Scleroderma, SystemicPhase 4CEASESTIFFNCT02480335
The Clinical And Subclinical Effects on Arterial Stiffness of Bosentan in Patients With Systemic Sclerosis
A Phase 4 study testing bosentan in people with Scleroderma, Systemic, run by University Medical Center Groningen at 1 site in Netherlands.
Trial 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). Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Scleroderma, Systemic
- What is being tested?
- bosentan
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 20 participants
- Where
- 1 siteNetherlands
- Study dates
- 26 Jun 2015to 30 Jul 2018
- Phase
- Phase 4
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Who cannot join
- 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
Trial locations and contacts
1 site in 1 country.
About this study
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
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.
Read the 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.
- Conditions
- Scleroderma, Systemic
- Being tested
- bosentan
- Medical subject headings
- Scleroderma, Systemic
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
bosentanDrug
Also called tracleer
62.5 mg oral twice daily for 4 weeks, then 125 mg oral twice daily.
| Study group | Role | What they receive |
|---|---|---|
| Usual care and bosentan | Experimental | Usual care and also treatment with bosentan. Receives: Drug: bosentan |
| Usual care | No intervention | Usual care only. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV)
assessed with Sphygmocor
Measured: 3 months
Secondary outcomes (31)
Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV)
assessed with Sphygmocor
Measured: 12 months
Right carotid-brachial arterial PWV (cbPWV)
assessed with Sphygmocor
Measured: 3 and 12 months
Left carotid-brachial arterial PWV (cbPWV)
assessed with Sphygmocor
Measured: 3 and 12 months
Right carotid-radial arterial PWV (crPWV)
assessed with Sphygmocor
Measured: 3 and 12 months
Left carotid-radial arterial PWV (crPWV)
assessed with Sphygmocor
Measured: 3 and 12 months
Local PWV of the right radial artery (rPWV)
ultrasound assessment using a MyLabOne Vascular machine
Measured: 3 and 12 months
Local PWV of the left radial artery (rPWV)
an ultrasound assessment using a MyLabOne Vascular machine
Measured: 3 and 12 months
Local PWV of the right brachial artery (bPWV)
an ultrasound assessment using a MyLabOne Vascular machine
Measured: 3 and 12 months
Local PWV of the left brachial artery (bPWV)
an ultrasound assessment using a MyLabOne Vascular machine
Measured: 3 and 12 months
Microangiopathy Evolution Score (MES)
With nailfold capillary microscopy
Measured: 3 and 12 months
Capillaroscopic Skin Ulcer Risk Index (CSURI)
With nailfold capillary microscopy
Measured: 3 and 12 months
Prognostic Index for Digital Lesions (PILD)
With nailfold capillary microscopy
Measured: 3 and 12 months
Mean widened capillaries of 8 fingers (dig 2-5)
number per finger, assessed with nailfold capillary microscopy
Measured: 3 and 12 months
Mean giant capillaries of 8 fingers (dig 2-5)
number per finger, assessed with nailfold capillary microscopy
Measured: 3 and 12 months
Mean capillary density of 8 fingers (dig 2-5)
number per mm per finger, assessed with nailfold capillary microscopy
Measured: 3 and 12 months
Mean loop width of 8 fingers (dig 2-5)
mm per capillary per finger, assessed with nailfold capillary microscopy
Measured: 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
Measured: 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
Measured: 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
Measured: 3 and 12 months
Skin Autofluorescence
assessed with the AGE Reader
Measured: 3 and 12 months
Number of new digital ulcers
Number
Measured: 3 and 12 months
Time to healing of digital ulcers
In days
Measured: 3 and 12 months
Urine albumin/creatinine ratio (ACR)
Measured in two separate morning samples of urine
Measured: 3 and 12 months
Plasma N-terminal of the prohormone brain natriuretic peptide (NT-proBNP)
assessed using a routine assay
Measured: 3 and 12 months
Serum levels of matrix metalloproteinase 3
measured according to the manufacturer's instructions
Measured: 3 and 12 months
Serum levels of matrix metalloproteinases 9
determined using in-house enzyme-linked immunosorbent assays (ELISAs)
Measured: 3 and 12 months
Serum levels of tissue inhibitors of metalloproteinases (TIMP)
determined using in-house enzyme-linked immunosorbent assays
Measured: 3 and 12 months
Blood pressure of the brachial artery
systolic/diastolic in mmHg
Measured: 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.
