Clinical trial NCT06887062: Dual Endothelin Receptor Antagonism in Large Vessel Vasculitis (DERAIL-LVV)
Official title: Dual Endothelin Receptor Antagonism in Large Vessel Vasculitis (DERAIL-LVV)
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Large Vessel Vasculitis
Giant Cell Arteritis (GCA)
Takayasu Arteritis
Keywords: Large vessel vasculitis
Takayasu arteritis
Giant cell arteritis
Endothelin
Bosentan
Inflammation
Endothelial dysfunction
Dual enodthelin receptor antagonism
Lead sponsor: University of Edinburgh
Sponsor class: OTHER
First posted: 2025-03-20
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Intervention model description: The study will incorporate both a prospective, case-control study and a nested prospective, open blinded study.

Case-control study: this will be cross-sectional and assess endothelial function, arterial stiffness and 24-hour blood pressure in 30 patients with LVV in disease remission and 30 age-, sex- and cardiovascular risk factor-matched control subjects.

Open-blinded study: This will be a 6-week open-blinded study in the same 30 subjects with LVV from the case-control study; 15 subjects will receive bosentan 62.5mg twice daily for 6 weeks and 15 subjects will receive matched placebo for 6 weeks.
Primary purpose: TREATMENT

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.

Eligibility criteria: 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

Primary outcomes:
measure: Change from baseline to week 6 in forearm blood flow
timeFrame: Before and after 6 weeks of treatment
Secondary outcomes:
measure: Change from Baseline to week 6 in fibrinolytic capacity
timeFrame: Before and after 6 weeks of treatment
measure: Change from Baseline to week 6 in 24h blood pressure
timeFrame: Before and after 6 weeks of treatment
measure: Change from baseline to week 6 in arterial stiffness
timeFrame: Before and after 6 weeks of treatment
measure: Change from baseline to week 6 assessment of eye microvasculature using retinal OCT
timeFrame: Before and after 6 weeks of treatment
measure: Change from baseline to week 6 peripheral blood cells (balance of inflammatory and anti-inflammatory cells) analysed using flow cytometry
timeFrame: Before and after 6 weeks of treatment
Other outcomes:
Locations:
city: Edinburgh
country: United Kingdom
facility: University of Edinburgh
Study officials:
References: