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

NCT01100736 | Completed Early Phase 1 DMC

• 2 other identifiers: 2008/W/CRC/0108/S1102/1
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Pulmonary Arterial Hypertension; Vasodilation; Vasoconstriction

Keywords

Forearm Blood Flow; Vasodilation; Vasoconstriction; Endothelin System; Endothelin-1; Endothelin-3; Endothelin antagonists; Bosentan; Sitaxsentan; Endothelin; Regional Blood Flow

Outcome Measures

Primary Outcomes (2)

• Plasma ET-1 after 7-day administration of bosentan, sitaxsentan and placebo

  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.

  60 mins

Study Arms (3)

Bosentan

EXPERIMENTAL

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; Biological: Endothelin-3

Sitaxsentan

EXPERIMENTAL

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; Drug: Placebo; Biological: Endothelin-3

Placebo

PLACEBO COMPARATOR

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; Biological: Endothelin-3

Interventions

Bosentan DRUG

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

Also known as: Tracleer

Bosentan

Sitaxsentan DRUG

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

Also known as: Thelin

Sitaxsentan

Placebo DRUG

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

Placebo; Sitaxsentan

Endothelin-3 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; Placebo; Sitaxsentan

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

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

You may not qualify if:

• 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

Sponsors & Collaborators

• University of Edinburgh: lead
• Encysive Pharmaceuticals: collaborator

Study Sites (1)

Clinical Research Centre, Western General Hospital

Edinburgh, Scotland, EH4 2XU, United Kingdom

Location

MeSH Terms

Conditions

Pulmonary Arterial Hypertension; Aneurysm

Interventions

Bosentan; sitaxsentan; Endothelin-3

Condition Hierarchy (Ancestors)

Hypertension, Pulmonary; Lung Diseases; Respiratory Tract Diseases; Vascular Diseases; Cardiovascular Diseases

Intervention Hierarchy (Ancestors)

Benzenesulfonamides; Sulfonamides; Amides; Organic Chemicals; Benzene Derivatives; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Sulfones; Sulfur Compounds; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Endothelins; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors

Study Design

• Study Type: interventional
• Phase: early phase 1
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: March 30, 2010
• First Posted: April 9, 2010
• Study Start: January 1, 2009
• Primary Completion: September 1, 2009
• Study Completion: January 1, 2010
• Last Updated: July 21, 2015

Record last verified: 2015-07

Locations

GB (1)