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    Clinical Trial Results:
    Prospective, randomized, placebo-controlled, double-blind, multicenter, parallel-group study to assess the efficacy, safety, and tolerability of macitentan in patients with ischemic digital ulcers associated with systemic sclerosis (DUAL-1)

    Summary
    EudraCT number
    2010-022710-77
    Trial protocol
    DE   HU   CZ   DK   BG   FI   IT   PL  
    Global end of trial date
    29 Nov 2013

    Results information
    Results version number
    v2(current)
    This version publication date
    07 Nov 2019
    First version publication date
    07 Aug 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Change of Sponsor

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    AC-055C301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01474109
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd.
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Clinical Trials Disclosure Desk, Actelion Pharmaceuticals Ltd., clinical-trials-disclosure@actelion.com
    Scientific contact
    Clinical Trials Disclosure Desk, Actelion Pharmaceuticals Ltd., clinical-trials-disclosure@actelion.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
    20 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Nov 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Nov 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the effect of macitentan on the reduction of the number of new digital ulcers in patients with systemic sclerosis and ongoing digital ulcer disease.
    Protection of trial subjects
    This study was conducted in full conformance with the principles of the ‘Declaration of Helsinki’, with the ICH Guidelines on Good Clinical Practice (GCP), and with the laws and regulations of the country in which the research was conducted. Written informed consent was obtained from each individual participating in the study prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study. It was made clear to each subject that he or she was completely free to refuse to enter the study, or to withdraw from it at any time for any reason. A 3-member Independent Data Monitoring Committee (IDMC) reviewed unblinded efficacy and safety data on a regular basis to ensure patient safety. The IDMC was empowered to recommend modifications to the protocol to enhance patient safety or early termination of the study if major concerns arose regarding patient safety at any time during the course of this or any other study with macitentan. An independent International Liver Safety Board (ILSB), an external expert committee of 3 hepatologists organized by Actelion Global Drug Safety (GDS), provided assessment and advice regarding hepatic events at the request of the Sponsor.
    Background therapy
    Allowed concomitant therapy • Patients’ usual treatments for DUs. Treatments with vasodilators (including calcium channel blockers, ACE-inhibitors, nitroglycerin, alpha adrenergic blockers, angiotensin II receptor antagonists), N-acetylcysteine, antiplatelet aggregation therapy, and low molecular weight heparin were to be administered at a stable dose for at least 2 weeks prior to screening and during Period 1. During Period 2, dose adjustments of these treatments were discouraged but may have been justified for the treatment of Raynaudʼs phenomenon. • Analgesics given for DU pain or for any other reason. Receipt of analgesics and any dose adjustments during the study was to be recorded in a patient diary. • Topical treatments for DUs such as antiseptics, antibiotics, nitrate ointment, protective ointments, etc. (except for growth factors, hyperbaric oxygen). Topical treatments were to be recorded in the concomitant medication section of the eCRF. • Statins (e.g., atorvastatin, simvastatin) that had been administered at a stable dose for at least 3 months prior to screening and were to remain unchanged during the study. • Disease modifying treatments (e.g., methotrexate, cyclophosphamide) that had been administered for at least 3 months and at a stable dose for at least 1 month prior to screening and was to remain unchanged during the study. • Systemic antibiotics (oral or i.v.). Systemic antibiotics for the treatment of DUs within the 4 weeks prior to screening was an exclusion criterion to exclude patients who had recalcitrant, chronic, hard-to-heal ulcers that were not amenable to healing. However, during the study, systemic antibiotics were allowed. Initiation of systemic antibiotics for the treatment of infection attributed to DUs was reported as a DU complication.
    Evidence for comparator
    -
    Actual start date of recruitment
    11 Jan 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
    United States: 37
    Country: Number of subjects enrolled
    Ukraine: 22
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Russian Federation: 21
    Country: Number of subjects enrolled
    Poland: 11
    Country: Number of subjects enrolled
    Croatia: 10
    Country: Number of subjects enrolled
    Colombia: 3
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    India: 13
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Hungary: 14
    Country: Number of subjects enrolled
    Chile: 17
    Country: Number of subjects enrolled
    Bulgaria: 46
    Country: Number of subjects enrolled
    Belarus: 11
    Country: Number of subjects enrolled
    Australia: 28
    Country: Number of subjects enrolled
    Germany: 27
    Worldwide total number of subjects
    289
    EEA total number of subjects
    131
    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)
    245
    From 65 to 84 years
    44
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Conducted at 70 centers in 17 countries. First patient randomized was 11 January 2012 and last patient, last visit was 29 November 2013.

