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

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

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.

Study Overview

• Status: Completed
• Conditions: Scleroderma, Systemic
• Intervention / Treatment: Drug: bosentan

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 Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Groningen, Netherlands, 9700 RB
    • University Medical Center Groningen

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / 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: tracleer
No Intervention: Usual care; Usual care only.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University Medical Center Groningen
• Collaborators: Actelion
• Investigators: Principal Investigator: Andries J Smit, MDPhD, University Medical Center Groningen

Study record dates

Study Major Dates

• Study Start (Actual): June 26, 2015
• Primary Completion (Actual): July 30, 2018
• Study Completion (Actual): July 30, 2018

Study Registration Dates

• First Submitted: June 15, 2015
• First Submitted That Met QC Criteria: June 19, 2015
• First Posted (Estimate): June 24, 2015

Study Record Updates

• Last Update Posted (Actual): December 13, 2018
• Last Update Submitted That Met QC Criteria: December 11, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Skin Diseases; Connective Tissue Diseases; Scleroderma, Systemic; Scleroderma, Diffuse; Molecular Mechanisms of Pharmacological Action; Antihypertensive Agents; Endothelin Receptor Antagonists; Bosentan
• Other Study ID Numbers: NL49919.042.14