Evaluation of Cilostazol in Combination With L-Carnitine

Condition(s) targeted: Peripheral Vascular Disease; Intermittent Claudication; Peripheral Arterial Disease

Intervention: Levocarnitine tartrate (Dietary Supplement); cilostazol (Drug)

Phase: Phase 4

Status: Recruiting

Sponsored by: Colorado Prevention Center

Official(s) and/or principal investigator(s):
Neil Goldenberg, MD, PhD, Study Chair, Affiliation: University of Colorado Heather Sciences Center

Overall contact:
Heather Uzdavinis, MSPH, Phone: 303-860-9900, Ext: 153, Email: heather.uzdavinis@cpcmed.org

The purpose of this study is to see how safe and effective L carnitine taken with cilostazol is compared to placebo taken with cilostazol for people with intermittent claudication. A second purpose of the study is to see if L-carnitine is absorbed into the blood stream.

Official title: Evaluation of Cilostazol in Combination With L-Carnitine in Subjects With Intermittent Claudication

Study design: Other, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Primary outcome:

To determine the effect of cilostazol combined with L-carnitine on change in peak walking time (PWT) compared to cilostazol alone from Baseline/Day 0 to Day 180 in subjects with PAD limited by intermittent claudication (IC).

To assess the safety of combining cilostazol with L-carnitine by evaluating laboratory abnormalities and adverse events (AEs).

Secondary outcome:

To evaluate the combination of cilostazol and L-carnitine on PWT compared to cilostazol alone from Baseline/Day 0 to Day 90 in subjects with PAD limited by IC.

To evaluate the effect of the combination of cilostazol and L-carnitine on claudication onset time (COT) and Quality of Life (QOL), as measured using the Walking Impairment Questionnaire (WIQ) and SF-36v2® at Days 90 and 180.

Detailed description: PAD is a narrowing of the blood vessels that supply the leg with blood. It is caused by atherosclerosis (hardening of the arteries).

Muscles require oxygen carried by the blood. When the leg muscles do not get enough blood and oxygen, this can cause pain, cramping, fatigue, and/or discomfort in the leg muscles during walking or exercise. These symptoms are called intermittent claudication (IC). In more severe cases, tissues do not get enough blood and oxygen at rest, and pain may also be present when the legs are resting. PAD is one of the most common causes of pain and disability in people between 55 and 75 years of age.

Cilostazol is a medication currently available by prescription for intermittent claudication. L-carnitine is an over-the-counter supplement. It is a natural substance in the human body and is also in some red meats, nuts, and energy drinks.

Some subjects in the study will take L-carnitine with cilostazol and others will take placebo with cilostazol. The purpose of this study is to see how safe and effective L carnitine taken with cilostazol is compared to placebo taken with cilostazol for people with intermittent claudication. A placebo is a tablet or pill that looks like regular medication, but it doesn't have any actual medicine in it. A second purpose of the study is to see if L-carnitine is absorbed into the blood stream.

Minimum age: 40 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

Inclusion Criteria:

- The subject is >40 years old.

- The subject has a diagnosis of IC due to PAD.

- Ankle brachial index (ABI) < 0. 90 in at least one extremity, or if ABI is ≥ 0. 90 to ≤

1. 0, a reduction of at least 20% in ABI, in at least one extremity, when measured within 1 minute after claudication-limiting treadmill testing. If the subject has non-compressible arteries then a toe brachial index (TBI) < 0. 70 is required in at least one extremity.

- Symptoms of IC must be stable for at least 3 months prior to Screening 1.

- PWT of ≥ 1 to ≤ 12 minutes on a Gardner protocol at Screening 2.

- If the subject is currently on statin therapy, they need to have been on statin

therapy for at least 3 months prior to Screening 1. Subjects who have recently discontinued statin therapy must "wash-out" for at least one month prior to Screening 1.

- Tolerance to background therapy of cilostazol (approximately 2 weeks of 50 mg by

mouth (PO) twice daily (BID), approximately 1 week of 100 mg PO BID) between Screening 2 and Baseline Visit.

- Subjects must be either male or females that are post-menopausal, surgically

incapable of bearing children or if they are of childbearing potential must have a negative serum pregnancy test at Screening 1 and a negative urine pregnancy test at Day 0 and must agree to use double-barrier contraceptive methods until the end of investigational therapy (Day 180 Visit).

