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

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groups will be withdrawn from study drug for an additional 2 weeks.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.