated: May 22, 2015

Record last verified: 2015-05

Locations

US (1)