- The subject is able to comply with scheduled visits, treatment plan and laboratory

tests.

- The subject is willing to participate in this study as documented by written informed

consent.

- During the tolerance phase of the Screening period, the subject demonstrates at least

70% compliance with cilostazol and is willing to continue treatment.

Exclusion Criteria:

- Evidence of critical limb ischemia (CLI) (e. g., ischemic rest pain or ischemic

ulceration).

- The subject has had a major amputation of the leg or any other amputation that limits

walking ability.

- The subject has diabetes mellitus type 1 or poorly controlled diabetes mellitus type

2 (hemoglobin A1c (HbA1c) > 10).

- The subject has had a transient ischemic attack (TIA) or deep vein thrombosis in the

last 3 months.

- The subject has had a stroke within the last 6 months.

- The subject has participated in an angiogenic gene therapy study, unless known to be

given placebo.

- The subject has any of the following laboratory parameters at Screening 1:

- Alanine aminotransferase (ALT), aspartate aminotransferase (AST) or total

bilirubin >3 times the upper limit of normal (ULN)

- Serum creatinine >2. 5 mg/dL

- Hemoglobin (Hb) <10 g/dL

- White blood cell (WBC) count <3. 0 x 103/µL; or > 15 x 103/µL

- Platelet count <100 x 103/µL

- The subject walks less than 1 minute at 2 miles per hour (mph), 0% grade as

determined during the Screening 1 treadmill familiarization.

- The subject has clinically significant electrocardiogram (ECG) abnormalities at rest

or changes during exercise or post-exercise at Screening 2 or Day 0.

- The subject has any history or clinical evidence of congestive heart failure (CHF),

with which the clinician-investigator concurs.

- The subject has uncontrolled hypertension (resting blood pressure (BP) > 180/100

mmHg) or uncontrolled arrhythmic disorders at Screening 1.

- History of coronary or peripheral revascularization within 6 months prior to

Screening 1.

- The subject plans to undergo coronary or peripheral revascularization during the

course of the study.

- The subject is currently taking L-carnitine or medication for claudication (including

pentoxifylline or cilostazol). In this situation, the subject would become eligible for Screening 1 after a 6 week washout of the medication.

- Subjects currently taking or those who anticipate taking ketoconazole, itraconazole,

or erythromycin. The subject would become eligible for Screening 1 immediately after completion of therapy or discontinuation of the drug(s).

- The subject has a known, active malignancy that requires active anti-neoplastic

therapy. (stable basal cell skin cancer allowed. Cancer being treated soley with hormonal therapy is allowed.)

- The subject has a severe co-morbidity with an expected survival of less than 2 years.

- The subject's PWT is limited by symptoms other than claudication (e. g., shortness of

breath (SOB), fatigue, angina, arthritis, etc.). If, in the opinion of the investigator, the subject were to improve their PWT from study therapy to the extent that his or her walking would then be limited by a symptom other than claudication, the subject should not be enrolled.

- The subject has a history of alcohol or other substance abuse within 6 months of

Screening 1.

- The subject has an inability to tolerate oral medication administration.

- The subject has a known or suspected allergy to the study medication(s) or class of

study medication(s) (cilostazol or L-carnitine) to be administered.

- The subject has initiated an exercise training program within 3 months of Screening

1, has the inability to maintain his or her current level of physical activity throughout the study, or the subject plans on enrolling in an exercise training program during the study.

- The subject plans to change his/her smoking status during the planned duration of

this study (subjects will be advised that stopping smoking is best for his/her health).

- The subject is currently pregnant or breastfeeding.

- The subject has received an investigational drug or biological agent within 30 days

prior to Screening 1.

- The subject is currently participating in or plans to enroll in another clinical

trial during this study.

- The subject has any other clinically significant medical or psychiatric condition

that in the opinion of the Investigator could impact the subject's ability to successfully complete this trial.

- In the Investigator's opinion, the subject experienced any AEs during the tolerance

phase of the Screening period that present a potential ongoing safety concern.

Heather Uzdavinis, MSPH, Phone: 303-860-9900, Ext: 153, Email: heather.uzdavinis@cpcmed.org

Internal Medicine Physicians Associates, Phoenix, Arizona 85006, United States; Terminated

Tatum Ridge Internal Medicine, Phoenix, Arizona 85032, United States; Recruiting
Sue Turner, Phone: 602-999-6495
Brian Jorgensen, MD, Principal Investigator

Central Arkansas Veteran's Healthcare System, Little Rock, Arkansas 72205, United States; Recruiting
Tia Prichett, Phone: 501-257-6906
Sandi Brock, Phone: (501) 257-6906
Mohammed Moursi, MD, Principal Investigator

Apex Research Institute, Santa Ana, California 92705, United States; Recruiting
Tarra Bixler, Phone: 714-542-3008, Ext: 316
Charle Morcos, MD, Principal Investigator

VA Palo Alto Health Care System, Palo Alto, California 94304, United States; Recruiting
Dona Bahmani, Phone: 650-849-0357
Wei Zhou, MD, Principal Investigator

University of California at Davis Vascular Center, Sacramento, California 95817, United States; Recruiting
Christy Pifer, Phone: 916-734-4156, Email: christy.pifer@ucdmc.ucdavis.edu
David Dawson, MD, Principal Investigator

Aurora Denver Cardiology Associates, Aurora, Colorado 80012, United States; Recruiting
Stephanie West, Phone: 303-597-4228
Barry Molk, MD, Principal Investigator

Aurora Denver Cardiology Associates, Denver, Colorado 80218, United States; Recruiting
Melinda Washam, Phone: 303-839-7100
Nampalli Vijay, MD, Principal Investigator

DMI Healthcare Group, Inc., Pinellas Park, Florida 33782, United States; Recruiting
Kathy Hann, Phone: 727-531-2848, Ext: 109
Dalton Benson, MD, Principal Investigator

Pensacola Research Consultants, Inc., Pensacola, Florida 32504, United States; Recruiting
Michelle McCafferty, Phone: 850-477-7900
Stuart Harlin, MD, Principal Investigator

Ochsner Medical Center, New Orleans, Louisiana 70121, United States; Recruiting
Maria Fleming, Phone: 504-842-2417
Yung-Wei Chi, DO, Principal Investigator

HPV Heart, PA, Columbia, Maryland 21044, United States; Recruiting
Tanya Burley, Phone: 443-276-9032
William Herzog, MD, Principal Investigator

University of Massachusetts Medical Center, Worcester, Massachusetts 01605, United States; Recruiting
Mary Beth Martella, Phone: 508-334-6373
Bruce Cutler, MD, Principal Investigator

Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire 03756, United States; Active, not recruiting

University of Rochester Medical Center, Rochester, New York 14623, United States; Recruiting
Mary Dowling, Phone: 585-279-5195
Karl Illig, MD, Principal Investigator

Durham VA-Medical Center, Durham, North Carolina 27705, United States; Recruiting
Marilyn Powell, Phone: 919-286-0411, Ext: 5222
Kenneth Morris, MD, Principal Investigator

Jobst Vascular Center, Toledo, Ohio 43606, United States; Recruiting
Joan Bick, Phone: 419-291-3563
Anthony Comerota, MD, Principal Investigator

Radiant Research, Inc, Columbus, Ohio 43212, United States; Recruiting
Vicki Gawel, Phone: 614-294-3854
Douglas Schumacher, MD, Principal Investigator

Peripheral Vascular Associates, San Antonio, Texas 78205, United States; Recruiting
Carl Negley, Phone: 210-237-4428, Email: cnegley@pvasatx.com
Kathy Britt, Phone: (210) 225-6508
Jeffery Martinez, MD, Principal Investigator

Clinical Trials of Texas, Inc., San Antonio, Texas 78229, United States; Recruiting
Frank Rodriguez, Phone: 210-949-0122
P. Allen Hartsell, MD, Principal Investigator

Radiant Research- Salt Lake City, Salt Lake City, Utah 84107, United States; Recruiting
Janeth Castaneda, Phone: 801-261-8930
Michael Adams, MD, Principal Investigator

CPC Home Page

Related publications:

Hiatt WR. Carnitine and peripheral arterial disease. Ann N Y Acad Sci. 2004 Nov;1033:92-8. Review.

Hiatt WR, Nawaz D, Brass EP. Carnitine metabolism during exercise in patients with peripheral vascular disease. J Appl Physiol. 1987 Jun;62(6):2383-7.

Hiatt WR. Management of Intermittent Claudication. Contemporary Diagnosis and management of Peripheral arterial Disease. 1 ed. Newtown: Handvbooks in Healthcare Co., Inc., 2004:51-9

Rowlands TE, Donnelly R. Medical therapy for intermittent claudication. Eur J Vasc Endovasc Surg. 2007 Sep;34(3):314-21. Epub 2007 May 29. Review.

Dawson DL, Cutler BS, Meissner MH, Strandness DE Jr. Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial. Circulation. 1998 Aug 18;98(7):678-86.

Money SR, Herd JA, Isaacsohn JL, Davidson M, Cutler B, Heckman J, Forbes WP. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg. 1998 Feb;27(2):267-74; discussion 274-5.

Elam MB, Heckman J, Crouse JR, Hunninghake DB, Herd JA, Davidson M, Gordon IL, Bortey EB, Forbes WP. Effect of the novel antiplatelet agent cilostazol on plasma lipoproteins in patients with intermittent claudication. Arterioscler Thromb Vasc Biol. 1998 Dec;18(12):1942-7.

Beebe HG, Dawson DL, Cutler BS, Herd JA, Strandness DE Jr, Bortey EB, Forbes WP. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med. 1999 Sep 27;159(17):2041-50.

Dawson DL, Cutler BS, Hiatt WR, Hobson RW 2nd, Martin JD, Bortey EB, Forbes WP, Strandness DE Jr. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med. 2000 Nov;109(7):523-30.

Strandness DE Jr, Dalman RL, Panian S, Rendell MS, Comp PC, Zhang P, Forbes WP. Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study. Vasc Endovascular Surg. 2002 Mar-Apr;36(2):83-91.

Regensteiner JG, Ware JE Jr, McCarthy WJ, Zhang P, Forbes WP, Heckman J, Hiatt WR. Effect of cilostazol on treadmill walking, community-based walking ability, and health-related quality of life in patients with intermittent claudication due to peripheral arterial disease: meta-analysis of six randomized controlled trials. J Am Geriatr Soc. 2002 Dec;50(12):1939-46.

Thompson PD, Zimet R, Forbes WP, Zhang P. Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. Am J Cardiol. 2002 Dec 15;90(12):1314-9.

Pratt CM. Analysis of the cilostazol safety database. Am J Cardiol. 2001 Jun 28;87(12A):28D-33D.

Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A Study in Long-term Effects). J Vasc Surg. 2008 Feb;47(2):330-336. Epub 2007 Dec 26.

Hiatt WR, Regensteiner JG, Creager MA, Hirsch AT, Cooke JP, Olin JW, Gorbunov GN, Isner J, Lukjanov YV, Tsitsiashvili MS, Zabelskaya TF, Amato A. Propionyl-L-carnitine improves exercise performance and functional status in patients with claudication. Am J Med. 2001 Jun 1;110(8):616-22.

Müller DM, Seim H, Kiess W, Löster H, Richter T. Effects of oral L-carnitine supplementation on in vivo long-chain fatty acid oxidation in healthy adults. Metabolism. 2002 Nov;51(11):1389-91.

Brass EP, Anthony R, Cobb FR, Koda I, Jiao J, Hiatt WR. The novel phosphodiesterase inhibitor NM-702 improves claudication-limited exercise performance in patients with peripheral arterial disease. J Am Coll Cardiol. 2006 Dec 19;48(12):2539-45. Epub 2006 Nov 28.

Hiatt WR, Hirsch AT, Regensteiner JG, Brass EP. Clinical trials for claudication. Assessment of exercise performance, functional status, and clinical end points. Vascular Clinical Trialists. Circulation. 1995 Aug 1;92(3):614-21. Review. No abstract available.

Rizza v, Lorefice R, Rizza N et al. Pharmacokinetics of L-Carnitine in Human Subjects. In: Ferrari R, DiMauro S, Sherwood G, eds. L-Carnitine and its Role in Medicine: From Function to Therapy. 1 ed San Diego: Academic Press, Inc., 1992:63-77.

