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    Clinical Trial Results:
    A multi-center, double-blind, randomized, placebo-controlled, parallel-group, Phase 3 study to evaluate the effects of macitentan on exercise capacity in subjects with Eisenmenger Syndrome

    Summary
    EudraCT number
    		 2012-003335-33
    Trial protocol
    		 GB   IT   BG   BE   DE   PT   NL   AT   ES   HU   CZ   GR  
    Global end of trial date
    01 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2017
    First version publication date
    24 Jun 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AC-055-305
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01743001
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestr. 16, Allschwil, Switzerland, 4123
    Public contact
    Actelion Pharmaceuticals Ltd, clinical trial disclosure desk, clinical-trials-disclosure@actelion.com
    Scientific contact
    Actelion Pharmaceuticals Ltd, clinical trial disclosure desk, 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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the effects of macitentan on exercise capacity in subjects with Eisenmenger Syndrome
    Protection of trial subjects
    Prior to the start of the study, each study site 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 study was conducted in compliance with the principles of the ‘Declaration of Helsinki’, the International Council for Harmonisation (ICH)-Good Clinical Practice (GCP) guidelines, and with the laws and regulations of the country in which the clinical research was conducted. 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 subjects’ interests. Prior to any study procedure and after adequate explanation of the aims, methods, objectives, and potential hazards of the study, written informed consent was obtained from each participating adult subject (including DS subjects who were able to consent), as well as from the parent(s) or legal representative(s) of each participating minor, and from the parent(s)/legal representative(s) or caregiver(s) of each participating subject with DS, who was not able to personally read and sign the informed consent. Additionally, written assent was obtained from each minor and each DS subject who was unable to give written consent. All subjects who participated in the hemodynamic sub-study were required to sign a separate informed consent form (ICF). Informed consent/assent was obtained in accordance with the national laws or regulations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 May 2013
    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
    China: 70
    Country: Number of subjects enrolled
    Malaysia: 3
    Country: Number of subjects enrolled
    Philippines: 2
    Country: Number of subjects enrolled
    Vietnam: 16
    Country: Number of subjects enrolled
    Bulgaria: 6
    Country: Number of subjects enrolled
    Poland: 10
    Country: Number of subjects enrolled
    Romania: 8
    Country: Number of subjects enrolled
    Russian Federation: 19
    Country: Number of subjects enrolled
    Serbia: 9
    Country: Number of subjects enrolled
    Chile: 7
    Country: Number of subjects enrolled
    Mexico: 30
    Country: Number of subjects enrolled
    United States: 7
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    Israel: 1
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Turkey: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    226
    EEA total number of subjects
    61
    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)
    15
    Adults (18-64 years)
    211
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 71 sites in 26 countries

    Pre-assignment
    Screening details
    		 The screening period lasted a maximum of 30 days from Visit 1 up to Randomization (Visit 2). Total of 319 screened subjects.

    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, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Macitentan
    Arm description
    		 Macitentan
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Macitentan 10 mg, once-daily, oral, film-coated tablet

    Arm title
    		 Placebo
    Arm description
    		 Placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, once-daily, oral, film-coated tablet

    Number of subjects in period 1
    		Macitentan Placebo
    Started
    114
    112
    Completed
    114
    112
    Period 2
    Period 2 title
    Overall Study
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Macitentan
    Arm description
    		 Subjects receive macitentan 10 mg oral tablet once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Macitentan 10 mg, once-daily, oral, film-coated tablet

    Arm title
    		 Placebo
    Arm description
    		 Subjects receive macitentan-matching placebo oral tablet once daily
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, once-daily, oral, film-coated tablet

    Number of subjects in period 2
    		Macitentan Placebo
    Started
    114
    112
    Completed
    111
    112
    Not completed
    3
    0
         Adverse event, serious fatal
    1
    -
         Physician decision
    1
    -
         Pregnancy
    1
    -

    Baseline characteristics

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

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo

    Reporting group values
    		 Macitentan Placebo Total
    Number of subjects
    		 114 112 226
    Age categorical
    Full analysis set (FAS)
    Units: Subjects
        Adolescents (12-17 years)
    		 13 2 15
        Adults (18 - 55 years)
    		 90 105 195
        Adults >= 55 years
    		 11 5 16
    Age continuous
    Full analysis set (FAS)
    Units: years
        median (full range (min-max))
    		 33 (12 to 82) 31 (13 to 62) -
    Gender categorical
    Units: Subjects
        Female
    		 82 68 150
        Male
    		 32 44 76
    Subject analysis sets

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) included all subjects from the SCR allocated to a randomized study treatment. Subjects were evaluated according to the study treatment to which they were assigned. All available data were taken into account for the analysis.

