The Clinical And Subclinical Effects on Arterial Stiffness of Bosentan in Patients With Systemic Sclerosis

Study Overview
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Brief Summary
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The aim of the study is to investigate whether bosentan added to usual care improves arterial stiffness after 3 months as measured as the pulse wave velocity (PWV) of the medium and large arteries corrected for blood pressure changes in patients with systemic sclerosis (SSc) with digital ulcers (DU). Patients will be randomized into a group with usual care and bosentan (n=10) or usual care only (n=10). PWV will be assessed at baseline, 3 months and 12 months.

Detailed Description
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Rationale: Digital ischemia is a major problem in patients with Raynaud's phenomenon (RP), especially in those with underlying connective tissue diseases such as systemic sclerosis (SSc). SSc is hallmarked by microvascular disease which can be assessed by nailfold capillary microscopy (NCM) to identify specific capillary patterns. However, it appears that vascular damage is not restricted to the capillaries, but may also extend to more upstream hand and forearm arteries. This may not only be reflected by clinically relevant structural abnormalities such as obliteration, but also by decreases in arterial function. The best characterised in RP is the occurrence of vasospasms after cold exposure. However, evidence points out that major stiffening of the arteries also occurs, potentially exaggerating digital ischemia and other vascular complications in SSc. Objective: To investigate whether bosentan added to usual care improves arterial stiffness after 3 months as measured as the pulse wave velocity of the medium and large arteries corrected for blood pressure changes in patients with systemic sclerosis with digital ulcers. Intervention: Group 1: Usual care AND bosentan 62.5 mg twice daily, titrated to 125 mg twice daily after one month if tolerated (n=10) Group 2: Usual care only (n=10) Nature and extent of the burden and risks associated with participation, benefit and group relatedness: Bosentan is a registered product in the Netherlands. In this study, it will be used within its indication and not in combination with other products for which it has not been registered. Therefore no additional unknown uncertainties and increased overall risk are applicable for the investigational product. In the usual care group, treatment will not differ from clinical practice. To minimize the risk of patients not receiving the most appropriate treatment in the control group, regular visits and lab assessments are planned. Patients are allowed to start with bosentan in the usual care group if indicated by the treating physician. The study will consist of one screening and three study visits. During the latter, patients clinical signs and symptoms will be assessed, vascular lab will be performed, blood will be drawn, and subjects be asked to fill in questionnaire, all of which will have a duration of no more than 2 hours per visits. In total 3 times 24cc of blood will be collected, preferably in combination will routine lab assessments. These measures render the risks acceptable and the burden minimal for the subjects participating in the study.

Official Title
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The Clinical Efficacy And Subclinical Effects on Arterial STIFFNESS of Bosentan Therapy Added to Usual Care in Patients With Systemic Sclerosis With Digital Ulcers

Conditions
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Scleroderma, Systemic

