Dual Endothelin Receptor Antagonism in Large Vessel Vasculitis (DERAIL-LVV)

Phase 2

Recruiting

• Conditions: Large Vessel Vasculitis; Giant Cell Arteritis (GCA); Takayasu Arteritis
• Interventions: Drug: Bosentan

• Registration Number: NCT06887062
• Lead Sponsor: University of Edinburgh

Brief Summary

Large vessel vasculitis is a disease that causes damage to blood vessels. This damage to blood vessels can increase the risk of patients with LVV developing cardiovascular disease, including heart attacks and strokes. A chemical produced in the body called endothelin may contribute to this increase in cardiovascular disease risk by causing the vessels to stiffen and blood pressure to increase.

It has previously been shown that by blocking the effects of endothelin, vessel stiffness and blood pressure improve. Bosentan is a tablet that blocks the effects of endothelin. The investigators plan to assess blood vessel function in those with LVV and participants without LVV. Participants with LVV will then be given Bosentan for 6 weeks to evaluate its impact on blood vessel function.

Detailed Description

Large vessel vasculitis (LVV) is an autoimmune disease characterised by inflammatory damage to the blood vessels. Although symptoms initially are non-specific, complications such as vessel stenosis can lead to heart failure and stroke. While current immunosuppressive treatments have improved short-term outcomes, they have not led to improvements in long-term outcomes. Patients with LVV remain at an increased risk of developing cardiovascular disease, the underlying mechanisms of which are not yet fully understood.

The inflammatory damage to blood vessels in LVV can result in endothelial dysfunction. Endothelin-1 (ET-1) is a potent vasoconstrictor produced by the endothelium. In endothelial dysfunction, excess ET-1 production causes raised blood pressure, increased arterial stiffness and reduced fibrinolytic capacity. Previous research has demonstrated that short-term blockade of endothelin receptors improves arterial stiffness and fibrinolytic capacity.

The investigators will conduct a cross-sectional, case-control study comparing endothelial function in patients with LVV with sex-, age-, and cardiovascular disease risk factor-matched control participants. This will be followed by an open-label study involving 6 weeks of treatment with Bosentan (a dual endothelin receptor antagonist) within the LVV group to assess whether this drug can improve endothelial function. Assessment of endothelial function will be carried out by forearm plethysmography which is the gold standard.

Study Timeline

• Status Verified: 2025-03
• Study First Submitted: 2025-03-13
• Study First Submitted QC: 2025-03-13
• Last Update Submitted: 2025-03-13
• Study First Posted: 2025-03-20
• Last Update Posted: 2025-03-20
• Study Start: 2025-03-21
• Primary Completion: 2027-07-01
• Study Completion: 2027-07-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 60

Inclusion Criteria

• A diagnosis of large vessel vasculitis that has been in remission for ≥ 6 months.

Exclusion Criteria

• Age <18 years
• Active LVV
• Any organ transplant recipients
• A requirement for any medications that are contra-indicated whilst taking Bosentan
• Congestive cardiac failure
• Patients not medically fit to attend study visits
• Patients without mental capacity or willingness to provide informed consent
• History of multiple and/or severe (clinical judgement as determined by the Investigator) allergic reactions to drugs, including the study drug, or food
• Patients who are pregnant or breast feeding, or those who plan to become pregnant during the study
• Participation in another clinical trial for 28 days before or 90 days after the study period

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
30 participants with large vessel vasculitis in disease remission	Bosentan	* Participants will undergo a forearm blood flow study where forearm vasodilatation will be assessed in response to acetylcholine (7.5, 15 and 30ug/min) and sodium nitroprusside (1, 2 and 4ug/min). * Participants will also receive bradykinin (100, 300 and 1000pmol/min) in order to assess tPA release to measure fibrinolytic capacity. * Participants will also have 24-hour blood pressure measured, as well as measurements of arterial stiffness, choroidal volume and balance of peripheral inflammatory and anti-inflammatory cells. * After these baseline measurements have been obtained, the subject will receive 6 week of Bosentan. The participant will undergo the same investigations to compare if measurements differ after treatment.

Primary Outcome Measures

Name	Time	Method
Change from baseline to week 6 in forearm blood flow	Before and after 6 weeks of treatment	Change from baseline to week 6 in acetylcholine-mediated forearm blood flow vasodilation

Secondary Outcome Measures

Name	Time	Method
Change from Baseline to week 6 in fibrinolytic capacity	Before and after 6 weeks of treatment	Plasma concentration of tissue plasminogen activator in response to bradykinin will be assessed before and after 6 weeks of intervention
Change from Baseline to week 6 in 24h blood pressure	Before and after 6 weeks of treatment	24-hour ambulatory systolic and diastolic blood pressure will be assessed at baseline and 6 weeks.
Change from baseline to week 6 in arterial stiffness	Before and after 6 weeks of treatment	Arterial stiffness will be assessed using pulse wave velocity as measured using SphygmoCor technology. Percentage change in pulse wave velocity will be compared between baseline and 6 weeks
Change from baseline to week 6 assessment of eye microvasculature using retinal OCT	Before and after 6 weeks of treatment	Choroidal volume will be assessed using optical coherence tomography which will be compared at baseline and 6 weeks
Change from baseline to week 6 peripheral blood cells (balance of inflammatory and anti-inflammatory cells) analysed using flow cytometry	Before and after 6 weeks of treatment	Flow cytometry will be used to assess peripheral blood cells (balance of pro-inflammatory and anti-inflammatory cells) at baseline and 6 weeks

Trial Locations

Locations (1)

University of Edinburgh; 🇬🇧 Edinburgh, United Kingdom