    Subject analysis set title
    Per-protocol analysis set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol analysis set (PPS) comprised data from all subjects included in the FAS without major protocol deviations or conditions, which might have affected the evaluation of the effect of the study treatment on the primary efficacy endpoint.

    Subject analysis sets values
    		 Full analysis set (FAS) Per-protocol analysis set (PPS)
    Number of subjects
    226
    200
    Age categorical
    Full analysis set (FAS)
    Units: Subjects
        Adolescents (12-17 years)
    15
    13
        Adults (18 - 55 years)
    195
    176
        Adults >= 55 years
    16
    11
    Age continuous
    Full analysis set (FAS)
    Units: years
        median (full range (min-max))
    32 (12 to 82)
    32 (12 to 82)
    Gender categorical
    Units: Subjects
        Female
    150
    132
        Male
    76
    68

    End points

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    End points reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    		 Macitentan

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo
    Reporting group title
    Macitentan
    Reporting group description
    		 Subjects receive macitentan 10 mg oral tablet once daily

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects receive macitentan-matching placebo oral tablet once daily

    Subject analysis set title
    Full analysis set (FAS)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) included all subjects from the SCR allocated to a randomized study treatment. Subjects were evaluated according to the study treatment to which they were assigned. All available data were taken into account for the analysis.

    Subject analysis set title
    Per-protocol analysis set (PPS)
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The per-protocol analysis set (PPS) comprised data from all subjects included in the FAS without major protocol deviations or conditions, which might have affected the evaluation of the effect of the study treatment on the primary efficacy endpoint.

    Primary: Change from baseline to Week 16 in exercise capacity, as measured by 6MWD

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    End point title
    		 Change from baseline to Week 16 in exercise capacity, as measured by 6MWD
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to Week 16
    End point values
    		 Macitentan Placebo Full analysis set (FAS)
    Number of subjects analysed
    114
    112
    0 [1]
    Units: meter
        arithmetic mean (standard deviation)
    18.3 ± 84.4
    19.7 ± 53
    ±
    Notes
    [1] - NA
    Statistical analysis title
    		 Main analysis
    Statistical analysis description
    ANCOVA for the change from baseline to Week 16 including randomized treatment group, presence of DS (yes/no), WHO FC (II vs III/IV) and baseline 6MWD value as covariates
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.612
    Method
    		 ANCOVA
    Parameter type
    		 Least-square mean difference
    Point estimate
    -4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.8
         upper limit
    		 13.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    9.2
    Notes
    [2] - ANCOVA

    Secondary: Change from baseline to Week 16 in WHO functional class

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    End point title
    		 Change from baseline to Week 16 in WHO functional class
    End point description
    WHO functional class dichotomized as improvement from baseline to Week 16 ‘Yes’ (i.e., shift to lower class [e.g., from III to II]) or ‘No’ (i.e., shift to higher class [e.g., from III to IV] or unchanged).
    End point type
    Secondary
    End point timeframe
    From baseline to Week 16
    End point values
    		 Macitentan Placebo Full analysis set (FAS)
    Number of subjects analysed
    114
    112
    0 [3]
    Units: Participants
    10
    16
    Notes
    [3] - NA
    Statistical analysis title
    		 Main analysis
    Statistical analysis description
    Logistic regression model for the improvement from baseline to Week 16 including randomized treatment group and location of cardiac defect (pre-tricuspid/ post-tricuspid) as categorical factors
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.145
    Method
    		 Wlad chi-square test
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.23
         upper limit
    		 1.24

    Secondary: Change from baseline to Week 16 in dyspnea (assessed by the Borg dyspnea index)