Intervention / Treatment
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* Drug: bosentan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: 18 years or older Systemic sclerosis based on the 2013 American College of Rheumatology/European League Against Rheumatism criteria Raynaud's phenomenon A history of digital ulcer disease Assessable Pulse Wave Velocity measurement at baseline Written informed consent Exclusion Criteria: Hypersensitivity to the active substance or to any of the excipients Systolic blood pressure lower than 85 mmHg Moderate to severe hepatic impairment, i.e., Child-Pugh class B or C Baseline values of liver aminotransferases, i.e., aspartate aminotransferases and/or alanine aminotransferases, greater than 3 times the upper limit of normal Concomitant use of cyclosporine A Pregnancy Women of child-bearing potential who are not using reliable methods of contraception Significant peripheral vascular disease as the sole consequence of atherosclerotic disease due to conventional vascular risk factors and coagulopathy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Usual care and bosentan<br>Usual care and also treatment with bosentan. | Drug: bosentan<br>* 62.5 mg oral twice daily for 4 weeks, then 125 mg oral twice daily.<br>* Other names: tracleer;|
| No Intervention: Usual care<br>Usual care only. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV) | assessed with Sphygmocor | 3 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV) | assessed with Sphygmocor | 12 months | 
| Right carotid-brachial arterial PWV (cbPWV) | assessed with Sphygmocor | 3 and 12 months | 
| Left carotid-brachial arterial PWV (cbPWV) | assessed with Sphygmocor | 3 and 12 months | 
| Right carotid-radial arterial PWV (crPWV) | assessed with Sphygmocor | 3 and 12 months | 
| Left carotid-radial arterial PWV (crPWV) | assessed with Sphygmocor | 3 and 12 months | 
| Local PWV of the right radial artery (rPWV) | ultrasound assessment using a MyLabOne Vascular machine | 3 and 12 months | 
| Local PWV of the left radial artery (rPWV) | an ultrasound assessment using a MyLabOne Vascular machine | 3 and 12 months | 
| Local PWV of the right brachial artery (bPWV) | an ultrasound assessment using a MyLabOne Vascular machine | 3 and 12 months | 
| Local PWV of the left brachial artery (bPWV) | an ultrasound assessment using a MyLabOne Vascular machine | 3 and 12 months | 
| Microangiopathy Evolution Score (MES) | With nailfold capillary microscopy | 3 and 12 months | 
| Capillaroscopic Skin Ulcer Risk Index (CSURI) | With nailfold capillary microscopy | 3 and 12 months | 
| Prognostic Index for Digital Lesions (PILD) | With nailfold capillary microscopy | 3 and 12 months | 
| Mean widened capillaries of 8 fingers (dig 2-5) | number per finger, assessed with nailfold capillary microscopy | 3 and 12 months | 
| Mean giant capillaries of 8 fingers (dig 2-5) | number per finger, assessed with nailfold capillary microscopy | 3 and 12 months | 
| Mean capillary density of 8 fingers (dig 2-5) | number per mm per finger, assessed with nailfold capillary microscopy | 3 and 12 months | 
| Mean loop width of 8 fingers (dig 2-5) | mm per capillary per finger, assessed with nailfold capillary microscopy | 3 and 12 months | 
| Blood flow in the hands in region of interest (ROI) 1: distal of the proximal interphalangeal (PIP) joint of the 3 middle fingers | Measured by Laser Doppler Perfusion Imaging | 3 and 12 months | 
| Blood flow in the hands in ROI 2: distal of the metacarpal joints and proximal of the PIP joint | Measured by Laser Doppler Perfusion Imaging | 3 and 12 months | 
| Blood flow in the hands in ROI 3: the hand proximal of the metacarpal joints | Measured by Laser Doppler Perfusion Imaging | 3 and 12 months | 
| Skin Autofluorescence | assessed with the AGE Reader | 3 and 12 months | 
| Number of new digital ulcers | Number | 3 and 12 months | 
| Time to healing of digital ulcers | In days | 3 and 12 months | 
| Urine albumin/creatinine ratio (ACR) | Measured in two separate morning samples of urine | 3 and 12 months | 
| Plasma N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) | assessed using a routine assay | 3 and 12 months | 
| Serum levels of matrix metalloproteinase 3 | measured according to the manufacturer's instructions | 3 and 12 months | 
| Serum levels of matrix metalloproteinases 9 | determined using in-house enzyme-linked immunosorbent assays (ELISAs) | 3 and 12 months | 
| Serum levels of tissue inhibitors of metalloproteinases (TIMP) | determined using in-house enzyme-linked immunosorbent assays | 3 and 12 months | 
| Blood pressure of the brachial artery | systolic/diastolic in mmHg | 3 and 12 months | 
| Modified Rodnan Skin Score (mRSS) | 17 body areas are examined by clinical palpation and scored based on examiner judgement of skin thickness on a 4-point ordinal scale. | 3 and 12 months | 
| Scleroderma Health Assessment Questionnaire (SHAQ) | questionnaire | 3 and 12 months | 
| Short Form (36) | questionnaire | 3 and 12 months |