Role of Endothelin-A (ETA) and Endothelin-B (ETB) Receptors in the Vasodilatory Response to Endothelin-3 (ET-3)

July 20, 2015 updated by: University of Edinburgh

Characterisation of the Role of ETA and ETB Receptors in Regulating Plasma ET-1 and the Vasodilator Response to ET-3 in Man

Endothelin-1 (ET-1) has been linked to a number of conditions including pulmonary arterial hypertension (PAH). ET-1 acts via 2 receptors, ETA and ETB. The ET-1 receptor blockers bosentan and sitaxsentan have been shown to be beneficial in patients with PAH. Bosentan blocks both ETA and ETB receptors. Sitaxsentan selectively blocks ETA receptors. Theoretically, selective ETA blockade may be associated with greater vasodilation and clearance of ET-1 by leaving the ETB receptor unblocked. This has not been directly studied in humans.

We aim to investigate the endothelial ETB-mediated vascular responses between bosentan and sitaxsentan by using a ETB selective agonist (ET-3). We hypothesise that at clinically relevant doses:

  • Bosentan will show evidence of ETB receptor blockade compared to sitaxsentan and placebo.
  • These effects will be confirmed by 2 functional markers of ETB receptor antagonism: plasma ET-1 (a very sensitive, but not necessarily clinically relevant marker), and the forearm vasodilator response to ET-3.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
10

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Early Phase 1

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 Kingdom
    • Scotland
      • Edinburgh, Scotland, United Kingdom, EH4 2XU
        • Clinical Research Centre, Western General 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

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

14 years to 66 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Healthy men and post-menopausal women
  • Age 18-70 years
  • BMI 18-35 kg/m2

Exclusion Criteria:

  • Are mentally or legally incapacitated
  • Have donated blood within the last 4 weeks
  • Have a history of past or present drug or alcohol abuse
  • Have participated in another clinical trial within 1 month
  • Are considered to be at a high risk of HIV or Hepatitis B
  • Are taking routine medicines
  • Are women taking hormone replacement therapy
  • Have significant medical or psychiatric illness

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: Basic Science
  • Allocation: Randomized
  • Interventional Model: Crossover Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Bosentan
Bosentan 125mg twice daily will be taken for 7 days, before ET-1 plasma sample taken. ET-3 infusion (5mins) and associated forearm blood flow study (60 mins) will also occur after 7 days of bosentan therapy
Drug: Bosentan
Bosentan 125mg tablets, orally, twice daily for 7 days
Other Names:
  • Tracleer
Biological: Endothelin-3
5 minute local intra-arterial infusion of endothelin-3 at a rate of rate of 60 pmol/min, during forearm blood flow studies
Experimental: Sitaxsentan
Sitaxsentan 100mg once daily + placebo tablet will be taken for 7 days, before ET-1 plasma sample taken. ET-3 infusion (5mins) and associated forearm blood flow study (60 mins) will also occur after 7 days of sitaxsentan therapy
Biological: Endothelin-3
5 minute local intra-arterial infusion of endothelin-3 at a rate of rate of 60 pmol/min, during forearm blood flow studies
Drug: Sitaxsentan
Sitaxsentan 100mg tablets, orally, once daily for 7 days
Other Names:
  • Thelin
Drug: Placebo
Placebo tablets taken twice daily, orally, for 7 days (placebo arm) or once daily for 7 days (sitaxsentan arm)
Placebo Comparator: Placebo
Placebo tablet twice daily will be taken for 7 days, before ET-1 plasma sample taken. ET-3 infusion (5mins) and associated forearm blood flow study (60 mins) will also occur after 7 days of placebo therapy
Biological: Endothelin-3
5 minute local intra-arterial infusion of endothelin-3 at a rate of rate of 60 pmol/min, during forearm blood flow studies
Drug: Placebo
Placebo tablets taken twice daily, orally, for 7 days (placebo arm) or once daily for 7 days (sitaxsentan arm)

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Plasma ET-1 after 7-day administration of bosentan, sitaxsentan and placebo
Time Frame: 7 days
7 days
Responses to ET-3 (maximum vasodilation after ET-3 administration and area under the curve of vasodilation) after bosentan compared with the results from sitaxsentan and placebo.
Time Frame: 60 mins
60 mins

Collaborators and Investigators

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

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University of Edinburgh

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Encysive Pharmaceuticals

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

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2009

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
September 1, 2009

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
January 1, 2010

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
March 30, 2010

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
April 8, 2010

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
April 9, 2010

Study Record Updates

Last Update Posted (Estimate)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 21, 2015

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 20, 2015

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2015

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 2008/W/CRC/01
  • 08/S1102/1

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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