    Pre-assignment
    Screening details
    A screening visit was performed between Day −14 and Day −1 of the study. Of the 327 patients screened for the study, 38 were screen failures.

    Period 1
    Period 1 title
    Period 1: Baseline to Week 16
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Data analyst, Carer, Subject
    Blinding implementation details
    To ensure double-blind conditions, each dose strength of the investigational drug and its matching placebo were indistinguishable with respect to appearance, taste, weight, and shape, and all medication bottles were identically packaged and labeled

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Macitentan 3 mg
    Arm description
    macitentan 3 mg once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 mg tablet once daily

    Arm title
    Placebo
    Arm description
    placebo once daily
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    matching placebo once daily

    Arm title
    Macitentan 10 mg
    Arm description
    macitentan 10 mg once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet once daily

    Number of subjects in period 1
    Macitentan 3 mg Placebo Macitentan 10 mg
    Started
    95
    97
    97
    Completed
    88
    95
    91
    Not completed
    7
    2
    6
         See "Overall Study" for details
    7
    2
    6
    Period 2
    Period 2 title
    Period 2: Week 16 to End of Study
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    To ensure double-blind conditions, each dose strength of the investigational drug and its matching placebo were indistinguishable with respect to appearance, taste, weight, and shape, and all medication bottles were identically packaged and labeled

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Macitentan 3 mg
    Arm description
    macitentan 3 mg once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 mg tablet once daily

    Arm title
    Macitentan 10 mg
    Arm description
    macitentan 10 mg once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet once daily

    Arm title
    Placebo
    Arm description
    matching placebo once daily
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    matching placebo once daily

    Number of subjects in period 2
    Macitentan 3 mg Macitentan 10 mg Placebo
    Started
    88
    91
    95
    Completed
    70
    73
    83
    Not completed
    18
    18
    12
         See "Overall Study" for details
    18
    18
    12
    Period 3
    Period 3 title
    Baseline period
    Is this the baseline period?
    Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    To ensure double-blind conditions, each dose strength of the investigational drug and its matching placebo were indistinguishable with respect to appearance, taste, weight, and shape, and all medication bottles were identically packaged and labeled

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Macitentan 3 mg
    Arm description
    Macitentan 3 mg
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 mg tablet once daily

    Arm title
    Macitentan 10 mg
    Arm description
    Macitentan 10 mg
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet once daily

    Arm title
    Placebo
    Arm description
    Placebo
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    matching placebo once daily

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: ...
    Number of subjects in period 3
    Macitentan 3 mg Macitentan 10 mg Placebo
    Started
    95
    97
    97
    Completed
    95
    97
    97
    Period 4
    Period 4 title
    Patients who completed study treatment
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    To ensure double-blind conditions, each dose strength of the investigational drug and its matching placebo were indistinguishable with respect to appearance, taste, weight, and shape, and all medication bottles were identically packaged and labeled

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Macitentan 3 mg
    Arm description
    Macitentan 3 mg once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan 3 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    3 mg tablet once daily

    Arm title
    Macitentan 10 mg
    Arm description
    Macitentan 10 mg once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg tablet once daily

    Arm title
    Placebo
    Arm description
    Placebo once daily
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    matching placebo once daily

    Number of subjects in period 4 [2]
    Macitentan 3 mg Macitentan 10 mg Placebo
    Started
    94
    97
    97
    Completed
    62
    69
    74
    Not completed
    32
    28
    23
         Physician decision
    1
    1
    -
         Non-compliance
    1
    -
    -
         Adverse event, serious fatal
    -
    1
    -
         Adverse event, non-fatal
    12
    14
    10
         Consent withdrawn by subject
    6
    3
    1
         Administrative
    -
    1
    -
         Patient decision
    11
    6
    12
         Lost to follow-up
    1
    2
    -
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: ...

