Darusentan Effect on PET Uptake Heterogeneity
Condition: Coronary Artery Disease; Endothelial Dysfunction
MeSH terms: Coronary Artery Disease; Myocardial Ischemia; Coronary Disease
Intervention: darusentan 100 mg
Intervention description: All subjects will receive oral darusentan 100 mg for a total of 2 weeks and placebo for 2 weeks.
Intervention MeSH terms: Darusentan
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Enrollment: 40.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: atherosclerosis; coronary artery disease; myocardial perfusion defect; endothelial dysfunction; endothelin receptor blockade

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.
    

Eligibility criteria:

        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