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Coronary Artery DiseasePhase 2DarusentanNCT00738049

Darusentan Effect on PET Uptake Heterogeneity

A Phase 2 study testing darusentan 100 mg in people with Coronary Artery Disease and Endothelial Dysfunction, run by K.Lance Gould at 1 site in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
darusentan 100 mg
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
40 participants
Where
1 siteUnited States
Study dates
Jun 2009to Aug 2011
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • Subjects must be greater than 18 years of age.
  • Female subjects must be surgically sterile or documented as post-menopausal for at least 2 years.
  • 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.
  • Subjects must have an abnormal PET scan.

Who cannot join

  • Subjects with acute heart failure
  • Subjects with sustained or symptomatic hypotension (SBP 90 mmHg)
  • Subjects with uncontrolled hypertension (SBP of 170 mmHg or DBP of 100 mmHg) at Screening
  • Subjects with unstable angina pectoris
  • Subjects with acute myocardial infarction, stroke, transient ischemic attack, or coronary angioplasty within the last 6 months
  • Subjects with primary valvular disease
Show all 24Show fewer
  • Subjects with significant vascular aneurysm
  • Subjects with a documented history of renal failure
  • Subjects with liver disease (total bilirubin 3 mg/dL or serum ALT or AST >2X ULN)
  • Subjects with active malignancy
  • Subjects with a fatal non-cardiovascular disease that they are expected to succumb to within 1 year
  • Female subjects that are pregnant or lactating
  • Female subjects with the potential for child-bearing
  • Female subjects being treated with hormone therapies
  • Subjects with uncontrolled diabetes mellitus
  • Subjects with diabetes with gastro paresis or severe neuropathy
  • Subjects with a history of substance abuse within the last 2 years
  • Subjects who have participated in a clinical study involving another investigational drug or device within 1 month of the Screening Visit
  • Subjects with known hypersensitivity or allergy to L-arginine, aminophylline, adenosine, or dipyridamole
  • Subjects who have a planned surgical procedure during the course of the study
  • Subjects taking herbal food supplements (L-carnitine, L-arginine or Ginko biloba)
  • Subjects with known active or dormant type 2 herpes simplex virus infections
  • 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
  • Subjects who are judged by the investigator to be ineligible for this study for any other reason

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Weatherhead PET Center for Preventing and Reversing Atherosclerosis, UT Medical School, Memorial Hermann Hospital

    Houston, Texas, 77030

Other trials in United States

About this study

Official title: 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.

Read the 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.

Being tested
darusentan 100 mg
Keywords
atherosclerosis, coronary artery disease, myocardial perfusion defect, endothelial dysfunction, endothelin receptor blockade
Medical subject headings
Coronary Artery Disease, Atherosclerosis

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • darusentan 100 mgDrug

    Also called darusentan, CID 177236, LU-135252, HMR-4005

    All subjects will receive oral darusentan 100 mg for a total of 2 weeks and placebo for 2 weeks.

Study groups in NCT00738049
Study groupRoleWhat they receive
Group 1Active comparatorGroup 1 will receive oral darusentan 100mg for 2 weeks during Phase 1 then placebo for 2 weeks during Phase 2.
Receives: Drug: darusentan 100 mg
Group 2Active comparatorGroup 2 will receive placebo for 2 weeks during Phase 1 then oral darusentan 100 mg for two weeks during Phase 2
Receives: Drug: darusentan 100 mg

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 0, 2, 4, and 6 weeks

Secondary outcomes (2)

  1. Change During Darusentan Treatment in Absolute Flow at Rest and Hyperemia

    Measured: 0, 2, 4, and 6 weeks

  2. Change During Darusentan Treatment in the Coronary Flow Reserve (CFR)

    CFR is calculated as the unitless ratio between hyperemic to resting flow

    Measured: 0, 2, 4, and 6 weeks

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted20 Aug 2008 (estimated)
  2. Study startJun 2009
  3. Primary completionAug 2011
  4. Study completionAug 2011

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Crossover
Masking
Double blind
Who is masked
Participant, Investigator
Enrolment
40 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00738049
Sponsor's protocol ID
HSC-MS-08-0380
Acronym
Darusentan
Status last verified
Jul 2014
First submitted
19 Aug 2008
Last updated
15 Aug 2014
Data monitoring committee
No

Publications

  • Verma S, Anderson TJ. Fundamentals of endothelial function for the clinical cardiologist. Circulation. 2002 Feb 5;105(5):546-9. doi: 10.1161/hc0502.104540. No abstract available.

