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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-2)

    Summary
    EudraCT number
    2010-022969-95
    Trial protocol
    GB   DE   IE   ES   BE   NL   PT   PL   GR  
    Global end of trial date
    02 Feb 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Jul 2016
    First version publication date
    07 Aug 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055C302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01474122
    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
    26 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    02 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Feb 2014
    Was the trial ended prematurely?
    Yes
    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 (DUs) in patients with systemic sclerosis (SSc) and ongoing DU disease
    Protection of trial subjects
    Prior to the start of the trial, each study center consulted an Independent Ethics Committee (IEC) or Institutional Review Board (IRB), i.e., a review panel that was responsible for ensuring the protection of the rights, safety, and well-being of human subjects involved in a clinical investigation. The investigator ensured that this study was conducted in full conformance with the principles of the ‘Declaration of Helsinki’ (and its amendments) and with the laws and regulations of the country in which the clinical research was conducted. The study was to be conducted according to International Committee on Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and, if applicable, the US Code of Federal Regulations (CFR) and other GCP guidelines. Documentary evidence of adequate GCP training of the investigator was collected prior to site initiation. Both Actelion and the investigator had the right to terminate the study at any time and, in such a case, were responsible for protecting the patients’ interests.
    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 intravenous). 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
    09 Feb 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
    Argentina: 18
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    China: 11
    Country: Number of subjects enrolled
    Colombia: 14
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Greece: 11
    Country: Number of subjects enrolled
    Ireland: 4
    Country: Number of subjects enrolled
    Israel: 24
    Country: Number of subjects enrolled
    Mexico: 21
    Country: Number of subjects enrolled
    Netherlands: 6
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Puerto Rico: 2
    Country: Number of subjects enrolled
    Russian Federation: 16
    Country: Number of subjects enrolled
    South Africa: 9
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    Ukraine: 20
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    United States: 48
    Worldwide total number of subjects
    265
    EEA total number of subjects
    75
    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)
    234
    From 65 to 84 years
    31
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Conducted at 73 centers in 20 countries.The first patient randomized was 9 Feb 2012 and last patient, last visit was 6 Feb 2014

    Pre-assignment
    Screening details
    A screening visit was performed between Day −14 and Day −1 of the study. Of the 324 patients screened for the study, 59 were screen failures.

    Period 1
    Period 1 title
    Baseline period
    Is this the baseline period?
    Yes
    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 tablet 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
    Macitentan tablet 3 mg once daily

    Arm title
    Placebo
    Arm description
    Matching 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

    Arm title
    Macitentan 10 mg
    Arm description
    Macitentan tablet 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
    Macitentan tablet 10 mg once daily

    Number of subjects in period 1
    Macitentan 3 mg Placebo Macitentan 10 mg
    Started
    88
    89
    88
    Completed
    88
    89
    88
    Period 2
    Period 2 title
    Period 1: Baseline to Week 16
    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. IMPORTANT NOTE for "Period Milestone Achievement": Overall Period 1&2: Administrative: 1-0-2; AE nonfatal: 8-15-13; Lost to follow-up:1-0-1; Non-conformity: 0-0-1; Pat. dec.: 10-1-4; Phys. dec.: 0-3-2; Consent withdr.: 3-1-3

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Macitentan 3 mg
    Arm description
    Macitentan tablet 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
    Macitentan tablet 3 mg 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 tablet 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
    Macitentan tablet 10 mg once daily

    Number of subjects in period 2
    Macitentan 3 mg Placebo Macitentan 10 mg
    Started
    88
    89
    88
    Completed
    87
    88
    86
    Not completed
    1
    1
    2
         see "Blinding details"
    1
    1
    2
    Period 3
    Period 3 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
    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. IMPORTANT NOTE for "Period Milestone Achievement": Overall Period 1&2: Administrative: 1-0-2; AE nonfatal: 8-15-13; Lost to follow-up:1-0-1; Non-conformity: 0-0-1; Pat. dec.: 10-1-4; Phys. dec.: 0-3-2; Consent withdr.: 3-1-3

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Macitentan 3 mg
    Arm description
    Macitentan 3 mg tablet 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
    Macitentan tablet 3 mg once daily

