Darusentan Effect on PET Uptake Heterogeneity

Coronary Artery Disease Clinical Trial

— Darusentan  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00738049
• Other study ID #: HSC-MS-08-0380
• Status: Completed
• Phase: Phase 2
• First received: August 19, 2008
• Last updated: July 25, 2014
• Start date: June 2009
• Est. completion date: August 2011

Study information

• Verified date: July 2014
• Source: The University of Texas Health Science Center, Houston
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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 Following 4 weeks of treatment with blinded study drug, subjects in both treatment groups will be withdrawn from study drug for an additional 2 weeks.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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 40
• Est. completion date: August 2011
• Est. primary completion date: August 2011
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. 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.

2. Subjects must be greater than 18 years of age.

3. Female subjects must be surgically sterile or documented as post-menopausal for at least 2 years.

4. 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.

5. Subjects must have an abnormal PET scan.

Exclusion Criteria:

1. Subjects with acute heart failure

2. Subjects with sustained or symptomatic hypotension (SBP 90 mmHg)

3. Subjects with uncontrolled hypertension (SBP of 170 mmHg or DBP of 100 mmHg) at Screening

4. Subjects with unstable angina pectoris

5. Subjects with acute myocardial infarction, stroke, transient ischemic attack, or coronary angioplasty within the last 6 months

6. Subjects with primary valvular disease

7. Subjects with significant vascular aneurysm

8. Subjects with a documented history of renal failure

9. Subjects with liver disease (total bilirubin 3 mg/dL or serum ALT or AST >2X ULN)

10. Subjects with active malignancy

11. Subjects with a fatal non-cardiovascular disease that they are expected to succumb to within 1 year

12. Female subjects that are pregnant or lactating

13. Female subjects with the potential for child-bearing

14. Female subjects being treated with hormone therapies

15. Subjects with uncontrolled diabetes mellitus

16. Subjects with diabetes with gastro paresis or severe neuropathy

17. Subjects with a history of substance abuse within the last 2 years

18. Subjects who have participated in a clinical study involving another investigational drug or device within 1 month of the Screening Visit

19. Subjects with known hypersensitivity or allergy to L-arginine, aminophylline, adenosine, or dipyridamole

20. Subjects who have a planned surgical procedure during the course of the study

21. Subjects taking herbal food supplements (L-carnitine, L-arginine or Ginko biloba)

22. Subjects with known active or dormant type 2 herpes simplex virus infections

23. 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

24. Subjects who are judged by the investigator to be ineligible for this study for any other reason

Study Design

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Coronary Artery Disease
• Coronary Disease
• Endothelial Dysfunction
• Myocardial Ischemia

Intervention

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

Locations

Country	Name	City	State
United States	Weatherhead PET Center for Preventing and Reversing Atherosclerosis, UT Medical School, Memorial Hermann Hospital	Houston	Texas

Sponsors (2)

Lead Sponsor	Collaborator
K.Lance Gould	Gilead Sciences

Country where clinical trial is conducted

United States, 

References & Publications (11)

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

Schächinger 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. — View Citation

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. — View Citation

Verma S, Anderson TJ. Fundamentals of endothelial function for the clinical cardiologist. Circulation. 2002 Feb 5;105(5):546-9. Review. — View Citation

* Note: There are 11 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	No
Secondary	Change During Darusentan Treatment in Absolute Flow at Rest and Hyperemia		0, 2, 4, and 6 weeks	No
Secondary	Change During Darusentan Treatment in the Coronary Flow Reserve (CFR)	CFR is calculated as the unitless ratio between hyperemic to resting flow	0, 2, 4, and 6 weeks	No