Measured: 3 and 12 months
Scleroderma Health Assessment Questionnaire (SHAQ)
questionnaire
Measured: 3 and 12 months
Short Form (36)
questionnaire
Measured: 3 and 12 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted24 Jun 2015 (estimated)
- Study start26 Jun 2015
- Primary completion30 Jul 2018
- Study completion30 Jul 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Scleroderma, SystemicStudies of the same condition, open and under way.
- More trials run by University Medical Center GroningenThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 20 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Collaborators
- Actelion
- Responsible party
- Principal investigator, dr. DJ Mulder, University Medical Center Groningen
- Investigators
- Andries J Smit, MDPhD, Principal investigator, University Medical Center Groningen
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02480335
- Sponsor's protocol ID
- NL49919.042.14
- Acronym
- CEASESTIFF
- Status last verified
- Dec 2018
- First submitted
- 15 Jun 2015
- Last updated
- 13 Dec 2018
- Results posted
- No
- Data monitoring committee
- No
Study at a glance
From the registry record, last updated by the sponsor on 13 Dec 2018. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02480335
- Acronym / sponsor ID
- CEASESTIFF / NL49919.042.14
- Conditions
- Scleroderma, Systemic
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 20 participants (actual)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Collaborators
- Actelion
- Study start
- 26 Jun 2015 (actual)
- Primary completion
- 30 Jul 2018 (actual)
- Study completion
- 30 Jul 2018 (actual)
- First posted
- 24 Jun 2015 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Usual care and bosentan | Experimental | Drug: bosentanUsual care and also treatment with bosentan. |
| Usual care | No intervention | –Usual care only. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (8 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| bosentanAlso: tracleer62.5 mg oral twice daily for 4 weeks, then 125 mg oral twice daily. | Drug | Usual care and bosentan |
Primary outcome
Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV)
Time frame: 3 months
assessed with Sphygmocor
31 secondary outcomes
Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV)
Time frame: 12 months
Right carotid-brachial arterial PWV (cbPWV)
Time frame: 3 and 12 months
Left carotid-brachial arterial PWV (cbPWV)
Time frame: 3 and 12 months
Right carotid-radial arterial PWV (crPWV)
Time frame: 3 and 12 months
Left carotid-radial arterial PWV (crPWV)
Time frame: 3 and 12 months
Local PWV of the right radial artery (rPWV)
Time frame: 3 and 12 months
Local PWV of the left radial artery (rPWV)
Time frame: 3 and 12 months
Local PWV of the right brachial artery (bPWV)
Time frame: 3 and 12 months
Local PWV of the left brachial artery (bPWV)
Time frame: 3 and 12 months
Microangiopathy Evolution Score (MES)
Time frame: 3 and 12 months
Capillaroscopic Skin Ulcer Risk Index (CSURI)
Time frame: 3 and 12 months
Prognostic Index for Digital Lesions (PILD)
Time frame: 3 and 12 months
Mean widened capillaries of 8 fingers (dig 2-5)
Time frame: 3 and 12 months
Mean giant capillaries of 8 fingers (dig 2-5)
Time frame: 3 and 12 months
Mean capillary density of 8 fingers (dig 2-5)
Time frame: 3 and 12 months
Mean loop width of 8 fingers (dig 2-5)
Time frame: 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
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
Blood flow in the hands in ROI 3: the hand proximal of the metacarpal joints
Time frame: 3 and 12 months
Skin Autofluorescence
Time frame: 3 and 12 months
Number of new digital ulcers
Time frame: 3 and 12 months
Time to healing of digital ulcers
Time frame: 3 and 12 months
Urine albumin/creatinine ratio (ACR)
Time frame: 3 and 12 months
Plasma N-terminal of the prohormone brain natriuretic peptide (NT-proBNP)
Time frame: 3 and 12 months
Serum levels of matrix metalloproteinase 3
Time frame: 3 and 12 months
Serum levels of matrix metalloproteinases 9
Time frame: 3 and 12 months
Serum levels of tissue inhibitors of metalloproteinases (TIMP)
Time frame: 3 and 12 months
Blood pressure of the brachial artery
Time frame: 3 and 12 months
Modified Rodnan Skin Score (mRSS)
Time frame: 3 and 12 months
Scleroderma Health Assessment Questionnaire (SHAQ)
Time frame: 3 and 12 months
Short Form (36)
Time frame: 3 and 12 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Dec 2018.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Andries J Smit, MDPhD principal investigator
University Medical Center Groningen
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing bosentan in people with Scleroderma, Systemic, run by University Medical Center Groningen at 1 site in Netherlands.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 8 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Dec 2018. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Netherlands. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Mean of right and left carotid-femoral arterial (i.e. aortic) Pulse Wave Velocity (cfPWV) (time frame: 3 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Dec 2018.