    Arm title
    Macitentan 10 mg
    Arm description
    Macitentan 10 mg tablet 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
    Macitentan tablet 10 mg 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 3
    Macitentan 3 mg Macitentan 10 mg Placebo
    Started
    87
    86
    88
    Completed
    70
    73
    73
    Not completed
    17
    13
    15
         see "Blinding details"
    17
    13
    15

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Macitentan 3 mg
    Reporting group description
    Macitentan tablet 3 mg once daily

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

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo

    Reporting group values
    Macitentan 3 mg Macitentan 10 mg Placebo Total
    Number of subjects
    88 88 89 265
    Age categorical
    Age categorical description
    Units: participants
        Between 18 and 65 years
    76 83 75 234
        >=65 years
    12 5 14 31
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    50.6 ± 13.2 47.4 ± 13.02 50.6 ± 12.88 -
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    75 71 71 217
        Male
    13 17 18 48
    Race/Ethnicity, Customized
    Units: Subjects
        White
    62 63 68 193
        Black or African American
    2 0 0 2
        Asian
    6 4 6 16
        Hispanic
    12 14 9 35
        Other
    6 7 6 19
    Region of Enrollment
    Units: Subjects
        Argentina
    12 3 3 18
        Belgium
    0 1 0 1
        China
    3 3 5 11
        Colombia
    3 5 6 14
        Germany
    2 3 2 7
        Greece
    2 4 5 11
        Ireland
    1 2 1 4
        Israel
    5 7 12 24
        Mexico
    6 9 6 21
        Netherlands
    3 2 1 6
        New Zealand
    2 1 3 6
        Poland
    7 11 5 23
        Portugal
    1 2 4 7
        Puerto Rico
    1 1 0 2
        Russian Federation
    5 4 7 16
        South Africa
    3 4 2 9
        Turkey
    0 0 1 1
        Ukraine
    9 7 4 20
        United Kingdom
    7 3 6 16
        United States
    16 16 16 48
    Subject analysis sets

    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 analysis of the primary endpoint, in line with the intention-to-treat principle as per ICH E9.

    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 might affect 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 • Received study treatment different from that randomized Measurements after the occurrence of certain pre-defined deviations in study conduct were excluded from the PP set.

    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. 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
    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 sets values
    Full analysis set Per-protocol (PP) set Safety set Modified intent-to-treat (mITT) set
    Number of subjects
    265
    255
    264
    255
    Age categorical
    Age categorical description
    Units: participants
        Between 18 and 65 years
    234
        >=65 years
    31
    Age continuous
    Age continuous description
    Units: years
        arithmetic mean (standard deviation)
    49.6 ± 13.06
    ±
    ±
    ±
    Gender categorical
    Gender categorical description
    Units: Subjects
        Female
    217
        Male
    48
    Race/Ethnicity, Customized
    Units: Subjects
        White
    193
        Black or African American
    2
        Asian
    16
        Hispanic
    35
        Other
    19
    Region of Enrollment
    Units: Subjects
        Argentina
    18
        Belgium
    1
        China
    11
        Colombia
    14
        Germany
    7
        Greece
    11
        Ireland
    4
        Israel
    24
        Mexico
    21
        Netherlands
    6
        New Zealand
    6
        Poland
    23
        Portugal
    7
        Puerto Rico
    2
        Russian Federation
    16
        South Africa
    9
        Turkey
    1
        Ukraine
    20
        United Kingdom
    16
        United States
    48

    End points

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

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo

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

    Reporting group title
    Placebo
    Reporting group description
    Placebo once daily

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

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

    Reporting group title
    Placebo
    Reporting group description
    Placebo once daily

    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 analysis of the primary endpoint, in line with the intention-to-treat principle as per ICH E9.

    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 might affect 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 • Received study treatment different from that randomized Measurements after the occurrence of certain pre-defined deviations in study conduct were excluded from the PP set.

    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. 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
    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.