    PubMed 11827916

  • Clarkson P, Celermajer DS, Powe AJ, Donald AE, Henry RM, Deanfield JE. Endothelium-dependent dilatation is impaired in young healthy subjects with a family history of premature coronary disease. Circulation. 1997 Nov 18;96(10):3378-83. doi: 10.1161/01.cir.96.10.3378.

    PubMed 9396430

  • Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Lerman A. Long-term follow-up of patients with mild coronary artery disease and endothelial dysfunction. Circulation. 2000 Mar 7;101(9):948-54. doi: 10.1161/01.cir.101.9.948.

    PubMed 10704159

  • Schachinger V, Britten MB, Zeiher AM. Prognostic impact of coronary vasodilator dysfunction on adverse long-term outcome of coronary heart disease. Circulation. 2000 Apr 25;101(16):1899-906. doi: 10.1161/01.cir.101.16.1899.

    PubMed 10779454

  • Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, Nour KR, Quyyumi AA. Prognostic value of coronary vascular endothelial dysfunction. Circulation. 2002 Aug 6;106(6):653-8. doi: 10.1161/01.cir.0000025404.78001.d8.

    PubMed 12163423

  • Bugiardini R, Manfrini O, Pizzi C, Fontana F, Morgagni G. Endothelial function predicts future development of coronary artery disease: a study of women with chest pain and normal coronary angiograms. Circulation. 2004 Jun 1;109(21):2518-23. doi: 10.1161/01.CIR.0000128208.22378.E3. Epub 2004 May 10.

    PubMed 15136498

  • Bottcher M, Madsen MM, Refsgaard J, Buus NH, Dorup I, Nielsen TT, Sorensen K. Peripheral flow response to transient arterial forearm occlusion does not reflect myocardial perfusion reserve. Circulation. 2001 Feb 27;103(8):1109-14. doi: 10.1161/01.cir.103.8.1109.

    PubMed 11222474

  • Nesto RW, Lamas GA, Barry J. Paradoxical elevation of threshold to angina pectoris by cold pressor test in men with significant coronary artery disease. Am J Cardiol. 1989 Mar 15;63(11):656-9. doi: 10.1016/0002-9149(89)90246-4.

    PubMed 2923057

  • Kjaer A, Meyer C, Nielsen FS, Parving HH, Hesse B. Dipyridamole, cold pressor test, and demonstration of endothelial dysfunction: a PET study of myocardial perfusion in diabetes. J Nucl Med. 2003 Jan;44(1):19-23.

    PubMed 12515871

  • el-Tamimi H, Mansour M, Wargovich TJ, Hill JA, Kerensky RA, Conti CR, Pepine CJ. Constrictor and dilator responses to intracoronary acetylcholine in adjacent segments of the same coronary artery in patients with coronary artery disease. Endothelial function revisited. Circulation. 1994 Jan;89(1):45-51. doi: 10.1161/01.cir.89.1.45.

    PubMed 8281679

  • Johnson NP, Gould KL. Physiology of endothelin in producing myocardial perfusion heterogeneity: a mechanistic study using darusentan and positron emission tomography. J Nucl Cardiol. 2013 Oct;20(5):835-44. doi: 10.1007/s12350-013-9756-5. Epub 2013 Jul 11.

    PubMed 23842710

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing darusentan 100 mg in people with Coronary Artery Disease and Endothelial Dysfunction, run by K.Lance Gould at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 15 Aug 2014. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 15 Aug 2014). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Change During Darusentan Treatment in the Markovian Homogeneity Number, a Value That Quantitates Myocardial Perfusion Heterogeneity (time frame: 0, 2, 4, and 6 weeks). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00738049, which also lists 11 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 15 Aug 2014.

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Darusentan Effect on PET Uptake Heterogeneity | AzTrials