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Macitentan 3 mg
    Reporting group description
    Macitentan 3 mg

    Reporting group title
    Macitentan 10 mg
    Reporting group description
    Macitentan 10 mg

    Reporting group title
    Placebo
    Reporting group description
    Placebo

    Reporting group values
    Macitentan 3 mg Macitentan 10 mg Placebo Total
    Number of subjects
    95 97 97 289
    Age categorical
    Age categorical description
    Units: participants
        Between 18 and 65 years
    77 84 84 245
        >=65 years
    18 13 13 44
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    51.4 ± 14.44 51.6 ± 11.1 50.6 ± 12.12 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    84 81 83 248
        Male
    11 16 14 41
    Race/Ethnicity, Customized
    Units: Subjects
        White
    86 82 88 256
        Black or African American
    0 3 1 4
        Asian
    5 6 4 15
        Hispanic
    3 4 3 10
        Other
    1 2 1 4
    Region of Enrollment
    Units: Subjects
        Australia
    10 9 9 28
        Belarus
    3 3 5 11
        Bulgaria
    13 16 17 46
        Canada
    1 3 2 6
        Chile
    6 7 4 17
        Colombia
    0 2 1 3
        Croatia
    3 1 6 10
        Czech Republic
    6 3 5 14
        France
    0 0 1 1
        Germany
    9 7 11 27
        Hungary
    4 7 3 14
        India
    4 5 4 13
        Italy
    3 3 2 8
        Poland
    5 3 3 11
        Russian Federation
    6 7 8 21
        Ukraine
    10 5 7 22
        United States
    12 16 9 37
    Subject analysis sets

    Subject analysis set title
    Per-protocol (PP) set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    This analysis set comprised all patients in the mITT set until the occurrence of a major protocol deviation that affected the evaluation of the effect of study treatment on the primary endpoint. The protocol deviations affecting this set were identified before database lock. Patients were excluded from the PP set if they did not meet any of the following entry criteria: • Diagnosis of limited or diffuse SSc according to the ACR classification or met the criteria for CREST syndrome. • Active DU according to protocol-defined qualifications. • History of at least 1 additional active ischemic DU up to 6 months, or at least 2 up to 12 months prior to screening. • No DUs due to conditions other than SSc. • No comorbidities, other than SSc, that could seriously affect the assessment of hand function. In addition, patients who received a study treatment different from that randomized were excluded from the PP set. Measurements after the occurrence of any of the following deviations in study

    Subject analysis set title
    Modified intent-to-treat (mITT) set
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    This analysis set included all patients in the Full analysis set who received at least one dose of study treatment and had at least one post-baseline primary efficacy assessment (i.e., an on-treatment post-baseline DU assessment during Period 1). Assignment to treatment arms was as randomized, regardless of the actual treatment received

    Subject analysis set title
    Safety set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This analysis set included all patients who received at least one dose of study treatment (definition modified with Amendment 2. Assignment to treatment arms was as treated, regardless of the randomization allocation, according to the following algorithm: • Patients who were dispensed macitentan 10 mg at least once were assigned to the macitentan 10 mg arm. • Patients who were dispensed macitentan 3 mg at least once, but not macitentan 10 mg, were assigned to the macitentan 3 mg arm.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This analysis set included all randomized patients as identified in the IVRS dataset. Assignment to treatment arms was as randomized, regardless of the treatment received. This analysis set was added in the SAP to use for the main analysis of the primary endpoint, in line with the intention-to-treat principle as per ICH E9.

