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    Clinical Trial Results:
    Effects of bosentan in a HOMogenEous population of SSc subjects with an early or active SSc nailfold capillaroscopic pattern (HOME II)

    Summary
    EudraCT number
    2011-005303-32
    Trial protocol
    NL  
    Global end of trial date
    03 Jun 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    04 Nov 2018
    First version publication date
    04 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-052-438
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Nederland bv
    Sponsor organisation address
    Beneluxlaan 2b, Woerden, Netherlands, 3446 GR
    Public contact
    Medical Director, Actelion Pharmaceuticals Nederland bv, sjansen8@its.jnj.com
    Scientific contact
    Medical Director, Actelion Pharmaceuticals Nederland bv, sjansen8@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Jun 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Evaluate the effect of bosentan on the blood flow in the hands from baseline to 12 weeks, measured by laser Doppler imaging, in SSc subjects with an early or active SSc pattern, measured with nailfold capillaroscopy (NFM), with ongoing digital ulcer disease and a history of DU disease in the past 2 years.
    Protection of trial subjects
    The clinical trial was designed and conducted in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, and with the ethical principles laid down in the Declaration of Helsinki.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    21 Mar 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 44
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    38
    From 65 to 84 years
    6
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Among the 55 screened patients, 44 were enrolled in the study.

    Pre-assignment
    Screening details
    Fifty-five patients with systemic sclerosis (SSc) and a history of digital ulcers (DU) in the past two years were screened by nailfold capillaroscopy (NFM) from seven sites in the Netherlands

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Bosentan
    Arm description
    All participants received bosentan for 3 months. They received 62.5 mg b.i.d of bosentan for the first 4 weeks followed by 125 mg b.i.d.during the next 8 weeks. Then they could continue to receive bosentan based on the clinical decision of the health care professional.
    Arm type
    Experimental

    Investigational medicinal product name
    Bosentan
    Investigational medicinal product code
    ACT-050088
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    tablets containing 62.5 mg or 125 mg of bosentan

    Number of subjects in period 1
    Bosentan
    Started
    44
    Completed
    33
    Not completed
    11
         Adverse event, non-fatal
    5
         subject abroad
    1
         Consent withdrawn by subject
    1
         Lost to follow-up
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    Overall trial

    Reporting group values
    Overall trial Total
    Number of subjects
    44
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50.5 ± 11.2 -
    Gender categorical
    Units:
        Male
    14 14
        Female
    30 30
    Systemic sclerosis (SSc) pattern
    Units: Subjects
        Early SSc pattern
    13 13
        Active SSc pattern
    31 31
    Systemic sclerosis (SSc) classification
    Units: Subjects
        Limited SSc
    38 38
        Diffuse SSc
    3 3
        Other
    3 3
    Digital ulcer (DU) status
    Units: Subjects
        None
    9 9
        Pitting scar
    19 19
        DU < 3 months
    7 7
        DU > 3 months
    9 9

    End points

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    End points reporting groups
    Reporting group title
    Bosentan
    Reporting group description
    All participants received bosentan for 3 months. They received 62.5 mg b.i.d of bosentan for the first 4 weeks followed by 125 mg b.i.d.during the next 8 weeks. Then they could continue to receive bosentan based on the clinical decision of the health care professional.

    Subject analysis set title
    Baseline efficacy data
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The baseline values of efficacy variables were used to assess the effects of bosentan on blood flow

    Subject analysis set title
    12-week efficacy data
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The values of efficacy variables at week 12 were compared to the baseline values for each subject because each subject was considered as his or her own control

    Primary: Change from baseline to week 12 in blood flow in the whole hand

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    End point title
    Change from baseline to week 12 in blood flow in the whole hand
    End point description
    Blood flow in the hands was measured by laser Doppler Imaging at baseline and after 12 weeks of treatment with bosentan.
    End point type
    Primary
    End point timeframe
    Baseline and Week 12
    End point values
    Baseline efficacy data 12-week efficacy data
    Number of subjects analysed
    44
    44
    Units: Perfusion units (PU)
        arithmetic mean (standard deviation)
    60.75 ± 21.26
    66.60 ± 25.93
    Statistical analysis title
    Change from baseline to Week 12 in hand blood flow
    Statistical analysis description
    Change from baseline in hand blood flow was evaluated with a mixed model analysis
    Comparison groups
    12-week efficacy data v Baseline efficacy data
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.052
    Method
    ANCOVA
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.066
         upper limit
    12.265
    Notes
    [1] - Each subject was considered as his/her own control (data at Week 12 were compared to baseline values for each subject). The blood flow of the hand was expected to be stable in time.

    Secondary: Change from baseline to week 12 in blood flow in fingertips (ROI1)

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    End point title
    Change from baseline to week 12 in blood flow in fingertips (ROI1)
    End point description
    A change in blood flow was measured by laser Doppler Imaging in different regions of interest of the hand (ROI), including the fingertips (ROI1)
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Baseline efficacy data 12-week efficacy data
    Number of subjects analysed
    44
    44
    Units: Perfusion units (PU)
        arithmetic mean (standard deviation)
    73.16 ± 32.45
    82.60 ± 38.80
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in blood flow in fingers (ROI2)

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    End point title
    Change from baseline to week 12 in blood flow in fingers (ROI2)
    End point description
    A change in blood flow was measured by laser Doppler Imaging in different regions of interest of the hand (ROI), including the fingers, excluding the tips (ROI2)
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Baseline efficacy data 12-week efficacy data
    Number of subjects analysed
    44
    44
    Units: Perfusion units (PU)
        arithmetic mean (standard deviation)
    63.29 ± 23.01
    69.83 ± 28.16
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in blood flow in the palms of the hands (ROI3)

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    End point title
    Change from baseline to week 12 in blood flow in the palms of the hands (ROI3)
    End point description
    A change in blood flow was measured by laser Doppler Imaging in different regions of interest of the hand (ROI), including the palms of the hands (ROI3).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Baseline efficacy data 12-week efficacy data
    Number of subjects analysed
    44
    44
    Units: Perfusion units (PU)
        arithmetic mean (standard deviation)
    57.66 ± 19.69
    62.61 ± 22.35
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in blood flow in the whole hand of patients who never received iloprost

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    End point title
    Change from baseline to week 12 in blood flow in the whole hand of patients who never received iloprost
    End point description
    Blood flow in the hands measured by laser Doppler Imaging was analyzed separately for subjects with no history of iloprost use.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Baseline efficacy data 12-week efficacy data
    Number of subjects analysed
    44
    44
    Units: Perfusion units
        arithmetic mean (standard deviation)
    60.10 ± 22.79
    68.01 ± 28.01
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in ROI1 blood flow of patients who never received iloprost

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    End point title
    Change from baseline to week 12 in ROI1 blood flow of patients who never received iloprost
    End point description
    ROI1 (fingertips) Blood flow measured by laser Doppler Imaging was analyzed separately for subjects with no history of iloprost use.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Baseline efficacy data 12-week efficacy data
    Number of subjects analysed
    44
    44
    Units: Perfusion units (PU)
        arithmetic mean (standard deviation)
    72.47 ± 32.84
    84.88 ± 39.53
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in ROI2 blood flow of patients who never received iloprost

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    End point title
    Change from baseline to week 12 in ROI2 blood flow of patients who never received iloprost
    End point description
    ROI2 (fingers, excluding tips) blood flow measured by laser Doppler Imaging was analyzed separately for subjects with no history of iloprost use.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Baseline efficacy data 12-week efficacy data
    Number of subjects analysed
    44
    44
    Units: Perfusion units (PU)
        arithmetic mean (standard deviation)
    62.45 ± 23.45
    69.07 ± 29.87
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in ROI3 blood flow of patients who never received iloprost

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    End point title
    Change from baseline to week 12 in ROI3 blood flow of patients who never received iloprost
    End point description
    ROI3 (hand palms) blood flow measured by laser Doppler Imaging was analyzed separately for subjects with no history of iloprost use.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Baseline efficacy data 12-week efficacy data
    Number of subjects analysed
    44
    44
    Units: Perfusion units (PU)
        arithmetic mean (standard deviation)
    56.26 ± 21.09
    63.70 ± 24.91
    No statistical analyses for this end point

    Secondary: Change from baseline to week 12 in number of digital ulcers and pitting scars

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    End point title
    Change from baseline to week 12 in number of digital ulcers and pitting scars
    End point description
    Photos were made of the hands of all patients using a digital camera to detect the presence of DUs or pitting scars. The sum of all DUs and pitting scars in all patients were reported at baseline and after 12 weeks of treatment with bosentan.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 12
    End point values
    Baseline efficacy data 12-week efficacy data
    Number of subjects analysed
    44
    44
    Units: Number
        Sum of all DUs
    23
    8
        Sum of pitting scars
    154
    133
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From study drug initiation up to 52 weeks of treatment (whole study period)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Bosentan
    Reporting group description
    43 Participants took at least one dose of bosentan, with 18 of them still on treatment at Week 52.

    Serious adverse events
    Bosentan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 43 (18.60%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Heart rate decreased
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic enzyme abnormal
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Vascular graft
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac pacemaker insertion
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Atrioventricular block
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Reduced vision
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Decreased appetite
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Bosentan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 43 (25.58%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Flushing
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Cardiac disorders
    Cyanosis
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Palpitations
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Anaemia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2
    Dizziness
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Drug ineffective
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Therapy non-responder
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Gastrointestinal disorders
    Oesophageal obstruction
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Dyspepsia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Dysphagia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Scar pain
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Fluid retention
         subjects affected / exposed
    1 / 43 (2.33%)
         occurrences all number
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    2 / 43 (4.65%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 May 2012
    The main reason was to increase the time window of visit at Week 12 from +/- 5 days to +/- 7 days.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to slow recruitment the study was prematurely terminated and the long term effects of bosentan on vasculopathy and other secondary endpoints could not be assessed.
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