    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 (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. 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.
    End point type
    Primary
    End point timeframe
    Baseline to Week 16
    End point values
    Macitentan 3 mg Macitentan 10 mg Placebo Full analysis set
    Number of subjects analysed
    88
    88
    89
    0 [1]
    Units: number of newDUs/observation days
        number (not applicable)
    1.44
    1.457
    1.206
    Notes
    [1] - Not applicable
    Statistical analysis title
    Statistical analysis 1 (Full analysis set)
    Comparison groups
    Macitentan 3 mg v Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.434
    Method
    negative binomial-2 regression (NB-2)
    Parameter type
    NB-2 estimate of new DUs per patient
    Point estimate
    1.194
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.766
         upper limit
    1.861
    Statistical analysis title
    Statistical analysis 2 (Full analysis set)
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    177
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.407
    Method
    NB-2
    Parameter type
    NB-2 estimate of new DUs per patient
    Point estimate
    1.208
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.773
         upper limit
    1.886

    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 [2]
    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
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis to be reported for this endpoint.
    End point values
    Placebo Macitentan 3 mg Macitentan 10 mg Full analysis set
    Number of subjects analysed
    87
    84
    84
    0 [3]
    Units: percentage of participants
        number (not applicable)
    59.8
    56
    54.8
    Notes
    [3] - Not applicable
    Statistical analysis title
    Statistical analysis 2 (full analysis set)
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.4624
    Method
    Chi-squared
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.789
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    1.484
    Statistical analysis title
    Statistical analysis 1 (full analysis set)
    Comparison groups
    Macitentan 3 mg v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.5668
    Method
    Chi-squared
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.831
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.442
         upper limit
    1.564

    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 95 weeks
    End point values
    Macitentan 3 mg Macitentan 10 mg Placebo Full analysis set
    Number of subjects analysed
    84
    84
    87
    0 [4]
    Units: percentage of participants
        number (not applicable)
    21.4
    19
    18.4
    Notes
    [4] - Not applicable
    Statistical analysis title
    Statistical analysis 1 (full analysis set)
    Comparison groups
    Macitentan 3 mg v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.6117
    Method
    Chi-squared
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.216
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.572
         upper limit
    2.582
    Statistical analysis title
    Statistical analysis 2 (full analysis set)
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9047
    Method
    Chi-squared
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.048
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.485
         upper limit
    2.264

    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 observed carried forward (LOCF) approach was applied to Week 16 data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16 (LOCF)
    End point values
    Macitentan 3 mg Macitentan 10 mg Placebo Modified intent-to-treat (mITT) set
    Number of subjects analysed
    84
    84
    87
    0 [5]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    1.4 ± 0.73
    1.3 ± 0.7
    1.4 ± 0.72
    ±
        Week 16 (LOCF)
    1.2 ± 0.75
    1.1 ± 0.76
    1.3 ± 0.77
    ±
    Notes
    [5] - Not applicable
    Statistical analysis title
    Statistical analysis 1 (mITT-analysis)
    Statistical analysis description
    ANCOVA on mITT analysis set
    Comparison groups
    Macitentan 3 mg v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.347
    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
    Statistical analysis title
    Statistical analysis 2 (mITT-analysis)
    Statistical analysis description
    ANCOVA on mITT analysis set
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.165
    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

    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 observed carried forward (LOCF) approach was applied to Week 16 data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16 (LOCF)
    End point values
    Macitentan 3 mg Macitentan 10 mg Placebo Modified intent-to-treat (mITT) set
    Number of subjects analysed
    84
    84
    87
    0 [6]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    1.2 ± 0.67
    1.1 ± 0.65
    1.2 ± 0.66
    ±
        Week 16 (LOCF)
    1.1 ± 0.7
    1 ± 0.71
    1.2 ± 0.68
    ±
    Notes
    [6] - Not applicable
    Statistical analysis title
    Statistical analysis 2 (mITT-analysis)
    Statistical analysis description
    ANCOVA on mITT analysis set
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.312
    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
    Statistical analysis title
    Statistical analysis 1 (mITT-analysis)
    Statistical analysis description
    ANCOVA on mITT analysis set
    Comparison groups
    Macitentan 3 mg v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.339
    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

    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 observed carried forward (LOCF) approach was applied to Week 16 data.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16 (LOCF)
    End point values
    Macitentan 3 mg Macitentan 10 mg Placebo Modified intent-to-treat (mITT) set
    Number of subjects analysed
    84
    84
    87
    0 [7]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Baseline
    3 ± 1.08
    2.9 ± 1.05
    2.9 ± 1.14
    ±
        Week 16 (LOCF)
    2.8 ± 1.17
    2.7 ± 1.11
    2.9 ± 1.12
    ±
    Notes
    [7] - Not applicable
    Statistical analysis title
    Statistical analysis 2 (mITT-analysis)
    Statistical analysis description
    ANCOVA on mITT analysis set
    Comparison groups
    Macitentan 10 mg v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.221
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.1
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    ANCOVA on mITT analysis set
    Comparison groups
    Macitentan 3 mg v Placebo
    Number of subjects included in analysis
    171
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.319
    Method
    ANCOVA
    Parameter type
    Mean difference (net)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events occurring during treatment period, up to 95 weeks and up to 30 days after treatment discontinuation
    Adverse event reporting additional description
    Safety set - all treated patients
    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 tablet 3 mg once daily

