ETA and AT1 Antagonism in ANCA-vasculitis (SPARVASC)

ANCA-associated vasculitis is an autoimmune disease that causes direct damage to the vascular endothelium. Recent improvements in the immunosuppressive drugs used have improved short term outcomes but this has not translated to improved longer term outcomes. This is largely due to the significantly increased rates of cardiovascular disease experienced by this group of patients. For vasculitis patients in long-term remission the commonest cause of death is cardiovascular disease.

Autoimmune damage to the endothelium causes endothelial dysfunction and this associates with future risk of cardiovascular disease.

Endothelin-1 is a peptide produced by the endothelium. It is the most potent endogenous vasoconstrictor. It raises blood pressure, causes arterial stiffness and endothelial dysfunction, impairs fibrinolytic capacity and is pro-inflammatory.

Previous work has demonstrated that short term blockade of endothelin receptors improves vessel stiffness and fibrinolytic capacity.

The investigators will conduct a randomised, double blind, active control, parallel group study. 40 patients with ANCA-associated vasculitis in long-term remission will be recruited. 20 will be treated with 6 weeks of the endothelin-A receptor and angiotensin-1 receptor blocker sparsentan and 20 will be treated with the angiotensin-1 receptor blocker irbesartan.

Patients will undergo a forearm blood flow study before and after 6 weeks of treatment. This will assess endothelial function and allow the investigators to assess if the improvement in endothelial function noted with short term endothelin receptor blockade previously is maintained longer term.

Inclusion criteria

• 18 years or older
• A diagnosis of ANCA-associated vasculitis that has been in remission for ≥6 months.

The diagnosis of AAV will have been made in accordance with the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides criteria. Remission will be defined as a Birmingham Vasculitis Activity Score (BVAS) of 0 for at least 2 months prior to the screening visit whilst taking prednisolone at daily dose ≤7.5mg, in conjunction with the treating clinician's assessment of clinically silent disease.

• eGFR ≥25ml/min/1.73m2 at screening.
• Women of childbearing potential, beginning at menarche, must agree to the use of one highly reliable method of contraception (ie, a failure rate of <1% per year) for at least 30 days prior to the first dose of the study medication (ie, for hormonal contraception) or according to manufacturer's recommendation (ie, for an intrauterine device) until 30 days after the last dose of the study medication, and must have a negative pregnancy test at screening. Women of childbearing potential are defined as those who are fertile, following menarche and until becoming postmenopausal, unless permanently sterile; permanent sterilization methods include hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as amenorrhea for more than 24 consecutive months without an alternative medical cause; women on hormone replacement therapy must have a documented plasma follicle-stimulating hormone level >40 mIU/mL.

Exclusion criteria

• Age <18 years
• Active vasculitis
• Liver disease
• Untreated hypertension (defined as systolic blood pressure >160 bpm and diastolic blood pressure >100 bpm)
• eGFR <25ml/min/1.73m2
• Any organ transplant recipients
• Haemodialysis/peritoneal dialysis patients
• A requirement for any medications contraindicated whilst taking sparsentan
• Congestive heart failure
• Patients not medically fit to attend for 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.