Hiatt WR, Wolfel EE, Regensteiner JG, Brass EP. Skeletal muscle carnitine metabolism in patients with unilateral peripheral arterial disease. J Appl Physiol. 1992 Jul;73(1):346-53.

Brevetti G, Angelini C, Rosa M, Carrozzo R, Perna S, Corsi M, Matarazzo A, Marcialis A. Muscle carnitine deficiency in patients with severe peripheral vascular disease. Circulation. 1991 Oct;84(4):1490-5.

Bauer TA, Brass EP, Hiatt WR. Impaired muscle oxygen use at onset of exercise in peripheral arterial disease. J Vasc Surg. 2004 Sep;40(3):488-93.

Bauer TA, Brass EP, Barstow TJ, Hiatt WR. Skeletal muscle StO2 kinetics are slowed during low work rate calf exercise in peripheral arterial disease. Eur J Appl Physiol. 2007 May;100(2):143-51. Epub 2007 Feb 20.

Brass EP, Hiatt WR, Gardner AW, Hoppel CL. Decreased NADH dehydrogenase and ubiquinol-cytochrome c oxidoreductase in peripheral arterial disease. Am J Physiol Heart Circ Physiol. 2001 Feb;280(2):H603-9.

Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr. 2000 Aug;72(2 Suppl):618S-23S. Review.

Hiatt WR, Regensteiner JG, Wolfel EE, Ruff L, Brass EP. Carnitine and acylcarnitine metabolism during exercise in humans. Dependence on skeletal muscle metabolic state. J Clin Invest. 1989 Oct;84(4):1167-73.

Eder K, Felgner J, Becker K, Kluge H. Free and total carnitine concentrations in pig plasma after oral ingestion of various L-carnitine compounds. Int J Vitam Nutr Res. 2005 Jan;75(1):3-9.

Rubin MR, Volek JS, Gómez AL, Ratamess NA, French DN, Sharman MJ, Kraemer WJ. Safety measures of L-carnitine L-tartrate supplementation in healthy men. J Strength Cond Res. 2001 Nov;15(4):486-90.

Giamberardino MA, Dragani L, Valente R, Di Lisa F, Saggini R, Vecchiet L. Effects of prolonged L-carnitine administration on delayed muscle pain and CK release after eccentric effort. Int J Sports Med. 1996 Jul;17(5):320-4.

Volek JS, Kraemer WJ, Rubin MR, Gómez AL, Ratamess NA, Gaynor P. L-Carnitine L-tartrate supplementation favorably affects markers of recovery from exercise stress. Am J Physiol Endocrinol Metab. 2002 Feb;282(2):E474-82.

Kraemer WJ, Volek JS, French DN, Rubin MR, Sharman MJ, Gómez AL, Ratamess NA, Newton RU, Jemiolo B, Craig BW, Häkkinen K. The effects of L-carnitine L-tartrate supplementation on hormonal responses to resistance exercise and recovery. J Strength Cond Res. 2003 Aug;17(3):455-62.

Spiering BA, Kraemer WJ, Vingren JL, Hatfield DL, Fragala MS, Ho JY, Maresh CM, Anderson JM, Volek JS. Responses of criterion variables to different supplemental doses of L-carnitine L-tartrate. J Strength Cond Res. 2007 Feb;21(1):259-64.

Brevetti G, Chiariello M, Ferulano G, Policicchio A, Nevola E, Rossini A, Attisano T, Ambrosio G, Siliprandi N, Angelini C. Increases in walking distance in patients with peripheral vascular disease treated with L-carnitine: a double-blind, cross-over study. Circulation. 1988 Apr;77(4):767-73.

Brevetti G, Perna S, Sabbà C, Rossini A, Scotto di Uccio V, Berardi E, Godi L. Superiority of L-propionylcarnitine vs L-carnitine in improving walking capacity in patients with peripheral vascular disease: an acute, intravenous, double-blind, cross-over study. Eur Heart J. 1992 Feb;13(2):251-5.

Brevetti G, Diehm C, Lambert D. European multicenter study on propionyl-L-carnitine in intermittent claudication. J Am Coll Cardiol. 1999 Nov 1;34(5):1618-24.

Starting date: September 2008
Ending date: December 2010
Last updated: September 2, 2009