Coronary Artery Disease, Endothelial Dysfunction
Conditions
Keywords
atherosclerosis, coronary artery disease, myocardial perfusion defect, endothelial dysfunction, endothelin receptor blockade
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.
Detailed 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 Following 4 weeks of treatment with blinded study drug, subjects in both treatment groups will be withdrawn from study drug for an additional 2 weeks.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.
Interventions
DRUGdarusentan 100 mg
All subjects will receive oral darusentan 100 mg for a total of 2 weeks and placebo for 2 weeks.
Sponsors
Gilead Sciences
K.Lance Gould
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change During Darusentan Treatment in the Markovian Homogeneity Number, a Value That Quantitates Myocardial Perfusion Heterogeneity | 0, 2, 4, and 6 weeks | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 | CFR is calculated as the unitless ratio between hyperemic to resting flow |
Countries
United States
Participant flow
Recruitment details
Potential subjects who had undergone prior PET studies were contacted by mailings after a preliminary chart review. They received information about the study and were asked if they were interested in taking part in the study. If interested a screening visit was scheduled to determine if they met other inclusion/exclusion criteria.
Pre-assignment details
After signing consent, study participants who met preliminary study criteria, were asked to come for the first PET scan. If rest homogeneity was too high by PET, the patient was excluded from randomization; otherwise the patient was randomized to receive placebo or study drug. 40 participants enrolled and 20 excluded by PET as explained above.
Participants by arm
| Arm | Count |
|---|---|
| Group 1 Group 1 received oral Darusentan 100mg during Phase 1 then placebo during Phase 2. | 13 |
| Group 2 Group 2 received placebo during Phase 1 then oral Darusentan 100 mg during Phase 2. | 7 |
| Total | 20 |
Baseline characteristics
| Characteristic | Group 1 | Group 2 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 5 Participants | 1 Participants | 6 Participants |
| Age, Categorical Between 18 and 65 years | 8 Participants | 6 Participants | 14 Participants |
| Sex: Female, Male Female | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Male | 13 Participants | 6 Participants | 19 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 13 | 0 / 7 |
| serious Total, serious adverse events | 0 / 13 | 0 / 7 |
Outcome results
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.
Time frame: 0, 2, 4, and 6 weeks
Population: Statistical analysis is exploratory, therefore not easily planned. A paired t-test with 40 subjects will provide approximately 89% power to test the null hypothesis of no change in the homogeneity number versus a two-sided alternative at alpha= 5%,if the true mean change is 0.15,e.g.,a homogeneity index of 0.5 at baseline and 0.65 after darusentan.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline | Change During Darusentan Treatment in the Markovian Homogeneity Number, a Value That Quantitates Myocardial Perfusion Heterogeneity | 0.33 No units | Standard Deviation 0.04 |
| Darusentan 100mg | Change During Darusentan Treatment in the Markovian Homogeneity Number, a Value That Quantitates Myocardial Perfusion Heterogeneity | 0.39 No units | Standard Deviation 0.1 |
Secondary
Change During Darusentan Treatment in Absolute Flow at Rest and Hyperemia
Time frame: 0, 2, 4, and 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline | Change During Darusentan Treatment in Absolute Flow at Rest and Hyperemia | 0.65 cc/min/gm | Standard Deviation 0.13 |
| Darusentan 100mg | Change During Darusentan Treatment in Absolute Flow at Rest and Hyperemia | 1.97 cc/min/gm | Standard Deviation 0.54 |
| Baseline at Rest | Change During Darusentan Treatment in Absolute Flow at Rest and Hyperemia | 0.50 cc/min/gm | Standard Deviation 0.1 |
| Baseline at Hyperemia | Change During Darusentan Treatment in Absolute Flow at Rest and Hyperemia | 2.03 cc/min/gm | Standard Deviation 0.56 |
Secondary
Change During Darusentan Treatment in the Coronary Flow Reserve (CFR)
CFR is calculated as the unitless ratio between hyperemic to resting flow
Time frame: 0, 2, 4, and 6 weeks
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Baseline | Change During Darusentan Treatment in the Coronary Flow Reserve (CFR) | 3.52 no units | Standard Deviation 0.8 |
| Darusentan 100mg | Change During Darusentan Treatment in the Coronary Flow Reserve (CFR) | 3.04 no units | Standard Deviation 0.61 |