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

The recruitment status of this study is unknown because the information has not been verified recently.
Verified February 2008 by University of Edinburgh.
Recruitment status was  Active, not recruiting
Sponsor:
Collaborator:
Encysive Pharmaceuticals
Information provided by:
University of Edinburgh
ClinicalTrials.gov Identifier:
NCT01100736
First received: March 30, 2010
Last updated: April 8, 2010
Last verified: February 2008
  Purpose

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.

Condition Intervention Phase
Pulmonary Arterial Hypertension
Vasodilation
Vasoconstriction
Drug: Bosentan
Drug: Sitaxsentan
Drug: Placebo
Biological: Endothelin-3
Phase 0

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

Resource links provided by NLM:


Further study details as provided by University of Edinburgh:

Primary Outcome Measures:
  • Plasma ET-1 after 7-day administration of bosentan, sitaxsentan and placebo [ Time Frame: 7 days ] [ Designated as safety issue: No ]
  • 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 ] [ Designated as safety issue: No ]

Estimated Enrollment: 10
Study Start Date: January 2009
Estimated Primary Completion Date: September 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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 Name: 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
Drug: Sitaxsentan
Sitaxsentan 100mg tablets, orally, once daily for 7 days
Other Name: Thelin
Drug: 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
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
Drug: 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

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01100736

Locations
United Kingdom
Clinical Research Centre, Western General Hospital
Edinburgh, Scotland, United Kingdom, EH4 2XU
Sponsors and Collaborators
University of Edinburgh
Encysive Pharmaceuticals
  More Information

No publications provided

Responsible Party: Professor David Webb, University of Edinburgh
ClinicalTrials.gov Identifier: NCT01100736     History of Changes
Other Study ID Numbers: 2008/W/CRC/01, 08/S1102/1
Study First Received: March 30, 2010
Last Updated: April 8, 2010
Health Authority: United Kingdom: Research Ethics Committee

Keywords provided by University of Edinburgh:
Forearm Blood Flow
Vasodilation
Vasoconstriction
Endothelin System
Endothelin-1
Endothelin-3
Endothelin antagonists
Bosentan
Sitaxsentan
Endothelin
Regional Blood Flow

Additional relevant MeSH terms:
Hypertension
Hypertension, Pulmonary
Cardiovascular Diseases
Lung Diseases
Respiratory Tract Diseases
Vascular Diseases
Bosentan
Antihypertensive Agents
Cardiovascular Agents
Pharmacologic Actions
Therapeutic Uses

ClinicalTrials.gov processed this record on October 22, 2014