    Subject analysis sets values
    Per-protocol (PP) set Modified intent-to-treat (mITT) set Safety set Full analysis set
    Number of subjects
    278
    278
    288
    289
    Age categorical
    Age categorical description
    Units: participants
        Between 18 and 65 years
    245
        >=65 years
    44
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    ±
    ±
    ±
    51.2 ± 12.58
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    248
        Male
    41
    Race/Ethnicity, Customized
    Units: Subjects
        White
    256
        Black or African American
    4
        Asian
    15
        Hispanic
    10
        Other
    4
    Region of Enrollment
    Units: Subjects
        Australia
    28
        Belarus
    11
        Bulgaria
    46
        Canada
    6
        Chile
    17
        Colombia
    3
        Croatia
    10
        Czech Republic
    14
        France
    1
        Germany
    27
        Hungary
    14
        India
    13
        Italy
    8
        Poland
    11
        Russian Federation
    21
        Ukraine
    22
        United States
    37

    End points

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    End points reporting groups
    Reporting group title
    Macitentan 3 mg
    Reporting group description
    macitentan 3 mg once daily

    Reporting group title
    Placebo
    Reporting group description
    placebo once daily

    Reporting group title
    Macitentan 10 mg
    Reporting group description
    macitentan 10 mg once daily
    Reporting group title
    Macitentan 3 mg
    Reporting group description
    macitentan 3 mg once daily

    Reporting group title
    Macitentan 10 mg
    Reporting group description
    macitentan 10 mg once daily

    Reporting group title
    Placebo
    Reporting group description
    matching placebo once daily
    Reporting group title
    Macitentan 3 mg
    Reporting group description
    Macitentan 3 mg

    Reporting group title
    Macitentan 10 mg
    Reporting group description
    Macitentan 10 mg

    Reporting group title
    Placebo
    Reporting group description
    Placebo
    Reporting group title
    Macitentan 3 mg
    Reporting group description
    Macitentan 3 mg once daily

    Reporting group title
    Macitentan 10 mg
    Reporting group description
    Macitentan 10 mg once daily

    Reporting group title
    Placebo
    Reporting group description
    Placebo once daily

    Subject analysis set title
    Per-protocol (PP) set
    Subject analysis set type
    Per protocol
    Subject analysis set description
    This analysis set comprised all patients in the mITT set until the occurrence of a major protocol deviation that affected the evaluation of the effect of study treatment on the primary endpoint. The protocol deviations affecting this set were identified before database lock. Patients were excluded from the PP set if they did not meet any of the following entry criteria: • Diagnosis of limited or diffuse SSc according to the ACR classification or met the criteria for CREST syndrome. • Active DU according to protocol-defined qualifications. • History of at least 1 additional active ischemic DU up to 6 months, or at least 2 up to 12 months prior to screening. • No DUs due to conditions other than SSc. • No comorbidities, other than SSc, that could seriously affect the assessment of hand function. In addition, patients who received a study treatment different from that randomized were excluded from the PP set. Measurements after the occurrence of any of the following deviations in study

    Subject analysis set title
    Modified intent-to-treat (mITT) set
    Subject analysis set type
    Modified intention-to-treat
    Subject analysis set description
    This analysis set included all patients in the Full analysis set who received at least one dose of study treatment and had at least one post-baseline primary efficacy assessment (i.e., an on-treatment post-baseline DU assessment during Period 1). Assignment to treatment arms was as randomized, regardless of the actual treatment received

    Subject analysis set title
    Safety set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This analysis set included all patients who received at least one dose of study treatment (definition modified with Amendment 2. Assignment to treatment arms was as treated, regardless of the randomization allocation, according to the following algorithm: • Patients who were dispensed macitentan 10 mg at least once were assigned to the macitentan 10 mg arm. • Patients who were dispensed macitentan 3 mg at least once, but not macitentan 10 mg, were assigned to the macitentan 3 mg arm.

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This analysis set included all randomized patients as identified in the IVRS dataset. Assignment to treatment arms was as randomized, regardless of the treatment received. This analysis set was added in the SAP to use for the main analysis of the primary endpoint, in line with the intention-to-treat principle as per ICH E9.

