Clinical trial NCT02480335: The Clinical And Subclinical Effects on Arterial Stiffness of Bosentan in Patients With Systemic Sclerosis
Official title: The Clinical Efficacy And Subclinical Effects on Arterial STIFFNESS of Bosentan Therapy Added to Usual Care in Patients With Systemic Sclerosis With Digital Ulcers
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Scleroderma, Systemic
Lead sponsor: University Medical Center Groningen
Sponsor class: OTHER
Collaborators: name: Actelion
First posted: 2015-06-24
Enrollment: 20
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV)
timeFrame: 3 months
Secondary outcomes:
measure: Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV)
timeFrame: 12 months
measure: Right carotid-brachial arterial PWV (cbPWV)
timeFrame: 3 and 12 months
measure: Left carotid-brachial arterial PWV (cbPWV)
timeFrame: 3 and 12 months
measure: Right carotid-radial arterial PWV (crPWV)
timeFrame: 3 and 12 months
measure: Left carotid-radial arterial PWV (crPWV)
timeFrame: 3 and 12 months
measure: Local PWV of the right radial artery (rPWV)
timeFrame: 3 and 12 months
measure: Local PWV of the left radial artery (rPWV)
timeFrame: 3 and 12 months
measure: Local PWV of the right brachial artery (bPWV)
timeFrame: 3 and 12 months
measure: Local PWV of the left brachial artery (bPWV)
timeFrame: 3 and 12 months
measure: Microangiopathy Evolution Score (MES)
timeFrame: 3 and 12 months
measure: Capillaroscopic Skin Ulcer Risk Index (CSURI)
timeFrame: 3 and 12 months
measure: Prognostic Index for Digital Lesions (PILD)
timeFrame: 3 and 12 months
measure: Mean widened capillaries of 8 fingers (dig 2-5)
timeFrame: 3 and 12 months
measure: Mean giant capillaries of 8 fingers (dig 2-5)
timeFrame: 3 and 12 months
measure: Mean capillary density of 8 fingers (dig 2-5)
timeFrame: 3 and 12 months
measure: Mean loop width of 8 fingers (dig 2-5)
timeFrame: 3 and 12 months
measure: Blood flow in the hands in region of interest (ROI) 1: distal of the proximal interphalangeal (PIP) joint of the 3 middle fingers
timeFrame: 3 and 12 months
measure: Blood flow in the hands in ROI 2: distal of the metacarpal joints and proximal of the PIP joint
timeFrame: 3 and 12 months
measure: Blood flow in the hands in ROI 3: the hand proximal of the metacarpal joints
timeFrame: 3 and 12 months
measure: Skin Autofluorescence
timeFrame: 3 and 12 months
measure: Number of new digital ulcers
timeFrame: 3 and 12 months
measure: Time to healing of digital ulcers
timeFrame: 3 and 12 months
measure: Urine albumin/creatinine ratio (ACR)
timeFrame: 3 and 12 months
measure: Plasma N-terminal of the prohormone brain natriuretic peptide (NT-proBNP)
timeFrame: 3 and 12 months
measure: Serum levels of matrix metalloproteinase 3
timeFrame: 3 and 12 months
measure: Serum levels of matrix metalloproteinases 9
timeFrame: 3 and 12 months
measure: Serum levels of tissue inhibitors of metalloproteinases (TIMP)
timeFrame: 3 and 12 months
measure: Blood pressure of the brachial artery
timeFrame: 3 and 12 months
measure: Modified Rodnan Skin Score (mRSS)
timeFrame: 3 and 12 months
measure: Scleroderma Health Assessment Questionnaire (SHAQ)
timeFrame: 3 and 12 months
measure: Short Form (36)
timeFrame: 3 and 12 months
Other outcomes:
Locations:
city: Groningen
country: Netherlands
facility: University Medical Center Groningen
Study officials:
affiliation: University Medical Center Groningen
name: Andries J Smit, MDPhD
role: PRINCIPAL_INVESTIGATOR
References: