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

NCT ID: NCT01100736

Last Updated: 2015-07-21

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

EARLY_PHASE1

Total Enrollment

10 participants

Study Classification

INTERVENTIONAL

Study Start Date

2009-01-31

Study Completion Date

2010-01-31

Brief Summary

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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.

Detailed Description

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Conditions

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Pulmonary Arterial Hypertension Vasodilation Vasoconstriction

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

BASIC_SCIENCE

Blinding Strategy

TRIPLE

Participants Caregivers Investigators

Study Groups

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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

Group Type EXPERIMENTAL

Endothelin-3

Intervention Type BIOLOGICAL

5 minute local intra-arterial infusion of endothelin-3 at a rate of rate of 60 pmol/min, during forearm blood flow studies

Bosentan

Intervention Type DRUG

Bosentan 125mg tablets, orally, twice daily for 7 days

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

Group Type EXPERIMENTAL

Sitaxsentan

Intervention Type DRUG

Sitaxsentan 100mg tablets, orally, once daily for 7 days

Placebo

Intervention Type DRUG

Placebo tablets taken twice daily, orally, for 7 days (placebo arm) or once daily for 7 days (sitaxsentan arm)

Endothelin-3

Intervention Type BIOLOGICAL

5 minute local intra-arterial infusion of endothelin-3 at a rate of rate of 60 pmol/min, during forearm blood flow studies

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

Group Type PLACEBO_COMPARATOR

Placebo

Intervention Type DRUG

Placebo tablets taken twice daily, orally, for 7 days (placebo arm) or once daily for 7 days (sitaxsentan arm)

Endothelin-3

Intervention Type BIOLOGICAL

5 minute local intra-arterial infusion of endothelin-3 at a rate of rate of 60 pmol/min, during forearm blood flow studies

Interventions

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Sitaxsentan

Sitaxsentan 100mg tablets, orally, once daily for 7 days

Intervention Type DRUG

Placebo

Placebo tablets taken twice daily, orally, for 7 days (placebo arm) or once daily for 7 days (sitaxsentan arm)

Intervention Type DRUG

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

Intervention Type BIOLOGICAL

Bosentan

Bosentan 125mg tablets, orally, twice daily for 7 days

Intervention Type DRUG

Other Intervention Names

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Tracleer Thelin

Eligibility Criteria

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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
Minimum Eligible Age

18 Years

Maximum Eligible Age

70 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

Yes

Sponsors

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Encysive Pharmaceuticals

INDUSTRY

Sponsor Role collaborator

University of Edinburgh

OTHER

Sponsor Role lead

Responsible Party

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University of Edinburgh

Locations

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Clinical Research Centre, Western General Hospital

Edinburgh, Scotland, United Kingdom

Site Status

Countries

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United Kingdom

Other Identifiers

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08/S1102/1

Identifier Type: -

Identifier Source: secondary_id

2008/W/CRC/01

Identifier Type: -

Identifier Source: org_study_id

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