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ETA and AT1 Antagonism in ANCA-vasculitis (SPARVASC) (SPARVASC)

Primary Purpose

ANCA Associated Vasculitis, Cardiovascular Diseases, Kidney Diseases

Status
Recruiting
Phase
Phase 2
Locations
United Kingdom
Study Type
Interventional
Intervention
Sparsentan
Sponsored by
University of Edinburgh
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for ANCA Associated Vasculitis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

  • Centre for Cardiovascular Science, Queen's Medical Research Institute, 47 Little France CrescentRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

Sparsentan

Irbesartan

Arm Description

20 participants with ANCA-associated vasculitis in long-term disease remission. 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 24h blood pressure assessed as well as measurements of arterial stiffness, systemic haemodynamics and measures of urinary protein. After these baseline measures have been obtained the subject will receive 6 weeks of sparsentan. Finally the subject will undergo the same investigations listed above and we will compare to see if measurements obtained differ after treatment.

20 participants with ANCA-associated vasculitis in long-term disease remission. 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 24h blood pressure assessed as well as measurements of arterial stiffness, systemic haemodynamics and measures of urinary protein. After these baseline measures have been obtained the subject will receive 6 weeks of irbesartan. Finally the subject will undergo the same investigations listed above and we will compare to see if measurements obtained differ after treatment.

Outcomes

Primary Outcome Measures

Forearm blood flow
Change from baseline to week 6 in acetylcholine-mediated forearm blood flow vasodilatation

Secondary Outcome Measures

Fibrinolytic capacity
Plasma concentration of tissue plasminogen activator in response to bradykinin will be assessed before and after 6 weeks of intervention. Both tPA activity (in IU/ml) and tPA antigen (in ng/mL) will be assessed.
Blood pressure
Change from baseline 24h blood pressure and office blood pressure to after 3 and 6 weeks of treatment. We will assess systolic and diastolic blood pressure values as well as mean arterial pressure in mmHg.
Arterial stiffness
Change from baseline arterial stiffness to after 3 and 6 weeks of treatment. We will use a high fidelity micromanometer connected to a Sphygmocor device to measure pulse wave velocity in metres/second and augmentation index corrected for a heart rate of 75bpm measured in percentage.
Systemic haemodynamics
Change from baseline measures of systemic haemodynamics to after 3 and 6 weeks of treatment. We will use a BioZ diagnostics machine produced by CardioDynamics. This machine uses electrodes placed on the thorax and neck to automatically measure the following parameters of the heart beat cycle. Heart rate in beats/minute Stroke volume in mL/beat Stroke index in mL/beat/metre squared Cardiac output in L/min Cardiac Index in L/min/metre squared Systemic vascular resistance in dyne sec cm-5 Systemic vascular resistance index in dyne sec cm-5 metre squared Systolic time ratio index in sec-1 Thoracic fluid content in kiloohm-1
Proteinuria
Change from baseline measures of proteinuria to after 3 and 6 weeks of treatment.

Full Information

First Posted
November 8, 2022
Last Updated
January 26, 2023
Sponsor
University of Edinburgh
Collaborators
Travere Therapeutics, Inc.
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1. Study Identification

Unique Protocol Identification Number
NCT05630612
Brief Title
ETA and AT1 Antagonism in ANCA-vasculitis (SPARVASC)
Acronym
SPARVASC
Official Title
Effects of Simultaneous ETA & AT1 Receptor Antagonism on Endothelial Function & Vascular Stiffness in ANCA-associated Vasculitis (SPARsentan in VASCulitis - SPARVASC)
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
December 8, 2022 (Actual)
Primary Completion Date
December 1, 2024 (Anticipated)
Study Completion Date
September 1, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
University of Edinburgh
Collaborators
Travere Therapeutics, Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
ANCA-associated vasculitis is an autoimmune disease that causes damage to blood vessels. This leads to organ damage with the number of organs affected and the severity of damage varying significantly between patients. Vasculitis patients also have a very high risk of heart attacks and strokes, called cardiovascular disease. A chemical called 'endothelin', produced by the blood vessels, causes vessels to stiffen and raises blood pressure and this associates with cardiovascular risk. The investigators have previously shown that by blocking the effects of endothelin you reduce vessel stiffness, lower blood pressure and improve vessel function. However, these studies only blocked endothelin for a few hours. Now, the investigators would like to see if it is possible to maintain these benefits by blocking endothelin for longer. Sparsentan is a tablet that blocks endothelin and lowers blood pressure. The investigators plan to give sparsentan to patients with vasculitis for 6 weeks. To determine if any beneficial effects of sparsentan are due to blood pressure lowering the investigators will give another group of vasculitis patients a tablet called irbesartan which lowers blood pressure but does not block endothelin. The investigators will compare the results between the two groups.
Detailed Description
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
ANCA Associated Vasculitis, Cardiovascular Diseases, Kidney Diseases

