Evaluation of Cilostazol in Combination With L-Carnitine

NCT00822172 | Completed Phase 4 Results

• 1 other identifier: CPC-08-01
• Study Type: interventional
• Target: 164
• Locations: 1 country
• Sites: 24

Brief 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.

Conditions

Peripheral Vascular Disease; Intermittent Claudication; Peripheral Arterial Disease

Keywords

Peripheral Vascular Disease; Peripheral Arterial Disease; Intermittent Claudication; Peak Walking Time; Claudication Onset Time; Cilostazol; Carnitine

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (6)

• Change From Baseline in Peak Walking Time at Day 180

  Baseline, Day 180

• Change From Baseline in Peak Walking Time at Day 90

  Baseline, Day 90

• Change From Baseline in Claudication Onset Time at Day 180

  Baseline, Day 180

• Change From Baseline in Claudication Onset Time at Day 90

  Baseline, Day 90

• Change From Baseline in Walking Impairment Questionnaire for Walking Distance at Day 180

  Baseline, Day 180

Study Arms (2)

Cilostazol + L-Carnitine

ACTIVE COMPARATOR

1 tablet cilostazol 100 mg PO BID and 3 capsules L-carnitine 334 mg PO BID

Dietary Supplement: Levocarnitine tartrate; Drug: cilostazol

Cilostazol + Placebo

PLACEBO COMPARATOR

1 tablet cilostazol 100 mg PO BID and 3 capsules placebo PO BID

Drug: cilostazol

Interventions

Levocarnitine tartrate DIETARY_SUPPLEMENT

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.

Also known as: Carnitine, L-carnitine, Levocarnitine

Cilostazol + L-Carnitine

cilostazol DRUG

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.

Also known as: Pletal

Cilostazol + L-Carnitine; Cilostazol + Placebo

Eligibility Criteria

• Age: 40 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Colorado Prevention Center: lead
• Otsuka Pharmaceutical Co., Ltd.: collaborator

Study Sites (24)

Internal Medicine Physicians Associates

Phoenix, Arizona, 85006, United States

Location

Tatum Ridge Internal Medicine

Phoenix, Arizona, 85032, United States

Location

Central Arkansas Veteran's Healthcare System

Little Rock, Arkansas, 72205, United States

Location

VA Palo Alto Health Care System

Palo Alto, California, 94304, United States

Location

University of California at Davis Vascular Center

Sacramento, California, 95817, United States

Location

Sacramento Heart and Vascular Research Center

Sacramento, California, 95825, United States

Location

Apex Research Institute

Santa Ana, California, 92705, United States

Location

Aurora Denver Cardiology Associates

Aurora, Colorado, 80012, United States

Location

Aurora Denver Cardiology Associates

Denver, Colorado, 80218, United States

Location

Pensacola Research Consultants, Inc.

Pensacola, Florida, 32504, United States

Location

DMI Healthcare Group, Inc.

Pinellas Park, Florida, 33782, United States

Location

Meridian Research

St. Petersburg, Florida, 33709, United States

Location

Ochsner Medical Center

New Orleans, Louisiana, 70121, United States

Location

HPV Heart, PA

Columbia, Maryland, 21044, United States

Location

University of Massachusetts Medical Center

Worcester, Massachusetts, 01605, United States

Location

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756, United States

Location

University of Rochester Medical Center

Rochester, New York, 14623, United States

Location

Durham VA-Medical Center

Durham, North Carolina, 27705, United States

Location

Radiant Research, Inc

Columbus, Ohio, 43212, United States

Location

Jobst Vascular Center

Toledo, Ohio, 43606, United States

Location

Peripheral Vascular Associates

San Antonio, Texas, 78205, United States

Location

Clinical Trials of Texas, Inc.

San Antonio, Texas, 78229, United States

Location

Radiant Research- Salt Lake City

Salt Lake City, Utah, 84107, United States

Location

Beloit Clinic Research Office

Beloit, Wisconsin, 53511, United States

Location

Related Publications (36)

• Hiatt WR. Carnitine and peripheral arterial disease. Ann N Y Acad Sci. 2004 Nov;1033:92-8. doi: 10.1196/annals.1320.008.

  PMID: 15591006 BACKGROUND

• 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. doi: 10.1152/jappl.1987.62.6.2383.

  PMID: 3610932 BACKGROUND

• 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

  BACKGROUND

• Rowlands TE, Donnelly R. Medical therapy for intermittent claudication. Eur J Vasc Endovasc Surg. 2007 Sep;34(3):314-21. doi: 10.1016/j.ejvs.2007.04.001. Epub 2007 May 29.

  PMID: 17532651 BACKGROUND

• 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. doi: 10.1161/01.cir.98.7.678.

  PMID: 9715861 BACKGROUND

• 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. doi: 10.1016/s0741-5214(98)70357-x.

  PMID: 9510281 BACKGROUND

• 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. doi: 10.1161/01.atv.18.12.1942.

  PMID: 9848888 BACKGROUND

• 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. doi: 10.1001/archinte.159.17.2041.

  PMID: 10510990 BACKGROUND

• 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. doi: 10.1016/s0002-9343(00)00569-6.

  PMID: 11063952 BACKGROUND

• 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. doi: 10.1177/153857440203600202.

  PMID: 11951094 BACKGROUND

• 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. doi: 10.1046/j.1532-5415.2002.50604.x.

  PMID: 12473004 BACKGROUND

• 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. doi: 10.1016/s0002-9149(02)02869-2.

  PMID: 12480040 BACKGROUND

• Pratt CM. Analysis of the cilostazol safety database. Am J Cardiol. 2001 Jun 28;87(12A):28D-33D. doi: 10.1016/s0002-9149(01)01719-2.

  PMID: 11434897 BACKGROUND

• 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. doi: 10.1016/j.jvs.2007.10.009. Epub 2007 Dec 26.

  PMID: 18155871 BACKGROUND

• 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. doi: 10.1016/s0002-9343(01)00704-5.

  PMID: 11382369 BACKGROUND

• Muller DM, Seim H, Kiess W, Loster 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. doi: 10.1053/meta.2002.35181.

  PMID: 12404185 BACKGROUND

• 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. doi: 10.1016/j.jacc.2006.07.064. Epub 2006 Nov 28.

  PMID: 17174195 BACKGROUND

• 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. doi: 10.1161/01.cir.92.3.614. No abstract available.

  PMID: 7634476 BACKGROUND

• 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.

  BACKGROUND

• Hiatt WR, Wolfel EE, Regensteiner JG, Brass EP. Skeletal muscle carnitine metabolism in patients with unilateral peripheral arterial disease. J Appl Physiol (1985). 1992 Jul;73(1):346-53. doi: 10.1152/jappl.1992.73.1.346.

  PMID: 1506390 BACKGROUND

• 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. doi: 10.1161/01.cir.84.4.1490.

  PMID: 1914091 BACKGROUND

• 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. doi: 10.1016/j.jvs.2004.06.025.

  PMID: 15337878 BACKGROUND

• 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. doi: 10.1007/s00421-007-0412-0. Epub 2007 Feb 20.

  PMID: 17310391 BACKGROUND

• 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. doi: 10.1152/ajpheart.2001.280.2.H603.

  PMID: 11158957 BACKGROUND

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

  PMID: 10919968 BACKGROUND

• 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. doi: 10.1172/JCI114281.

  PMID: 2794054 BACKGROUND

• 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. doi: 10.1024/0300-9831.75.1.3.

  PMID: 15830915 BACKGROUND

• Rubin MR, Volek JS, Gomez 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.

  PMID: 11726261 BACKGROUND

• 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. doi: 10.1055/s-2007-972854.

  PMID: 8858401 BACKGROUND

• Volek JS, Kraemer WJ, Rubin MR, Gomez 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. doi: 10.1152/ajpendo.00277.2001.

  PMID: 11788381 BACKGROUND

• Kraemer WJ, Volek JS, French DN, Rubin MR, Sharman MJ, Gomez AL, Ratamess NA, Newton RU, Jemiolo B, Craig BW, Hakkinen 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. doi: 10.1519/1533-4287(2003)0172.0.co;2.

  PMID: 12930169 BACKGROUND

• 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. doi: 10.1519/00124278-200702000-00046.

  PMID: 17313301 BACKGROUND

• 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. doi: 10.1161/01.cir.77.4.767.

  PMID: 3280157 BACKGROUND

• Brevetti G, Perna S, Sabba 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. doi: 10.1093/oxfordjournals.eurheartj.a060155.

  PMID: 1555624 BACKGROUND

• 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. doi: 10.1016/s0735-1097(99)00373-3.

  PMID: 10551714 BACKGROUND

• Goldenberg NA, Krantz MJ, Hiatt WR. L-Carnitine plus cilostazol versus cilostazol alone for the treatment of claudication in patients with peripheral artery disease: a multicenter, randomized, double-blind, placebo-controlled trial. Vasc Med. 2012 Jun;17(3):145-54. doi: 10.1177/1358863X12442264.

  PMID: 22615190 DERIVED

Related Links

• CPC Home Page

MeSH Terms

Conditions

Peripheral Vascular Diseases; Intermittent Claudication; Peripheral Arterial Disease

Interventions

Carnitine; Cilostazol

Condition Hierarchy (Ancestors)

Vascular Diseases; Cardiovascular Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Atherosclerosis; Arteriosclerosis; Arterial Occlusive Diseases

Intervention Hierarchy (Ancestors)

Trimethyl Ammonium Compounds; Quaternary Ammonium Compounds; Amines; Organic Chemicals; Tetrazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Results Point of Contact

• Title: William Hiatt, MD, President
• Organization: CPC Clinical Research

william.hiatt@cpcmed.org

3038609900

Study Officials

• Neil Goldenberg, MD, PhD

  University of Colorado Heather Sciences Center

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: January 13, 2009
• First Posted: January 14, 2009
• Study Start: September 1, 2008
• Primary Completion: November 1, 2010
• Study Completion: December 1, 2010
• Last Updated: November 29, 2019
• Results First Posted: May 22, 2013

Record last verified: 2019-11

Locations

US (24)