    Primary: Cumulative number of new digital ulcers (DUs) up to week 16 (NB-2 model adjusted)

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    End point title
    Cumulative number of new digital ulcers (DUs) up to week 16 (NB-2 model adjusted)
    End point description
    DUs were assessed at each visit starting with the screening visit. Only DUs from the proximal interphalangeal joint distally (both on the dorsal and volar surface of the hand, including the digital tip) were recorded. The location of each DU was noted. At each subsequent visit the location of each new DU was noted. DUs that occurred and healed between visits and were reported by patients were not recorded as new DUs. The evaluation was performed by an experienced physician or a trained rater with expertise in the assessment of DUs. For a given patient, DUs were assessed by the same rater at each visit, whenever possible. Any DU that developed over a previously healed ulcer was recorded as a new DU. Incidence rate is adjusted for 16 weeks of observation, hence is calculated as the number of new DUs/total number of observation days. Note that NB-2 model estimates are presented. Measures are adjusted by the stratification factor (number of DUs at BL <=3 vs >3) by the model.
    End point type
    Primary
    End point timeframe
    Baseline to week 16
    End point values
    Macitentan 3 mg Placebo Macitentan 10 mg
    Number of subjects analysed
    95
    97
    97
    Units: Number of new DUs/observation days
        number (not applicable)
    0.94
    0.852
    1.081
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Macitentan 3 mg
    Number of subjects included in analysis
    192
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0.706
    Method
    negative binomial-2 regression (NB-2)
    Parameter type
    NB-2 estimate of new DUs per patient
    Point estimate
    1.103
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.663
         upper limit
    1.834
    Notes
    [1] - Negative binomial-2 regression (NB-2) on Full Analysis set
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Macitentan 10 mg
    Number of subjects included in analysis
    194
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    = 0.36
    Method
    negative binomial-2 regression (NB-2)
    Parameter type
    NB-2 estimate of new DUs per patient
    Point estimate
    1.268
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.763
         upper limit
    2.106
    Notes
    [2] - Negative binomial-2 regression (NB-2) on Full Analysis set

    Secondary: Percentage of participants without a new DU up to week 16

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    End point title
    Percentage of participants without a new DU up to week 16
    End point description
    DUs were assessed at each visit starting with the screening visit. Only DUs from the proximal interphalangeal joint (PIP) distally (both on the dorsal and volar surface of the hand, including the digital tip) were recorded. The location of each DU was noted. At each subsequent visit the location of each new DU was noted. DUs that occurred and healed between visits and were reported by patients were not recorded as new DUs. The evaluation was performed by an experienced physician or a trained rater with expertise in the assessment of DUs in systemic sclerosis (SSc). For a given patient, DUs were assessed by the same rater at each visit, whenever possible. Any DU that developed over a previously healed ulcer was recorded as a new DU. Numbers of patients with no new DU at Week 16 are imputed using the last observation carried forward method.
    End point type
    Secondary
    End point timeframe
    Baseline to week 16
    End point values
    Macitentan 3 mg Placebo Macitentan 10 mg
    Number of subjects analysed
    92
    94
    92
    Units: Percentage of participants
        number (not applicable)
    64.1
    67
    63
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Macitentan 3 mg
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0.667
    Method
    Chi-squared
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.875
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.477
         upper limit
    1.606
    Notes
    [3] - Chi-squared analysis on mITT analysis set
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Macitentan 10 mg
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    other [4]
    P-value
    = 0.5518
    Method
    Chi-squared
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.832
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.454
         upper limit
    1.524
    Notes
    [4] - Chi-squared analysis on mITT analysis set

    Secondary: Percentage of participants with at least one DU complication

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    End point title
    Percentage of participants with at least one DU complication
    End point description
    DU complications were defined as any one of the following, resulting from DU worsening: critical ischemic crisis necessitating hospitalization; gangrene, (auto)amputation; failure of conservative management; surgical and chemical sympathectomy, vascular reconstructions, or any unplanned surgery in the management of hand SSc manifestations; use of parenteral prostanoids; use of endothelin-receptor antagonists; class II, III, or IV narcotics or a > 50% increase in the existing dose compared with baseline; initiation of systemic antibiotics for the treatment of infection attributed to DUs.
    End point type
    Secondary
    End point timeframe
    Up to approximately 90 weeks
    End point values
    Macitentan 3 mg Placebo Macitentan 10 mg
    Number of subjects analysed
    92
    94
    92
    Units: percentage of participants
        number (not applicable)
    14.1
    19.1
    19.6
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Macitentan 3 mg v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    other [5]
    P-value
    = 0.3625
    Method
    Chi-squared
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.696
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.319
         upper limit
    1.518
    Notes
    [5] - Chi-squared analysis on mITT analysis set
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0.9362
    Method
    Chi-squared
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.03
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.498
         upper limit
    2.133
    Notes
    [6] - Chi-squared analysis on mITT analysis set

