Evaluation of Cilostazol in Combination With L-Carnitine

Peripheral Arterial Disease Clinical Trial

— ECLECTIC  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00822172
• Other study ID #: CPC-08-01
• Status: Completed
• Phase: Phase 4
• Start date: September 2008
• Est. completion date: December 2010

Study information

• Verified date: November 2019
• Source: Colorado Prevention Center
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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.

Description:

Peripheral Artery Disease (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. Peripheral Artery Disease (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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 164
• Est. completion date: December 2010
• Est. primary completion date: November 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• The subject is >40 years old.

• The subject has a diagnosis of Intermittent Claudication (IC) due to Peripheral Artery Disease (PAD).

• Ankle brachial index (ABI) < 0.90 in at least one extremity, or if Ankle brachial index (ABI)is = 0.90 to = 1.0, a reduction of at least 20% in Ankle brachial index (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 Intermittent Claudication (IC)must be stable for at least 3 months prior to Screening 1.

• Peak Walking Time (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 Peak Walking Time (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 Peak Walking Time (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 Adverse Events (AEs) during the tolerance phase of the Screening period that present a potential ongoing safety concern.

Related Conditions & MeSH terms

• Intermittent Claudication
• Peripheral Arterial Disease
• Peripheral Vascular Disease
• Peripheral Vascular Diseases
• Vascular Diseases

Intervention

Dietary Supplement:
• Levocarnitine tartrate
Capsule form, 1,002 mg (3 capsules) taken by mouth two times per day (morning and evening). L-carnitine will be taken from Day 0 to Day 180.

Drug:
• cilostazol
Background therapy beginning at 50mg (1 pill) taken by mouth two times per day for two to three weeks. Then 100 mg (1 pill) to be taken by mouth two times per day (morning and evening) for one to two weeks. Randomized therapy will consist of 100 mg (1 pill) to be taken by mouth two times per day (morning and evening) for approximately 180 days.

Locations

Country	Name	City	State
United States	Aurora Denver Cardiology Associates	Aurora	Colorado
United States	Beloit Clinic Research Office	Beloit	Wisconsin
United States	HPV Heart, PA	Columbia	Maryland
United States	Radiant Research, Inc	Columbus	Ohio
United States	Aurora Denver Cardiology Associates	Denver	Colorado
United States	Durham VA-Medical Center	Durham	North Carolina
United States	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire
United States	Central Arkansas Veteran's Healthcare System	Little Rock	Arkansas
United States	Ochsner Medical Center	New Orleans	Louisiana
United States	VA Palo Alto Health Care System	Palo Alto	California
United States	Pensacola Research Consultants, Inc.	Pensacola	Florida
United States	Internal Medicine Physicians Associates	Phoenix	Arizona
United States	Tatum Ridge Internal Medicine	Phoenix	Arizona
United States	DMI Healthcare Group, Inc.	Pinellas Park	Florida
United States	University of Rochester Medical Center	Rochester	New York
United States	Sacramento Heart and Vascular Research Center	Sacramento	California
United States	University of California at Davis Vascular Center	Sacramento	California
United States	Meridian Research	Saint Petersburg	Florida
United States	Radiant Research- Salt Lake City	Salt Lake City	Utah
United States	Clinical Trials of Texas, Inc.	San Antonio	Texas
United States	Peripheral Vascular Associates	San Antonio	Texas
United States	Apex Research Institute	Santa Ana	California
United States	Jobst Vascular Center	Toledo	Ohio
United States	University of Massachusetts Medical Center	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Colorado Prevention Center	Otsuka Pharmaceutical Co., Ltd.

Country where clinical trial is conducted

United States, 

References & Publications (35)

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Brass EP. Supplemental carnitine and exercise. Am J Clin Nutr. 2000 Aug;72(2 Suppl):618S-23S. doi: 10.1093/ajcn/72.2.618S. Review. — View Citation

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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. — View Citation

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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. — View Citation

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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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Hiatt WR, Nawaz D, Brass EP. Carnitine metabolism during exercise in patients with peripheral vascular disease. J Appl Physiol (1985). 1987 Jun;62(6):2383-7. — View Citation

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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. — View Citation

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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. — View Citation

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

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. — View Citation

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.

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 35 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in Peak Walking Time (PWT) at Day 180	Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. This maximum time walked is referred to as the peak walking time (PWT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed.	Baseline, Day 180
Secondary	Change From Baseline in Peak Walking Time at Day 180	Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. This maximum time walked is referred to as the peak walking time (PWT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed.	Baseline, Day 180
Secondary	Change From Baseline in Peak Walking Time at Day 90	Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. This maximum time walked is referred to as the peak walking time (PWT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed.	Baseline, Day 90
Secondary	Change From Baseline in Claudication Onset Time at Day 180	Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. The time during the conduct of the exercise treadmill test at which the subject first reported claudication symptoms is referred to as the claudication onset time (COT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed.	Baseline, Day 180
Secondary	Change From Baseline in Claudication Onset Time at Day 90	Subjects were asked to complete a standardized exercise treadmill test using a modified Gardner protocol. Subjects walked on the treadmill until they were physically unable to walk further either as a result of their peripheral artery disease (PAD) symptoms or other non-PAD symptoms. The time during the conduct of the exercise treadmill test at which the subject first reported claudication symptoms is referred to as the claudication onset time (COT) and reported in minutes/seconds. The exercise treadmill test was conducted at Screening, Baseline, Day 90, and Day 180 visits. The log transformation is used to make highly skewed distributions less skewed.	Baseline, Day 90
Secondary	Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 180	Subjects completed the Walking Impairment Questionnaire (WIQ) whereby they were asked about their maximal walking distance before having to rest as a result of claudication symptoms associated with their peripheral artery disease (PAD). The WIQ was administered at the Baseline, Day 90, and Day 180 visits. On the WIQ subjects were asked a series of questions related to their degree of physical difficulty that best described how hard it was for the subject to walk on level ground without stopping to rest. The questions began by asking the degree of difficulty walking around indoors, then 50 feet, 150 feet, 300 feet, 600 feet, 900 feet, and lastly 1500 feet. The responses range from None (best outcome) to Slight, then Some, then Much, then lastly Unable (worst outcome). The walking distance score was calculated from the 7 questions in the section by way of a weighted sum. A score of 100 indicated no walking impairment. A score of 0 corresponded to the highest degree of walking impairment	Baseline, Day 180
Secondary	Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 90	Subjects completed the Walking Impairment Questionnaire (WIQ) whereby they were asked about their maximal walking distance before having to rest as a result of claudication symptoms associated with their peripheral artery disease (PAD). The WIQ was administered at the Baseline, Day 90, and Day 180 visits. On the WIQ subjects were asked a series of questions related to their degree of physical difficulty that best described how hard it was for the subject to walk on level ground without stopping to rest. The questions began by asking the degree of difficulty walking around indoors, then 50 feet, 150 feet, 300 feet, 600 feet, 900 feet, and lastly 1500 feet. The responses range from None (best outcome) to Slight, then Some, then Much, then lastly Unable (worst outcome). The walking distance score was calculated from the 7 questions in the section by way of a weighted sum. A score of 100 indicated no walking impairment. A score of 0 corresponded to the highest degree of walking impairment	Baseline, Day 90

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