Darusentan Effect on PET Uptake Heterogeneity (Darusentan)

July 25, 2014 updated by: K.Lance Gould

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.

Study Overview

Status

Completed

Conditions

Intervention / Treatment

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 Following 4 weeks of treatment with blinded study drug, subjects in both treatment groups will be withdrawn from study drug for an additional 2 weeks.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

Study Type

Interventional

Enrollment (Actual)

40

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • Texas
      • Houston, Texas, United States, 77030
        • Weatherhead PET Center for Preventing and Reversing Atherosclerosis, UT Medical School, Memorial Hermann Hospital

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

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 Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Group 1
Group 1 will receive oral darusentan 100mg for 2 weeks during Phase 1 then placebo for 2 weeks during Phase 2.
Drug: darusentan 100 mg
All subjects will receive oral darusentan 100 mg for a total of 2 weeks and placebo for 2 weeks.
Other Names:
  • darusentan
  • CID 177236
  • LU-135252
  • HMR-4005
  • 171714-84-4
Active Comparator: Group 2
Group 2 will receive placebo for 2 weeks during Phase 1 then oral darusentan 100 mg for two weeks during Phase 2
Drug: darusentan 100 mg
All subjects will receive oral darusentan 100 mg for a total of 2 weeks and placebo for 2 weeks.
Other Names:
  • darusentan
  • CID 177236
  • LU-135252
  • HMR-4005
  • 171714-84-4

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change During Darusentan Treatment in the Markovian Homogeneity Number, a Value That Quantitates Myocardial Perfusion Heterogeneity
Time Frame: 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.
0, 2, 4, and 6 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change During Darusentan Treatment in Absolute Flow at Rest and Hyperemia
Time Frame: 0, 2, 4, and 6 weeks
0, 2, 4, and 6 weeks
Change During Darusentan Treatment in the Coronary Flow Reserve (CFR)
Time Frame: 0, 2, 4, and 6 weeks
CFR is calculated as the unitless ratio between hyperemic to resting flow
0, 2, 4, and 6 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

K.Lance Gould

Collaborators

Gilead Sciences

Investigators

  • Principal Investigator: K Lance Gould, MD, University of Texas Medical School at Houston
  • Principal Investigator: Nils Johnson, MD, University of Texas Medical School at Houston

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

June 1, 2009

Primary Completion (Actual)

August 1, 2011

Study Completion (Actual)

August 1, 2011

Study Registration Dates

First Submitted

August 19, 2008

First Submitted That Met QC Criteria

August 19, 2008

First Posted (Estimate)

August 20, 2008

Study Record Updates

Last Update Posted (Estimate)

August 15, 2014

Last Update Submitted That Met QC Criteria

July 25, 2014

Last Verified

July 1, 2014

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • HSC-MS-08-0380

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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