    Secondary: Change in Hand Functionality Health Assessment Questionnaire – Disability Index (HAQ-DI) Hand Component from baseline to Week 16

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    End point title
    Change in Hand Functionality Health Assessment Questionnaire – Disability Index (HAQ-DI) Hand Component from baseline to Week 16
    End point description
    HAQ-DI assesses functional ability regarding fine movements of the upper extremities, locomotor activities in the lower extremities, and movements of the upper and lower limbs. Responses were extracted from the Scleroderma Health Assessment Questionnaire covering 8 domains of functional disability (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other daily activities). A mean score ranging from 0-3 was calculated for each domain, and a composite score by dividing the summed domain scores by the number of domains. The composite score was interpreted as 0 (no impairment in function) to 3 (maximal impairment of function). Hand functionality was assessed using a composite of 4 domains (dressing and grooming, grip, hygiene, and eating). Note that the last observation carried forward (LOCF) approach was applied for Week 16 data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16 (LOCF)
    End point values
    Macitentan 3 mg Placebo Macitentan 10 mg
    Number of subjects analysed
    92
    94
    92
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    1.3 ± 0.73
    1.3 ± 0.68
    1.4 ± 0.7
        Week 16 (LOCF)
    1.2 ± 0.79
    1.2 ± 0.73
    1.2 ± 0.66
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Macitentan 3 mg
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    other [7]
    P-value
    = 0.863
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.1
         upper limit
    0.2
    Notes
    [7] - ANCOVA on mITT analysis set
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Macitentan 10 mg
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    other [8]
    P-value
    = 0.649
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [8] - ANCOVA on mITT analysis set

    Secondary: Health Assessment Questionnaire – Disability Index (HAQ-DI) Overall Score from baseline to Week 16

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    End point title
    Health Assessment Questionnaire – Disability Index (HAQ-DI) Overall Score from baseline to Week 16
    End point description
    HAQ-DI assesses functional ability regarding fine movements of the upper extremities, locomotor activities in the lower extremities, and movements of the upper and lower limbs. Responses were extracted from the Scleroderma Health Assessment Questionnaire covering 8 domains of functional disability (dressing and grooming, arising, eating, walking, hygiene, reach, grip, and other daily activities). A mean score ranging from 0-3 was calculated for each domain, and a composite score by dividing the summed domain scores by the number of domains. The composite score was interpreted as 0 (no impairment in function) to 3 (maximal impairment of function). Note that the last observation carried forward (LOCF) approach was applied for Week 16 data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16 (LOCF)
    End point values
    Macitentan 3 mg Placebo Macitentan 10 mg
    Number of subjects analysed
    92
    94
    92
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    1.1 ± 0.71
    1.1 ± 0.62
    1.2 ± 0.66
        Week 16 (LOCF)
    1.1 ± 0.73
    1.1 ± 0.67
    1.1 ± 0.64
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Placebo v Macitentan 3 mg
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    other [9]
    P-value
    = 0.456
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [9] - ANCOVA on mITT analysis set
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Placebo v Macitentan 10 mg
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    other [10]
    P-value
    = 0.44
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.2
         upper limit
    0.1
    Notes
    [10] - ANCOVA on mITT analysis set

    Secondary: Change in hand functionality - Hand Disability in Systemic Sclerosis – Digital Ulcers (HDISS-DU) score from baseline to Week 16

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    End point title
    Change in hand functionality - Hand Disability in Systemic Sclerosis – Digital Ulcers (HDISS-DU) score from baseline to Week 16
    End point description
    Patients were asked to answer 24 questions on the use of the hand(s) affected by DUs over the past 7 days on a 6-point scale from 0 (yes without difficulty) to 5 (impossible). The HDISS-DU score is the arithmetic mean of the valid non-missing items. The scores are interpreted as 1 (better ability in completing activities) to 6 (worst ability in completing activities). Note that the last observation carried forward (LOCF) approach was applied for Week 16 data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16 (LOCF)
    End point values
    Macitentan 3 mg Placebo Macitentan 10 mg
    Number of subjects analysed
    92
    94
    92
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    3 ± 1.15
    3 ± 1.09
    3 ± 1.09
        Week 16 (LOCF)
    2.7 ± 1.14
    2.7 ± 1.1
    2.6 ± 0.99
    Statistical analysis title
    Statistical analysis 2
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    other [11]
    P-value
    = 0.342
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.1
    Notes
    [11] - ANCOVA on mITT analysis set
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Macitentan 3 mg v Placebo
    Number of subjects included in analysis
    186
    Analysis specification
    Pre-specified
    Analysis type
    other [12]
    P-value
    = 0.464
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.3
         upper limit
    0.1
    Notes
    [12] - ANCOVA on mITT analysis set

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study treatment up to 30 days after treatment discontinuation, up to approximately 90 weeks.
    Adverse event reporting additional description
    Safety analysis set. One patient was excluded in the safety analysis set as the patient did not receive study drug after randomisation.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Macitentan 3 mg
    Reporting group description
    Macitentan 3 mg tablet once daily

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo once daily

    Reporting group title
    Macitentan 10 mg
    Reporting group description
    Macitentan 10 mg tablet once daily

    Serious adverse events
    Macitentan 3 mg Placebo Macitentan 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    17 / 94 (18.09%)
    13 / 97 (13.40%)
    14 / 97 (14.43%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    GRANULOMATOSIS WITH POLYANGIITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NECROSIS ISCHAEMIC
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOTENSION
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ISCHAEMIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ARTERIAL OCCLUSIVE DISEASE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RAYNAUD'S PHENOMENON
         subjects affected / exposed
    1 / 94 (1.06%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    EXTREMITY NECROSIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    PROSTATIC OPERATION
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-CELL LYMPHOMA
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    METASTATIC BRONCHIAL CARCINOMA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHEST PAIN
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    CONFUSIONAL STATE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    UTERINE PROLAPSE
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    POST PROCEDURAL HAEMORRHAGE
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    CARDIAC ARREST
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    ACUTE CORONARY SYNDROME
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    VENTRICULAR EXTRASYSTOLES
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PLEUROPERICARDITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANGINA PECTORIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ANGINA UNSTABLE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FIBRILLATION
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ATRIAL FLUTTER
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL ISCHAEMIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    MYOCARDIAL FIBROSIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERICARDITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    PNEUMONIA ASPIRATION
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYDROTHORAX
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PULMONARY CONGESTION
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    NEURALGIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LOSS OF CONSCIOUSNESS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GASTRITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    RENAL FAILURE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    URINARY INCONTINENCE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEPHROTIC SYNDROME
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SCLERODERMA RENAL CRISIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL DISORDER
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    SKIN ULCER
         subjects affected / exposed
    3 / 94 (3.19%)
    3 / 97 (3.09%)
    2 / 97 (2.06%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    DRY GANGRENE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LEUKOCYTOCLASTIC VASCULITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERKERATOSIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    INTERVERTEBRAL DISC PROTRUSION
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LUMBAR SPINAL STENOSIS
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SYSTEMIC SCLEROSIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEONECROSIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SCLERODERMA
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DIABETES MELLITUS INADEQUATE CONTROL
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FAILURE TO THRIVE
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPOGLYCAEMIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    INFECTED SKIN ULCER
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    3 / 97 (3.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    2 / 94 (2.13%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE COLITIS
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BACTERIAL SEPSIS
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CLOSTRIDIUM DIFFICILE INFECTION
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SEPSIS
         subjects affected / exposed
    0 / 94 (0.00%)
    0 / 97 (0.00%)
    1 / 97 (1.03%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GANGRENE
         subjects affected / exposed
    3 / 94 (3.19%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHOPNEUMONIA
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ERYSIPELAS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SINUSITIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMOCOCCAL SEPSIS
         subjects affected / exposed
    1 / 94 (1.06%)
    0 / 97 (0.00%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OESOPHAGEAL CANDIDIASIS
         subjects affected / exposed
    0 / 94 (0.00%)
    1 / 97 (1.03%)
    0 / 97 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Macitentan 3 mg Placebo Macitentan 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    61 / 94 (64.89%)
    69 / 97 (71.13%)
    73 / 97 (75.26%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    2 / 94 (2.13%)
    1 / 97 (1.03%)
    6 / 97 (6.19%)
         occurrences all number
    2
    1
    6
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    3 / 94 (3.19%)
    1 / 97 (1.03%)
    5 / 97 (5.15%)
         occurrences all number
    5
    1
    5
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    4 / 94 (4.26%)
    7 / 97 (7.22%)
    8 / 97 (8.25%)
         occurrences all number
    6
    9
    11
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    14 / 94 (14.89%)
    12 / 97 (12.37%)
    19 / 97 (19.59%)
         occurrences all number
    19
    19
    22
    DIZZINESS
         subjects affected / exposed
    4 / 94 (4.26%)
    2 / 97 (2.06%)
    5 / 97 (5.15%)
         occurrences all number
    4
    2
    5
    General disorders and administration site conditions
    OEDEMA PERIPHERAL
         subjects affected / exposed
    7 / 94 (7.45%)
    6 / 97 (6.19%)
    12 / 97 (12.37%)
         occurrences all number
    7
    7
    12
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    6 / 94 (6.38%)
    7 / 97 (7.22%)
    5 / 97 (5.15%)
         occurrences all number
    8
    9
    6
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    0 / 94 (0.00%)
    5 / 97 (5.15%)
    6 / 97 (6.19%)
         occurrences all number
    0
    5
    7
    NAUSEA
         subjects affected / exposed
    5 / 94 (5.32%)
    6 / 97 (6.19%)
    4 / 97 (4.12%)
         occurrences all number
    5
    7
    4
    Skin and subcutaneous tissue disorders
    SKIN ULCER
         subjects affected / exposed
    6 / 94 (6.38%)
    9 / 97 (9.28%)
    8 / 97 (8.25%)
         occurrences all number
    8
    12
    9
    Musculoskeletal and connective tissue disorders
    BACK PAIN
         subjects affected / exposed
    3 / 94 (3.19%)
    3 / 97 (3.09%)
    5 / 97 (5.15%)
         occurrences all number
    4
    3
    5
    ARTHRALGIA
         subjects affected / exposed
    6 / 94 (6.38%)
    7 / 97 (7.22%)
    4 / 97 (4.12%)
         occurrences all number
    8
    7
    4
    PAIN IN EXTREMITY
         subjects affected / exposed
    4 / 94 (4.26%)
    6 / 97 (6.19%)
    4 / 97 (4.12%)
         occurrences all number
    4
    6
    6
    Infections and infestations
    INFECTED SKIN ULCER
         subjects affected / exposed
    7 / 94 (7.45%)
    11 / 97 (11.34%)
    12 / 97 (12.37%)
         occurrences all number
    11
    15
    22
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    3 / 94 (3.19%)
    4 / 97 (4.12%)
    7 / 97 (7.22%)
         occurrences all number
    4
    4
    8
    BRONCHITIS
         subjects affected / exposed
    7 / 94 (7.45%)
    5 / 97 (5.15%)
    1 / 97 (1.03%)
         occurrences all number
    10
    8
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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.
    Mean number of new DUs over 16 wks was lower than historic observations. Up to 60% of pts did not develop any new DUs. Epidemiology of DUs in SSc may be changing, reflective of earlier diagnosis, better wound care, greater availability of treatments.
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