A Phase 2, Investigator-Initiated, Feasibility Study to Evaluate the Mechanisms of Coronary Endothelial Dysfunction Imaged As Resting Myocardial Perfusion Heterogeneity After Endothelin Receptor Blockade With Darusentan - Full Text View

Purpose

The primary objective of this study is to test the hypothesis that myocardial perfusion heterogeneity, quantified by Markovian Homogeneity analysis of cardiac PET perfusion images, will improve in a quantitative manner after treatment with selective ETA receptor antagonist darusentan 100 mg per day for 2 weeks compared to baseline and post-treatment PET scans in clinically stable subjects with coronary atherosclerosis and/or risk factors.

Condition	Intervention	Phase
Coronary Artery Disease Endothelial Dysfunction Myocardial Perfusion Defect	Drug: darusentan 100 mg	Phase 2

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Crossover Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	A Phase 2, Investigator-Initiated, Feasibility Study to Evaluate the Mechanisms of Coronary Endothelial Dysfunction Imaged As Resting Myocardial Perfusion Heterogeneity After Endothelin Receptor Blockade With Darusentan

Resource links provided by NLM:

MedlinePlus related topics: Atherosclerosis Coronary Artery Disease

U.S. FDA Resources

Further study details as provided by The University of Texas Health Science Center, Houston:

Primary Outcome Measures:

Change during darusentan treatment in the Markovian Homogeneity Number, a value that quantitates myocardial perfusion heterogeneity [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

Secondary Outcome Measures:

Change during darusentan treatment in absolute flow at rest and hyperemia [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]
Change during darusentan treatment in the coronary flow reserve (CFR) [ Time Frame: 6 weeks ] [ Designated as safety issue: No ]

Enrollment:	40
Study Start Date:	June 2009
Study Completion Date:	August 2011
Primary Completion Date:	August 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Active Comparator: Group 1 Group 1 will receive oral darusentan 100mg for 2 weeks during Phase 1 then placebo for 2 weeks during Phase 2.	Drug: darusentan 100 mg All subjects will receive oral darusentan 100 mg for a total of 2 weeks and placebo for 2 weeks.
Active Comparator: Group 2 Group 2 will receive placebo for 2 weeks during Phase 1 then oral darusentan 100 mg for two weeks during Phase 2	Drug: darusentan 100 mg All subjects will receive oral darusentan 100 mg for a total of 2 weeks and placebo for 2 weeks.

Detailed Description:

This 6-week, Phase 2, randomized, double-blind, crossover, investigator-initiated, single-center study will determine the feasibility of detecting the effect of darusentan 100 mg once daily on the extent of myocardial perfusion heterogeneity in subjects with documented CAD, as measured by cardiac PET imaging. Prior to the initiation of any study procedures, an Informed Consent Form and HIPAA Authorization will be reviewed and signed by each subject. Screening assessments and evaluations may be conducted over a period of not more than 4 weeks.

Following a baseline PET scan (PET 1) subjects will be randomized to one of two treatment groups (Group 1 or Group 2), and receive blinded treatment for a total of 4 weeks. The 4-week treatment period will have two phases, Phase 1 and Phase 2. Group 1 will receive darusentan 100 mg for 2 weeks during Phase 1, then placebo for 2 weeks during Phase 2. Group 2 will receive placebo for 2 weeks during Phase 1, then darusentan 100 mg for 2 weeks during Phase 2. Following 4 weeks of treatment with blinded study drug, subjects in both treatment groups will be withdrawn from study drug for an additional 2 weeks. Maximum darusentan exposure in this study will be 2 weeks, and maximum placebo exposure in this study will be 2 weeks. Adjustments to the number or dosage of concomitant medications required for study entry will not be permitted at any time during the study.

A physical exam will be done at baseline and week 6 as well as blood chemistry and hematology samples taken. Vital signs and any adverse events will be monitored at each visit.

Efficacy will be assessed through cardiac PET imaging. In total, four PET scans will be administered: the first at the Randomization Visit (PET 1, Week 0); the second at the conclusion of Phase 1 (PET 2, Week 2); the third at the conclusion of Phase 2 (PET 3, Week 4) and the fourth at the conclusion of the Withdrawal period (PET 4, Week 6).

Subjects will be instructed to take their study drug with or without food once daily at approximately the same time in the morning throughout the course of the study. Subjects will also be instructed to take all concomitant medications consistently and at the same time each day throughout the study.

Eligibility

Ages Eligible for Study:	18 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Subjects must be competent to provide written informed consent. Subjects must sign an IRB approved ICF and HIPAA Authorization prior to the initiation of any study procedures. All men must be informed of the potential risks of testicular tubular atrophy and infertility associated with taking study drug, and queried regarding their understanding of the potential risks as described in the ICF.
Subjects must be greater than 18 years of age.
Female subjects must be surgically sterile or documented as post-menopausal for at least 2 years.
Subjects must have documented coronary artery disease as evidenced by previous myocardial infarction, interventional procedure, significant stenosis by cardiac catheterization, or an abnormal perfusion study.
Subjects must have an abnormal PET scan.

