Endothelin Antagonism in ANCA Vasculitis

The Vascular Effects of Endothelin Receptor Antagonism in Systemic Vasculitis

Patients with vasculitis commonly develop cardiovascular disease. The reasons for this are not clear and is not adequately treated with current drugs. It is thus understand the reasons why patients with vasculitis develop cardiovascular disease in order to develop new drugs to reduced this risk.

Endothelin is a chemical produced by blood vessels that contributes to the development of hypertension and cardiovascular disease Higher than normal levels of endothelin are seen in patients with vasculitis but how this contributes to cardiovascular disease in patients with vasculitis is not clear. By using drugs that block the effects of endothelin ('endothelin receptor antagonists') the investigators can hopefully reduce the risk of cardiovascular disease in patients with vasculitis. The purpose of the study is to ascertain if endothelin receptor antagonists improve blood vessel function in patients with vasculitis.

Study Overview

• Status: Completed
• Conditions: Vasculitis
• Intervention / Treatment: Drug: Placebo; Drug: BQ123; Drug: BQ123/788

Detailed Description

Vasculitis patients and healthy controls matched for age, sex will be enrolled into the study. Patients will attend for 4 study days >1 week apart, whereas controls will attend for single day. Circulating Mφ and other immune cells will be confirmed using FACS prior each study.

Study 1 Both patients and control will attend for visit 1: assessment of vascular function using forearm plethysmography as part of case control study.

Vasculitis patients will then attend for visits 2, 3 & 4 as part of randomised three way crossover study (randomised & infusions given in a double-blind method): comparison of the effects of selective ETA receptor antagonism (BQ123; 1000nmol/min for 15min iv), mixed ETA/B antagonism (BQ123/788; 1000 nmol/min & 300 nmol/min for 15 min), and placebo on systemic haemodynamics.

• Study Type: Interventional
• Enrollment (Actual): 64
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United Kingdom
  • Edinburgh, United Kingdom
    • University of Edinburgh
  • Midlothian
    • Edinburgh, Midlothian, United Kingdom, EH16 4TJ
      • University of Edinburgh

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

• Male or female
• Age 18 years and over
• Body mass index ≤35
• Normal serum albumin

Exclusion Criteria:

• Subject with diabetes or current smoking or chronic kidney disease (eGFR <60ml/min)
• Subject with pre-existing cardiovascular disease
• Subject is below the age of legal consent, or is mentally or legally incapacitated
• History of multiple and/or severe allergic reactions to drugs (including study drugs)
• The subject has donated blood (450 ml) within the last 4 weeks
• Past or present drug or alcohol abuse including intravenous drug abuse at any time
• Participation in another clinical trial within 1 month
• Considered to be at high risk of HIV or hepatitis B
• Women of child-bearing potential (only women who are post-menopausal or surgically-sterilised will be included in the study)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Saline placebo	Drug: Placebo; Intravenous infusion of saline; Other Names: Saline
Experimental: BQ123; Intravenous infusion of BQ123 1000nmol/min for 15min	Drug: BQ123; Intravenous infusion of BQ123 ( selective ETA antagonist ); Other Names: Selective ETA antagonism
Experimental: BQ123/788; Intravenous infusion of BQ123 1000nmol/min and BQ788 300nmol/min	Drug: BQ123/788; or BQ123/788 (mixed ETA/B antagonists); Other Names: mixed ETA/B antagonism
No Intervention: Assessment of forearm vascular function; Response of forearm blood flow to endothelium-dependent and endothelium-independent vasodilators

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study 1 - forearm blood flow	Response to endothelium-dependent vasodilators	20mins
Study 2 - pulse wave velocity	Response of participants to ET antagonism	4 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Study 1 - tPA release	Response of fibrinolytic system to endothelial vasodilators	20min
Study 1 - baseline pulse wave velocity	Baseline arterial stiffness	Baseline
Study 2 - tPA release	Response of participants to ET antagonism	4 hours

Collaborators and Investigators

• Sponsor: University of Edinburgh
• Collaborators: British Heart Foundation
• Investigators: Principal Investigator: Neeraj Dhaun, University of Edinburgh

Study record dates

Study Major Dates

• Study Start: August 1, 2016
• Primary Completion (Actual): January 1, 2020
• Study Completion (Actual): January 1, 2020

Study Registration Dates

• First Submitted: February 11, 2014
• First Submitted That Met QC Criteria: February 12, 2014
• First Posted (Estimated): February 13, 2014

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 28, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: vasculitis; endothelin;; blood pressure
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Vasculitis; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; cyclo(Trp-Asp-Pro-Val-Leu)
• Other Study ID Numbers: Bean ICRF clinical study