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

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ClinicalTrials.gov Identifier: NCT02480335
Recruitment Status : Unknown
Verified June 2015 by dr. DJ Mulder, University Medical Center Groningen.
Recruitment status was:  Not yet recruiting
First Posted : June 24, 2015
Last Update Posted : June 24, 2015
Sponsor:
Collaborator:
Actelion
Information provided by (Responsible Party):
dr. DJ Mulder, University Medical Center Groningen

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=20) or usual care only (n=20). PWV will be assessed at baseline, 3 months and 12 months.

Condition or disease Intervention/treatment Phase
Scleroderma, Systemic Drug: bosentan 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=20) Group 2: Usual care only (n=20)

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  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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 Start Date : June 2015
Estimated Primary Completion Date : June 2017
Estimated Study Completion Date : June 2017

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Scleroderma
Drug Information available for: Bosentan

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 Name: tracleer

No Intervention: Usual care
Usual care only.



Primary Outcome Measures :
  1. Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV) [ Time Frame: 3 months ]
    assessed with Sphygmocor


Secondary Outcome Measures :
  1. Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV) [ Time Frame: 12 months ]
    assessed with Sphygmocor

  2. Right carotid-brachial arterial PWV (cbPWV) [ Time Frame: 3 and 12 months ]
    assessed with Sphygmocor

  3. Left carotid-brachial arterial PWV (cbPWV) [ Time Frame: 3 and 12 months ]
    assessed with Sphygmocor

  4. Right carotid-radial arterial PWV (crPWV) [ Time Frame: 3 and 12 months ]
    assessed with Sphygmocor

  5. Left carotid-radial arterial PWV (crPWV) [ Time Frame: 3 and 12 months ]
    assessed with Sphygmocor

  6. Local PWV of the right radial artery (rPWV) [ Time Frame: 3 and 12 months ]
    ultrasound assessment using a MyLabOne Vascular machine

  7. Local PWV of the left radial artery (rPWV) [ Time Frame: 3 and 12 months ]
    an ultrasound assessment using a MyLabOne Vascular machine

  8. Local PWV of the right brachial artery (bPWV) [ Time Frame: 3 and 12 months ]
    an ultrasound assessment using a MyLabOne Vascular machine

  9. Local PWV of the left brachial artery (bPWV) [ Time Frame: 3 and 12 months ]
    an ultrasound assessment using a MyLabOne Vascular machine

  10. Microangiopathy Evolution Score (MES) [ Time Frame: 3 and 12 months ]
    With nailfold capillary microscopy

  11. Capillaroscopic Skin Ulcer Risk Index (CSURI) [ Time Frame: 3 and 12 months ]
    With nailfold capillary microscopy

  12. Prognostic Index for Digital Lesions (PILD) [ Time Frame: 3 and 12 months ]
    With nailfold capillary microscopy

  13. Mean widened capillaries of 8 fingers (dig 2-5) [ Time Frame: 3 and 12 months ]
    number per finger, assessed with nailfold capillary microscopy

  14. Mean giant capillaries of 8 fingers (dig 2-5) [ Time Frame: 3 and 12 months ]
    number per finger, assessed with nailfold capillary microscopy

  15. Mean capillary density of 8 fingers (dig 2-5) [ Time Frame: 3 and 12 months ]
    number per mm per finger, assessed with nailfold capillary microscopy

  16. Mean loop width of 8 fingers (dig 2-5) [ Time Frame: 3 and 12 months ]
    mm per capillary per finger, assessed with nailfold capillary microscopy

  17. Blood flow in the hands in region of interest (ROI) 1: distal of the proximal interphalangeal (PIP) joint of the 3 middle fingers [ Time Frame: 3 and 12 months ]
    Measured by Laser Doppler Perfusion Imaging

  18. Blood flow in the hands in ROI 2: distal of the metacarpal joints and proximal of the PIP joint [ Time Frame: 3 and 12 months ]
    Measured by Laser Doppler Perfusion Imaging

  19. Blood flow in the hands in ROI 3: the hand proximal of the metacarpal joints [ Time Frame: 3 and 12 months ]
    Measured by Laser Doppler Perfusion Imaging

  20. Skin Autofluorescence [ Time Frame: 3 and 12 months ]
    assessed with the AGE Reader

  21. Number of new digital ulcers [ Time Frame: 3 and 12 months ]
    Number

  22. Time to healing of digital ulcers [ Time Frame: 3 and 12 months ]
    In days

  23. Urine albumin/creatinine ratio (ACR) [ Time Frame: 3 and 12 months ]
    Measured in two separate morning samples of urine

  24. Plasma N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) [ Time Frame: 3 and 12 months ]
    assessed using a routine assay

  25. Serum levels of matrix metalloproteinase 3 [ Time Frame: 3 and 12 months ]
    measured according to the manufacturer's instructions

  26. Serum levels of matrix metalloproteinases 9 [ Time Frame: 3 and 12 months ]
    determined using in-house enzyme-linked immunosorbent assays (ELISAs)

  27. Serum levels of tissue inhibitors of metalloproteinases (TIMP) [ Time Frame: 3 and 12 months ]
    determined using in-house enzyme-linked immunosorbent assays

  28. Blood pressure of the brachial artery [ Time Frame: 3 and 12 months ]
    systolic/diastolic in mmHg

  29. Modified Rodnan Skin Score (mRSS) [ Time Frame: 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.

  30. Scleroderma Health Assessment Questionnaire (SHAQ) [ Time Frame: 3 and 12 months ]
    questionnaire

  31. Short Form (36) [ Time Frame: 3 and 12 months ]
    questionnaire



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02480335


Locations
Netherlands
University Medical Center Groningen Not yet recruiting
Groningen, Netherlands, 9700 RB
Contact: Douwe J Mulder, MD, PhD    +31-50-3612350    d.j.mulder@umcg.nl   
Contact: Andries J Smit, MD, PhD       a.j.smit@umcg.nl   
Principal Investigator: Douwe J. Mulder, MD, PhD         
Principal Investigator: Andries J. Smit, MD, PhD         
Sub-Investigator: Anniek M. van Roon         
Sub-Investigator: Saskia C. van de Zande         
Sponsors and Collaborators
University Medical Center Groningen
Actelion

Responsible Party: dr. DJ Mulder, dr. Douwe J. Mulder, University Medical Center Groningen
ClinicalTrials.gov Identifier: NCT02480335     History of Changes
Other Study ID Numbers: NL49919.042.14
First Posted: June 24, 2015    Key Record Dates
Last Update Posted: June 24, 2015
Last Verified: June 2015

Additional relevant MeSH terms:
Scleroderma, Systemic
Scleroderma, Diffuse
Connective Tissue Diseases
Skin Diseases
Bosentan
Antihypertensive Agents
Endothelin Receptor Antagonists
Molecular Mechanisms of Pharmacological Action