Exclusion Criteria:

Subjects with acute heart failure
Subjects with sustained or symptomatic hypotension (SBP 90 mmHg)
Subjects with uncontrolled hypertension (SBP of 170 mmHg or DBP of 100 mmHg) at Screening
Subjects with unstable angina pectoris
Subjects with acute myocardial infarction, stroke, transient ischemic attack, or coronary angioplasty within the last 6 months
Subjects with primary valvular disease
Subjects with significant vascular aneurysm
Subjects with a documented history of renal failure
Subjects with liver disease (total bilirubin 3 mg/dL or serum ALT or AST >2X ULN)
Subjects with active malignancy
Subjects with a fatal non-cardiovascular disease that they are expected to succumb to within 1 year
Female subjects that are pregnant or lactating
Female subjects with the potential for child-bearing
Female subjects being treated with hormone therapies
Subjects with uncontrolled diabetes mellitus
Subjects with diabetes with gastro paresis or severe neuropathy
Subjects with a history of substance abuse within the last 2 years
Subjects who have participated in a clinical study involving another investigational drug or device within 1 month of the Screening Visit
Subjects with known hypersensitivity or allergy to L-arginine, aminophylline, adenosine, or dipyridamole
Subjects who have a planned surgical procedure during the course of the study
Subjects taking herbal food supplements (L-carnitine, L-arginine or Ginko biloba)
Subjects with known active or dormant type 2 herpes simplex virus infections
Subjects with a contraindication to treatment with an ERA. Contraindications may include, but are not limited to, evidence of elevated liver function tests (e.g., aminotransferases >2X ULN) or an event defined as a serious adverse event attributed to previous treatment with an ERA
Subjects who are judged by the investigator to be ineligible for this study for any other reason

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00738049

Locations

United States, Texas
Weatherhead PET Center for Preventing and Reversing Atherosclerosis, UT Medical School, Memorial Hermann Hospital
Houston, Texas, United States, 77030

Sponsors and Collaborators

K.Lance Gould

Gilead Sciences

Investigators

Principal Investigator:

K Lance Gould, MD

University of Texas Medical School at Houston

More Information

Publications:

Verma S, Anderson TJ. Fundamentals of endothelial function for the clinical cardiologist. Circulation. 2002 Feb 5;105(5):546-9. Review. No abstract available.

Clarkson P, Celermajer DS, Powe AJ, Donald AE, Henry RM, Deanfield JE. Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease. Circulation. 1997 Nov 18;96(10):3378-83.

Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000 Mar 7;101(9):948-54.

Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000 Apr 25;101(16):1899-906.

Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002 Aug 6;106(6):653-8.

Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation. 2004 Jun 1;109(21):2518-23. Epub 2004 May 10.

Bøttcher M, Madsen MM, Refsgaard J, Buus NH, Dørup I, Nielsen TT, Sørensen K. Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve. Circulation. 2001 Feb 27;103(8):1109-14.

Nesto RW, Lamas GA, Barry J. Paradoxical elevation of threshold to angina pectoris by cold pressor test in men with significant coronary artery disease. Am J Cardiol. 1989 Mar 15;63(11):656-9.

Kjaer A, Meyer C, Nielsen FS, Parving HH, Hesse B. Dipyridamole, cold pressor test, and demonstration of endothelial dysfunction: a PET study of myocardial perfusion in diabetes. J Nucl Med. 2003 Jan;44(1):19-23.

el-Tamimi H, Mansour M, Wargovich TJ, Hill JA, Kerensky RA, Conti CR, Pepine CJ. Constrictor and dilator responses to intracoronary acetylcholine in adjacent segments of the same coronary artery in patients with coronary artery disease. Endothelial function revisited. Circulation. 1994 Jan;89(1):45-51.

Responsible Party:	K.Lance Gould, Martin Bucksbaum distinguished University chair, Professor of Cardiovascualr MEdicine and Executive Director, Weatherhead P.E.T. Center for Preventing and Reversing Atherosclerosis, The University of Texas Health Science Center, Houston
ClinicalTrials.gov Identifier:	NCT00738049 History of Changes
Other Study ID Numbers:	HSC-MS-08-0380
Study First Received:	August 19, 2008
Last Updated:	May 9, 2012
Health Authority:	United States: Food and Drug Administration

Keywords provided by The University of Texas Health Science Center, Houston:

atherosclerosis
coronary artery disease
myocardial perfusion defect
endothelial dysfunction
endothelin receptor blockade

Additional relevant MeSH terms:

Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Heart Diseases

Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases

ClinicalTrials.gov processed this record on June 18, 2013