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

December 11, 2018 updated by: dr. DJ Mulder, University Medical Center Groningen

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

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

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

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
20

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

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

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

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

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

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

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
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

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV)
Time Frame: 3 months
assessed with Sphygmocor
3 months

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV)
Time Frame: 12 months
assessed with Sphygmocor
12 months
Right carotid-brachial arterial PWV (cbPWV)
Time Frame: 3 and 12 months
assessed with Sphygmocor
3 and 12 months
Left carotid-brachial arterial PWV (cbPWV)
Time Frame: 3 and 12 months
assessed with Sphygmocor
3 and 12 months
Right carotid-radial arterial PWV (crPWV)
Time Frame: 3 and 12 months
assessed with Sphygmocor
3 and 12 months
Left carotid-radial arterial PWV (crPWV)
Time Frame: 3 and 12 months
assessed with Sphygmocor
3 and 12 months
Local PWV of the right radial artery (rPWV)
Time Frame: 3 and 12 months
ultrasound assessment using a MyLabOne Vascular machine
3 and 12 months
Local PWV of the left radial artery (rPWV)
Time Frame: 3 and 12 months
an ultrasound assessment using a MyLabOne Vascular machine
3 and 12 months
Local PWV of the right brachial artery (bPWV)
Time Frame: 3 and 12 months
an ultrasound assessment using a MyLabOne Vascular machine
3 and 12 months
Local PWV of the left brachial artery (bPWV)
Time Frame: 3 and 12 months
an ultrasound assessment using a MyLabOne Vascular machine
3 and 12 months
Microangiopathy Evolution Score (MES)
Time Frame: 3 and 12 months
With nailfold capillary microscopy
3 and 12 months
Capillaroscopic Skin Ulcer Risk Index (CSURI)
Time Frame: 3 and 12 months
With nailfold capillary microscopy
3 and 12 months
Prognostic Index for Digital Lesions (PILD)
Time Frame: 3 and 12 months
With nailfold capillary microscopy
3 and 12 months
Mean widened capillaries of 8 fingers (dig 2-5)
Time Frame: 3 and 12 months
number per finger, assessed with nailfold capillary microscopy
3 and 12 months
Mean giant capillaries of 8 fingers (dig 2-5)
Time Frame: 3 and 12 months
number per finger, assessed with nailfold capillary microscopy
3 and 12 months
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
3 and 12 months
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
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
Time Frame: 3 and 12 months
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
Time Frame: 3 and 12 months
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
Time Frame: 3 and 12 months
Measured by Laser Doppler Perfusion Imaging
3 and 12 months
Skin Autofluorescence
Time Frame: 3 and 12 months
assessed with the AGE Reader
3 and 12 months
Number of new digital ulcers
Time Frame: 3 and 12 months
Number
3 and 12 months
Time to healing of digital ulcers
Time Frame: 3 and 12 months
In days
3 and 12 months
Urine albumin/creatinine ratio (ACR)
Time Frame: 3 and 12 months
Measured in two separate morning samples of urine
3 and 12 months
Plasma N-terminal of the prohormone brain natriuretic peptide (NT-proBNP)
Time Frame: 3 and 12 months
assessed using a routine assay
3 and 12 months
Serum levels of matrix metalloproteinase 3
Time Frame: 3 and 12 months
measured according to the manufacturer's instructions
3 and 12 months
Serum levels of matrix metalloproteinases 9
Time Frame: 3 and 12 months
determined using in-house enzyme-linked immunosorbent assays (ELISAs)
3 and 12 months
Serum levels of tissue inhibitors of metalloproteinases (TIMP)
Time Frame: 3 and 12 months
determined using in-house enzyme-linked immunosorbent assays
3 and 12 months
Blood pressure of the brachial artery
Time Frame: 3 and 12 months
systolic/diastolic in mmHg
3 and 12 months
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.
3 and 12 months
Scleroderma Health Assessment Questionnaire (SHAQ)
Time Frame: 3 and 12 months
questionnaire
3 and 12 months
Short Form (36)
Time Frame: 3 and 12 months
questionnaire
3 and 12 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
University Medical Center Groningen

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
Actelion

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Andries J Smit, MDPhD, University Medical Center Groningen

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
June 26, 2015

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
July 30, 2018

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
July 30, 2018

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
June 15, 2015

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
June 19, 2015

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
June 24, 2015

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
December 13, 2018

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 11, 2018

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
December 1, 2018

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • NL49919.042.14

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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