Darusentan Effect on PET Uptake Heterogeneity

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

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.

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 Following 4 weeks of treatment with blinded study drug, subjects in both treatment groups will be withdrawn from study drug for an additional 2 weeks.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

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