Clinical trial NCT02490527: Effects of Epicatechin on Statins for Mitochondrial Dysfunction and Impaired Exercise Capacity
Official title: Effects of Epicatechin on Patients With Statin-induced Mitochondrial Dysfunction and Impaired Exercise Capacity
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Statin Intolerance
Keywords: myopathy
muscular weakness
cramping
fatigue
Lead sponsor: University of California, San Diego
Sponsor class: OTHER
Collaborators: name: American Heart Association
First posted: 2015-07-07
Enrollment: 19
Sex: ALL
Minimum age (years): 30
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to gain insight into the side-effects of statin consumption, and assess the ability of epicatechin (a compound in dark chocolate) to counteract or reverse these changes. The investigators' prior research has shown that epicatechin can improve skeletal muscle structure and mitochondrial (which gives us energy) structure.

Detailed description: Patient Inclusion Criteria:

1. Must be between 30-75 years of age.
2. Must have a VO2max greater than 18 ml/kg/min(non-sedentary individuals).
3. Subjects with LDL\>100mg/dL (or on drug treatment)
4. Subjects without a prior cerebrovascular event (example: stroke)
5. Subjects without a prior cardiovascular event (example: heart attack)

Patient Exclusion Criteria:

1. Liver, thyroid, or kidney disease.
2. Currently taking drugs that interfere with statin metabolism (calcium channel blockers, colchicine etc.).
3. Acute or chronic infectious disease; autoimmune/inflammatory disease, cancer, COPD, anemia, diabetes, psychiatric illness.
4. Non-smokers, prior smokers, or illicit drug users with abstinence \>1 year.
5. Subjects taking blood thinners (Coumadin, xarelto, pradaxa, Plavix, effient, apixiban, etc) will be excluded. If subjects are taking aspirin for routine prevention they will be asked to hold aspirin for 7 days prior to biopsy. Routine prevention means that the patients are taking aspirin to reduce their risks, but do not have established cardiovascular disease.
6. History of previous knee surgery and active history of knee pain or neuromuscular disease are exclusions as they are known to affect muscle structure and function.

The study will be a double blind placebo controlled study where subjects will be randomized to either of two groups:

1. Simvastatin 40 mg + placebo once daily (statin only group) for 3 months
2. Simvastatin 40 mg + Epi 50 mg once daily (statin + Epi group) for 3 months

Eligibility criteria: Patient Inclusion Criteria:

* Must be between 30-75 years of age
* LDL\>100mg/dL (or on drug treatment)
* VO2 max greater than 25 ml/kg/min

Patient Exclusion Criteria:

* Liver or kidney disease
* Currently taking drugs that interfere with statin metabolism
* Currently taking blood thinners
* Acute or chronic infectious disease; autoimmune/inflammatory disease, cancer, COPD, anemia, psychiatric illness, insulin-dependent diabetes
* smokers or illicit drug users
* adverse cardiovascular event (ex: heart attack)
* history of knee surgery or active history of knee pain