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
Randomised, double blind, active control, parallel group study
Masking
ParticipantCare ProviderInvestigatorOutcomes Assessor
Masking Description
All investigators will be blinded as will the participants.
Allocation
Randomized
Enrollment
40 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Sparsentan
Arm Type
Experimental
Arm Description
20 participants with ANCA-associated vasculitis in long-term disease remission. 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 24h blood pressure assessed as well as measurements of arterial stiffness, systemic haemodynamics and measures of urinary protein. After these baseline measures have been obtained the subject will receive 6 weeks of sparsentan. Finally the subject will undergo the same investigations listed above and we will compare to see if measurements obtained differ after treatment.
Arm Title
Irbesartan
Arm Type
Active Comparator
Arm Description
20 participants with ANCA-associated vasculitis in long-term disease remission. 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 24h blood pressure assessed as well as measurements of arterial stiffness, systemic haemodynamics and measures of urinary protein. After these baseline measures have been obtained the subject will receive 6 weeks of irbesartan. Finally the subject will undergo the same investigations listed above and we will compare to see if measurements obtained differ after treatment.
Intervention Type
Drug
Intervention Name(s)
Sparsentan
Intervention Description
6 weeks of treatment with sparsentan or irbesartan. This will be administered in a double-blind fashion.
Primary Outcome Measure Information:
Title
Forearm blood flow
Description
Change from baseline to week 6 in acetylcholine-mediated forearm blood flow vasodilatation
Time Frame
Comparing baseline to after 6 weeks of intervention.
Secondary Outcome Measure Information:
Title
Fibrinolytic capacity
Description
Plasma concentration of tissue plasminogen activator in response to bradykinin will be assessed before and after 6 weeks of intervention. Both tPA activity (in IU/ml) and tPA antigen (in ng/mL) will be assessed.
Time Frame
Comparing baseline to after 6 weeks of intervention.
Title
Blood pressure
Description
Change from baseline 24h blood pressure and office blood pressure to after 3 and 6 weeks of treatment. We will assess systolic and diastolic blood pressure values as well as mean arterial pressure in mmHg.
Time Frame
Comparing baseline to after 3 and 6 weeks of treatment.
Title
Arterial stiffness
Description
Change from baseline arterial stiffness to after 3 and 6 weeks of treatment. We will use a high fidelity micromanometer connected to a Sphygmocor device to measure pulse wave velocity in metres/second and augmentation index corrected for a heart rate of 75bpm measured in percentage.
Time Frame
Comparing baseline to after 3 and 6 weeks of treatment.
Title
Systemic haemodynamics
Description
Change from baseline measures of systemic haemodynamics to after 3 and 6 weeks of treatment. We will use a BioZ diagnostics machine produced by CardioDynamics. This machine uses electrodes placed on the thorax and neck to automatically measure the following parameters of the heart beat cycle. Heart rate in beats/minute Stroke volume in mL/beat Stroke index in mL/beat/metre squared Cardiac output in L/min Cardiac Index in L/min/metre squared Systemic vascular resistance in dyne sec cm-5 Systemic vascular resistance index in dyne sec cm-5 metre squared Systolic time ratio index in sec-1 Thoracic fluid content in kiloohm-1
Time Frame
Comparing baseline to after 3 and 6 weeks of treatment.
Title
Proteinuria
Description
Change from baseline measures of proteinuria to after 3 and 6 weeks of treatment.
Time Frame
Comparing baseline to after 3 and 6 weeks of treatment.
Other Pre-specified Outcome Measures:
Title
Optical Coherence Tomography (OCT)
Description
Change from baseline OCT measures to after 3 and 6 weeks of treatment.
Time Frame
Comparing baseline to after 3 and 6 weeks of treatment.
Title
Fluorescence-activated cell sorting
Description
Change from Baseline peripheral blood cells (balance of inflammatory and anti-inflammatory cells) analyzed using flow cytometry to after 6 weeks of treatment.
Time Frame
Comparing baseline to after 6 weeks of treatment.
Title
Endothelin-1 clearance
Description
Change from Baseline peripheral blood monocytes ability to clear endothelin-1 using fluorescence-activated cell sorting (FACS) to after 6 weeks of treatment.
Time Frame
Comparing baseline to after 6 weeks of treatment.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Matthew Sayer
Phone
0131 242 3326
Email
msayer2@ed.ac.uk
First Name & Middle Initial & Last Name or Official Title & Degree
Neeraj Dhaun
Phone
0131 242 3326
Email
bean.dhaun@ed.ac.uk
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Neeraj Dhaun
Organizational Affiliation
University of Edinburgh
Official's Role
Principal Investigator
Facility Information:
Facility Name
Centre for Cardiovascular Science, Queen's Medical Research Institute, 47 Little France Crescent
City
Edinburgh
ZIP/Postal Code
EH16 4TJ
Country
United Kingdom
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Matthew Sayer
Phone
0131 242 3326
Email
msayer2@ed.ac.uk
First Name & Middle Initial & Last Name & Degree
Neeraj Dhaun
Phone
0131 242 3326
Email
bean.dhaun@ed.ac.uk

12. IPD Sharing Statement

Plan to Share IPD
No
IPD Sharing Plan Description
We will not share individual participant data.
Citations:
PubMed Identifier
35998848
Citation
Farrah TE, Melville V, Czopek A, Fok H, Bruce L, Mills NL, Bailey MA, Webb DJ, Dear JW, Dhaun N. Arterial stiffness, endothelial dysfunction and impaired fibrinolysis are pathogenic mechanisms contributing to cardiovascular risk in ANCA-associated vasculitis. Kidney Int. 2022 Nov;102(5):1115-1126. doi: 10.1016/j.kint.2022.07.026. Epub 2022 Aug 20.
Results Reference
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ETA and AT1 Antagonism in ANCA-vasculitis (SPARVASC)

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