Darusentan Effect on PET Uptake Heterogeneity

NCT00738049 | Completed Phase 2 Results

• 1 other identifier: HSC-MS-08-0380
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Coronary Artery Disease; Endothelial Dysfunction

Keywords

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

Outcome Measures

Primary Outcomes (1)

• Change During Darusentan Treatment in the Markovian Homogeneity Number, a Value That Quantitates Myocardial Perfusion Heterogeneity

  Markovian homogeneity analysis characterizes an image produced by a PET scan by examining the probability that a pixel with a given intensity will have a neighbor with a different intensity. The homogeneity index ranges from \>0 to 1, where a value near 0 represents an image with a high probability that neighboring pixels have intensity values that differ greatly, and a value near 1 represents an image with a high probability that neighboring pixels have similar intensity values.

  0, 2, 4, and 6 weeks

Secondary Outcomes (2)

• Change During Darusentan Treatment in Absolute Flow at Rest and Hyperemia

  0, 2, 4, and 6 weeks

• Change During Darusentan Treatment in the Coronary Flow Reserve (CFR)

  0, 2, 4, and 6 weeks

Study Arms (2)

Group 1

ACTIVE COMPARATOR

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

Group 2

ACTIVE COMPARATOR

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

Interventions

darusentan 100 mg DRUG

All subjects will receive oral darusentan 100 mg for a total of 2 weeks and placebo for 2 weeks.

Also known as: darusentan, CID 177236, LU-135252, HMR-4005, 171714-84-4

Group 1; Group 2

Eligibility Criteria

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

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• K.Lance Gould: lead
• Gilead Sciences: collaborator

Study Sites (1)

Weatherhead PET Center for Preventing and Reversing Atherosclerosis, UT Medical School, Memorial Hermann Hospital

Houston, Texas, 77030, United States

Location

Related Publications (11)

• Verma S, Anderson TJ. Fundamentals of endothelial function for the clinical cardiologist. Circulation. 2002 Feb 5;105(5):546-9. doi: 10.1161/hc0502.104540. No abstract available.

  PMID: 11827916 BACKGROUND

• 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. doi: 10.1161/01.cir.96.10.3378.

  PMID: 9396430 BACKGROUND

• 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. doi: 10.1161/01.cir.101.9.948.

  PMID: 10704159 BACKGROUND

• 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. doi: 10.1161/01.cir.101.16.1899.

  PMID: 10779454 BACKGROUND

• 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. doi: 10.1161/01.cir.0000025404.78001.d8.

  PMID: 12163423 BACKGROUND

• 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. doi: 10.1161/01.CIR.0000128208.22378.E3. Epub 2004 May 10.

  PMID: 15136498 BACKGROUND

• Bottcher M, Madsen MM, Refsgaard J, Buus NH, Dorup I, Nielsen TT, Sorensen K. Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve. Circulation. 2001 Feb 27;103(8):1109-14. doi: 10.1161/01.cir.103.8.1109.

  PMID: 11222474 BACKGROUND

• 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. doi: 10.1016/0002-9149(89)90246-4.

  PMID: 2923057 BACKGROUND

• 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.

  PMID: 12515871 BACKGROUND

• 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. doi: 10.1161/01.cir.89.1.45.

  PMID: 8281679 BACKGROUND

• Johnson NP, Gould KL. Physiology of endothelin in producing myocardial perfusion heterogeneity: a mechanistic study using darusentan and positron emission tomography. J Nucl Cardiol. 2013 Oct;20(5):835-44. doi: 10.1007/s12350-013-9756-5. Epub 2013 Jul 11.

  PMID: 23842710 BACKGROUND

MeSH Terms

Conditions

Coronary Artery Disease; Atherosclerosis

Interventions

darusentan

Condition Hierarchy (Ancestors)

Coronary Disease; Myocardial Ischemia; Heart Diseases; Cardiovascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Vascular Diseases

Limitations and Caveats

The trial was stopped after 20 enrollments as the manufacturer of darusentan halted further development of the drug after a negative phase 3 trial in resistant hypertension.

Results Point of Contact

• Title: K. Lance Gould, MD
• Organization: University of Texas Medical School at Houston

K.Lance.Gould@uth.tmc.edu

713-500-6611

Study Officials

• K Lance Gould, MD

  University of Texas Medical School at Houston

  PRINCIPAL INVESTIGATOR

• Nils Johnson, MD

  University of Texas Medical School at Houston

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Martin Bucksbaum distinguished University chair, Professor of Cardiovascualr MEdicine and Executive Director, Weatherhead P.E.T. Center for Preventing and Reversing Atherosclerosis

Study Record Dates

• First Submitted: August 19, 2008
• First Posted: August 20, 2008
• Study Start: June 1, 2009
• Primary Completion: August 1, 2011
• Study Completion: August 1, 2011
• Last Updated: August 15, 2014
• Results First Posted: August 15, 2014

Record last verified: 2014-07

Locations

US (1)