CEASESTIFF: The Clinical And Subclinical Effects on Arterial Stiffness of Bosentan in Patients With Systemic Sclerosis
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 4 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Usual care and bosentan Usual care and also treatment with bosentan. |
Drug: bosentan
62.5 mg oral twice daily for 4 weeks, then 125 mg oral twice daily.
Other Names:
|
| No Intervention: Usual care Usual care only. |
Outcome Measures
Primary Outcome Measures
- Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV) [3 months]
assessed with Sphygmocor
Secondary Outcome Measures
- Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV) [12 months]
assessed with Sphygmocor
- Right carotid-brachial arterial PWV (cbPWV) [3 and 12 months]
assessed with Sphygmocor
- Left carotid-brachial arterial PWV (cbPWV) [3 and 12 months]
assessed with Sphygmocor
- Right carotid-radial arterial PWV (crPWV) [3 and 12 months]
assessed with Sphygmocor
- Left carotid-radial arterial PWV (crPWV) [3 and 12 months]
assessed with Sphygmocor
- Local PWV of the right radial artery (rPWV) [3 and 12 months]
ultrasound assessment using a MyLabOne Vascular machine
- Local PWV of the left radial artery (rPWV) [3 and 12 months]
an ultrasound assessment using a MyLabOne Vascular machine
- Local PWV of the right brachial artery (bPWV) [3 and 12 months]
an ultrasound assessment using a MyLabOne Vascular machine
- Local PWV of the left brachial artery (bPWV) [3 and 12 months]
an ultrasound assessment using a MyLabOne Vascular machine
- Microangiopathy Evolution Score (MES) [3 and 12 months]
With nailfold capillary microscopy
- Capillaroscopic Skin Ulcer Risk Index (CSURI) [3 and 12 months]
With nailfold capillary microscopy
- Prognostic Index for Digital Lesions (PILD) [3 and 12 months]
With nailfold capillary microscopy
- Mean widened capillaries of 8 fingers (dig 2-5) [3 and 12 months]
number per finger, assessed with nailfold capillary microscopy
- Mean giant capillaries of 8 fingers (dig 2-5) [3 and 12 months]
number per finger, assessed with nailfold capillary microscopy
- Mean capillary density of 8 fingers (dig 2-5) [3 and 12 months]
number per mm per finger, assessed with nailfold capillary microscopy
- Mean loop width of 8 fingers (dig 2-5) [3 and 12 months]
mm per capillary per finger, assessed with nailfold capillary microscopy
- Blood flow in the hands in region of interest (ROI) 1: distal of the proximal interphalangeal (PIP) joint of the 3 middle fingers [3 and 12 months]
Measured by Laser Doppler Perfusion Imaging
- Blood flow in the hands in ROI 2: distal of the metacarpal joints and proximal of the PIP joint [3 and 12 months]
Measured by Laser Doppler Perfusion Imaging
- Blood flow in the hands in ROI 3: the hand proximal of the metacarpal joints [3 and 12 months]
Measured by Laser Doppler Perfusion Imaging
- Skin Autofluorescence [3 and 12 months]
assessed with the AGE Reader
- Number of new digital ulcers [3 and 12 months]
Number
- Time to healing of digital ulcers [3 and 12 months]
In days
- Urine albumin/creatinine ratio (ACR) [3 and 12 months]
Measured in two separate morning samples of urine
- Plasma N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) [3 and 12 months]
assessed using a routine assay
- Serum levels of matrix metalloproteinase 3 [3 and 12 months]
measured according to the manufacturer's instructions
- Serum levels of matrix metalloproteinases 9 [3 and 12 months]
determined using in-house enzyme-linked immunosorbent assays (ELISAs)
- Serum levels of tissue inhibitors of metalloproteinases (TIMP) [3 and 12 months]
determined using in-house enzyme-linked immunosorbent assays
- Blood pressure of the brachial artery [3 and 12 months]
systolic/diastolic in mmHg
- Modified Rodnan Skin Score (mRSS) [3 and 12 months]
17 body areas are examined by clinical palpation and scored based on examiner judgement of skin thickness on a 4-point ordinal scale.
- Scleroderma Health Assessment Questionnaire (SHAQ) [3 and 12 months]
questionnaire
- Short Form (36) [3 and 12 months]
questionnaire
Eligibility Criteria
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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Medical Center Groningen | Groningen | Netherlands | 9700 RB |
Sponsors and Collaborators
- University Medical Center Groningen
- Actelion
Investigators
- Principal Investigator: Andries J Smit, MDPhD, University Medical Center Groningen
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NL49919.042.14