    Reporting group title
    Placebo
    Reporting group description
    Matching placebo once daily

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

    Serious adverse events
    Macitentan 3 mg Placebo Macitentan 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    10 / 88 (11.36%)
    13 / 89 (14.61%)
    21 / 87 (24.14%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    RAYNAUD'S PHENOMENON
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ISCHAEMIA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    Surgical and medical procedures
    DEBRIDEMENT
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    FINGER AMPUTATION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    IMMUNOSUPPRESSANT DRUG THERAPY
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERIPHERAL ARTERY ANGIOPLASTY
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    SYMPATHECTOMY
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 89 (1.12%)
    0 / 87 (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
    DRUG THERAPY
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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)
    GASTRIC CANCER
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    GENERAL PHYSICAL HEALTH DETERIORATION
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    ISCHAEMIC ULCER
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    Injury, poisoning and procedural complications
    PELVIC FRACTURE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SPINAL CORD INJURY
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CONCUSSION
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    FEMUR FRACTURE
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    THORACIC VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    Cardiac disorders
    CARDIAC FAILURE
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERICARDITIS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RIGHT VENTRICULAR FAILURE
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    AORTIC VALVE STENOSIS
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    ARRHYTHMIA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    ACUTE MYOCARDIAL INFARCTION
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    ANGINA PECTORIS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    Respiratory, thoracic and mediastinal disorders
    PULMONARY FIBROSIS
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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 HYPERTENSION
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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 ALVEOLAR HAEMORRHAGE
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    RESPIRATORY FAILURE
         subjects affected / exposed
    1 / 88 (1.14%)
    1 / 89 (1.12%)
    0 / 87 (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
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VESTIBULAR DISORDER
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    SMALL INTESTINAL OBSTRUCTION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SUBILEUS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENTERITIS
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    NAUSEA
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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 ULCER
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    VOMITING
         subjects affected / exposed
    1 / 88 (1.14%)
    0 / 89 (0.00%)
    0 / 87 (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
    Renal and urinary disorders
    SCLERODERMA RENAL CRISIS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RENAL FAILURE ACUTE
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEPHROPATHY TOXIC
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    GLOMERULONEPHRITIS RAPIDLY PROGRESSIVE
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    DRUG-INDUCED LIVER INJURY
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ISCHAEMIC HEPATITIS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    Skin and subcutaneous tissue disorders
    SKIN ULCER
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    SKIN NECROSIS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    SYSTEMIC SCLEROSIS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    RHEUMATOID ARTHRITIS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    MYOPATHY
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    INFECTED SKIN ULCER
         subjects affected / exposed
    1 / 88 (1.14%)
    2 / 89 (2.25%)
    3 / 87 (3.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    BRONCHITIS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    2 / 87 (2.30%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    GANGRENE
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    ENTEROCOLITIS INFECTIOUS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    PERITONITIS
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         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 / 88 (0.00%)