Primary outcomes:
measure: Changes in Functional Capacity
timeFrame: Baseline and 3 months
Secondary outcomes:
Other outcomes:
measure: Changes in Blood-Based Biomarkers
timeFrame: Baseline and 3 months
measure: Composite Outcome: Changes in Skeletal Muscle Structure and Protein Levels
timeFrame: Baseline and 3 months
Locations:
city: La Jolla
country: United States
facility: University of California, San Diego
state: California
Study officials:
affiliation: University of California, San Diego
name: Pam Taub, M.D.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Taub PR, Ramirez-Sanchez I, Ciaraldi TP, Perkins G, Murphy AN, Naviaux R, Hogan M, Maisel AS, Henry RR, Ceballos G, Villarreal F. Alterations in skeletal muscle indicators of mitochondrial structure and biogenesis in patients with type 2 diabetes and heart failure: effects of epicatechin rich cocoa. Clin Transl Sci. 2012 Feb;5(1):43-7. doi: 10.1111/j.1752-8062.2011.00357.x. Epub 2011 Nov 7.
citation: Yamazaki KG, Taub PR, Barraza-Hidalgo M, Rivas MM, Zambon AC, Ceballos G, Villarreal FJ. Effects of (-)-epicatechin on myocardial infarct size and left ventricular remodeling after permanent coronary occlusion. J Am Coll Cardiol. 2010 Jun 22;55(25):2869-76. doi: 10.1016/j.jacc.2010.01.055.
citation: Nogueira L, Ramirez-Sanchez I, Perkins GA, Murphy A, Taub PR, Ceballos G, Villarreal FJ, Hogan MC, Malek MH. (-)-Epicatechin enhances fatigue resistance and oxidative capacity in mouse muscle. J Physiol. 2011 Sep 15;589(Pt 18):4615-31. doi: 10.1113/jphysiol.2011.209924. Epub 2011 Jul 25.
citation: Ramirez-Sanchez I, Nogueira L, Moreno A, Murphy A, Taub P, Perkins G, Ceballos GM, Hogan M, Malek M, Villarreal F. Stimulatory effects of the flavanol (-)-epicatechin on cardiac angiogenesis: additive effects with exercise. J Cardiovasc Pharmacol. 2012 Nov;60(5):429-38. doi: 10.1097/FJC.0b013e318269ae0d.
citation: Ramirez-Sanchez I, Taub PR, Ciaraldi TP, Nogueira L, Coe T, Perkins G, Hogan M, Maisel AS, Henry RR, Ceballos G, Villarreal F. (-)-Epicatechin rich cocoa mediated modulation of oxidative stress regulators in skeletal muscle of heart failure and type 2 diabetes patients. Int J Cardiol. 2013 Oct 9;168(4):3982-3990. doi: 10.1016/j.ijcard.2013.06.089. Epub 2013 Jul 17.
citation: Taub PR, Ramirez-Sanchez I, Ciaraldi TP, Gonzalez-Basurto S, Coral-Vazquez R, Perkins G, Hogan M, Maisel AS, Henry RR, Ceballos G, Villarreal F. Perturbations in skeletal muscle sarcomere structure in patients with heart failure and type 2 diabetes: restorative effects of (-)-epicatechin-rich cocoa. Clin Sci (Lond). 2013 Oct;125(8):383-9. doi: 10.1042/CS20130023.
citation: Barnett CF, Moreno-Ulloa A, Shiva S, Ramirez-Sanchez I, Taub PR, Su Y, Ceballos G, Dugar S, Schreiner G, Villarreal F. Pharmacokinetic, partial pharmacodynamic and initial safety analysis of (-)-epicatechin in healthy volunteers. Food Funct. 2015 Mar;6(3):824-33. doi: 10.1039/c4fo00596a.
citation: Ortiz-Vilchis P, Yamazaki KG, Rubio-Gayosso I, Ramirez-Sanchez I, Calzada C, Romero-Perez D, Ortiz A, Meaney E, Taub P, Villarreal F, Ceballos G. Co-administration of the flavanol (-)-epicatechin with doxycycline synergistically reduces infarct size in a model of ischemia reperfusion injury by inhibition of mitochondrial swelling. Eur J Pharmacol. 2014 Dec 5;744:76-82. doi: 10.1016/j.ejphar.2014.09.042. Epub 2014 Oct 2.
citation: Gutierrez-Salmean G, Ciaraldi TP, Nogueira L, Barboza J, Taub PR, Hogan MC, Henry RR, Meaney E, Villarreal F, Ceballos G, Ramirez-Sanchez I. Effects of (-)-epicatechin on molecular modulators of skeletal muscle growth and differentiation. J Nutr Biochem. 2014 Jan;25(1):91-4. doi: 10.1016/j.jnutbio.2013.09.007. Epub 2013 Oct 18.