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

Pulmonary Arterial Hypertension Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01100736
• Other study ID #: 2008/W/CRC/01
• Secondary ID: 08/S1102/1
• Status: Completed
• Phase: Phase 0
• First received: March 30, 2010
• Last updated: July 20, 2015
• Start date: January 2009
• Est. completion date: January 2010

Study information

• Verified date: July 2015
• Source: University of Edinburgh
• Contact: n/a
• Is FDA regulated: No
• Health authority: United Kingdom: Research Ethics Committee
• Study type: Interventional

Clinical Trial Summary

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 10
• Est. completion date: January 2010
• Est. primary completion date: September 2009
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Both
• Age group: 18 Years to 70 Years

Eligibility

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 Design

Allocation: Randomized, Intervention Model: Crossover Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Basic Science

Related Conditions & MeSH terms

• Hypertension
• Pulmonary Arterial Hypertension
• Vasoconstriction
• Vasodilation

Intervention

Drug:
• Bosentan
Bosentan 125mg tablets, orally, twice daily for 7 days
• Sitaxsentan
Sitaxsentan 100mg tablets, orally, once daily for 7 days
• Placebo
Placebo tablets taken twice daily, orally, for 7 days (placebo arm) or once daily for 7 days (sitaxsentan arm)

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

Locations

Country	Name	City	State
United Kingdom	Clinical Research Centre, Western General Hospital	Edinburgh	Scotland

Sponsors (2)

Lead Sponsor	Collaborator
University of Edinburgh	Encysive Pharmaceuticals

Country where clinical trial is conducted

United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Plasma ET-1 after 7-day administration of bosentan, sitaxsentan and placebo		7 days	No
Primary	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.		60 mins	No