    1 / 89 (1.12%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    0 / 88 (0.00%)
    0 / 89 (0.00%)
    1 / 87 (1.15%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    OSTEOMYELITIS
         subjects affected / exposed
    2 / 88 (2.27%)
    0 / 89 (0.00%)
    0 / 87 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    CELLULITIS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    PARONYCHIA
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    GASTROENTERITIS
         subjects affected / exposed
    0 / 88 (0.00%)
    1 / 89 (1.12%)
    0 / 87 (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
    73 / 88 (82.95%)
    70 / 89 (78.65%)
    73 / 87 (83.91%)
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    5 / 88 (5.68%)
    2 / 89 (2.25%)
    3 / 87 (3.45%)
         occurrences all number
    5
    2
    3
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    5 / 88 (5.68%)
    1 / 89 (1.12%)
    2 / 87 (2.30%)
         occurrences all number
    6
    1
    2
    Respiratory, thoracic and mediastinal disorders
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    3 / 88 (3.41%)
    6 / 89 (6.74%)
    1 / 87 (1.15%)
         occurrences all number
    3
    7
    1
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    6 / 88 (6.82%)
    5 / 89 (5.62%)
    10 / 87 (11.49%)
         occurrences all number
    6
    5
    12
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    17 / 88 (19.32%)
    19 / 89 (21.35%)
    15 / 87 (17.24%)
         occurrences all number
    31
    66
    30
    DIZZINESS
         subjects affected / exposed
    5 / 88 (5.68%)
    3 / 89 (3.37%)
    7 / 87 (8.05%)
         occurrences all number
    6
    3
    8
    General disorders and administration site conditions
    OEDEMA PERIPHERAL
         subjects affected / exposed
    10 / 88 (11.36%)
    4 / 89 (4.49%)
    14 / 87 (16.09%)
         occurrences all number
    12
    5
    16
    FATIGUE
         subjects affected / exposed
    2 / 88 (2.27%)
    4 / 89 (4.49%)
    7 / 87 (8.05%)
         occurrences all number
    3
    5
    7
    Gastrointestinal disorders
    DIARRHOEA
         subjects affected / exposed
    10 / 88 (11.36%)
    6 / 89 (6.74%)
    10 / 87 (11.49%)
         occurrences all number
    14
    9
    13
    NAUSEA
         subjects affected / exposed
    4 / 88 (4.55%)
    2 / 89 (2.25%)
    5 / 87 (5.75%)
         occurrences all number
    4
    3
    6
    DYSPEPSIA
         subjects affected / exposed
    1 / 88 (1.14%)
    6 / 89 (6.74%)
    3 / 87 (3.45%)
         occurrences all number
    1
    7
    3
    CONSTIPATION
         subjects affected / exposed
    7 / 88 (7.95%)
    3 / 89 (3.37%)
    2 / 87 (2.30%)
         occurrences all number
    9
    3
    2
    Skin and subcutaneous tissue disorders
    SKIN ULCER
         subjects affected / exposed
    14 / 88 (15.91%)
    9 / 89 (10.11%)
    8 / 87 (9.20%)
         occurrences all number
    21
    10
    17
    DERMATITIS
         subjects affected / exposed
    5 / 88 (5.68%)
    1 / 89 (1.12%)
    2 / 87 (2.30%)
         occurrences all number
    5
    1
    2
    Musculoskeletal and connective tissue disorders
    PAIN IN EXTREMITY
         subjects affected / exposed
    8 / 88 (9.09%)
    13 / 89 (14.61%)
    9 / 87 (10.34%)
         occurrences all number
    15
    15
    18
    MYALGIA
         subjects affected / exposed
    5 / 88 (5.68%)
    3 / 89 (3.37%)
    4 / 87 (4.60%)
         occurrences all number
    7
    3
    4
    ARTHRALGIA
         subjects affected / exposed
    7 / 88 (7.95%)
    4 / 89 (4.49%)
    3 / 87 (3.45%)
         occurrences all number
    8
    4
    5
    BACK PAIN
         subjects affected / exposed
    8 / 88 (9.09%)
    6 / 89 (6.74%)
    2 / 87 (2.30%)
         occurrences all number
    8
    6
    2
    BURSITIS
         subjects affected / exposed
    2 / 88 (2.27%)
    5 / 89 (5.62%)
    2 / 87 (2.30%)
         occurrences all number
    2
    6
    2
    Infections and infestations
    INFECTED SKIN ULCER
         subjects affected / exposed
    15 / 88 (17.05%)
    13 / 89 (14.61%)
    9 / 87 (10.34%)
         occurrences all number
    33
    18
    15
    NASOPHARYNGITIS
         subjects affected / exposed
    7 / 88 (7.95%)
    5 / 89 (5.62%)
    10 / 87 (11.49%)
         occurrences all number
    11
    5
    10
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    11 / 88 (12.50%)
    6 / 89 (6.74%)
    8 / 87 (9.20%)
         occurrences all number
    14
    10
    9
    INFLUENZA
         subjects affected / exposed
    2 / 88 (2.27%)
    3 / 89 (3.37%)
    5 / 87 (5.75%)
         occurrences all number
    2
    3
    5
    PHARYNGITIS
         subjects affected / exposed
    5 / 88 (5.68%)
    0 / 89 (0.00%)
    0 / 87 (0.00%)
         occurrences all number
    5
    0
    0

    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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