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    End point title
    		 Change from baseline to Week 16 in dyspnea (assessed by the Borg dyspnea index)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline to Week 16
    End point values
    		 Macitentan Placebo Full analysis set (FAS)
    Number of subjects analysed
    114
    112
    0 [4]
    Units: Index
    arithmetic mean (standard deviation)
        Index
    -0.22 ± 1.56
    -0.29 ± 1.5
    ±
    Notes
    [4] - NA
    Statistical analysis title
    		 Main analysis
    Statistical analysis description
    ANCOVA for the change from baseline to Week 16 including randomized treatment group and location of cardiac defect (pre-tricuspid/ post-tricuspid) and baseline Borg dyspnea index as covariates
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    226
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8456 [5]
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Macitentan - Placebo
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.34
         upper limit
    		 0.46
    Notes
    [5] - P-value Wilcoxon rank sum test

    Secondary: Change from baseline to Week 16 in quality of life (assessed by the SF-36 questionnaire)

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    End point title
    		 Change from baseline to Week 16 in quality of life (assessed by the SF-36 questionnaire)
    End point description
    SF-36 PHYSICAL FUNCTIONING, SF-36 ROLE-PHYSICAL, SF-36 PAIN INDEX, SF-36 GENERAL HEALTH PERCEPTIONS, SF-36 VITALITY, SF-36 SOCIAL FUNCTIONING, SF-36 ROLE-EMOTIONAL, and SF-36 MENTAL HEALTH INDEX
    End point type
    Secondary
    End point timeframe
    From baseline to Week 16
    End point values
    		 Macitentan Placebo Full analysis set (FAS)
    Number of subjects analysed
    101
    99
    0 [6]
    Units: Scores
    least squares mean (standard error)
        SF-36 PHYSICAL FUNCTIONING
    4.4 ± 1.5
    5.3 ± 1.6
    ±
        SF-36 ROLE-PHYSICAL
    5.7 ± 2
    7.2 ± 2.1
    ±
        SF-36 PAIN INDEX
    3.2 ± 2.3
    3.1 ± 2.4
    ±
        SF-36 GENERAL HEALTH PERCEPTIONS
    5 ± 1.6
    1.9 ± 1.7
    ±
        SF-36 VITALITY
    6.9 ± 1.6
    5.8 ± 1.7
    ±
        SF-36 SOCIAL FUNCTIONING
    1.3 ± 2.2
    2.6 ± 2.3
    ±
        SF-36 ROLE-EMOTIONAL
    1.7 ± 2.2
    4.6 ± 2.4
    ±
        SF-36 MENTAL HEALTH INDEX
    2.8 ± 1.5
    5.1 ± 1.6
    ±
    Notes
    [6] - NA
    Statistical analysis title
    		 SF-36 PHYSICAL FUNCTIONING
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    Method
    		 ANCOVA
    Parameter type
    		 Macitentan - Placebo
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5
         upper limit
    		 3.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1
    Notes
    [7] - Statistical model is an ANCOVA (analysis of covariance) adjusting for randomized treatment group and location of cardiac defect (as factors), and baseline score (as covariate).
    Statistical analysis title
    		 SF-36 ROLE-PHYSICAL
    Statistical analysis description
    Statistical model is an ANCOVA (analysis of covariance) adjusting for randomized treatment group and location of cardiac defect (as factors), and baseline score (as covariate).
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 ANCOVA
    Parameter type
    		 Macitentan - Placebo
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.7
         upper limit
    		 3.9
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.7
    Statistical analysis title
    		 SF-36 PAIN INDEX
    Statistical analysis description
    Statistical model is an ANCOVA (analysis of covariance) adjusting for randomized treatment group and location of cardiac defect (as factors), and baseline score (as covariate).
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 ANCOVA
    Parameter type
    		 Macitentan - Placebo
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.9
         upper limit
    		 6.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.1
    Statistical analysis title
    		 SF-36 GENERAL HEALTH PERCEPTIONS
    Statistical analysis description
    Statistical model is an ANCOVA (analysis of covariance) adjusting for randomized treatment group and location of cardiac defect (as factors), and baseline score (as covariate).
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    		 ANCOVA
    Parameter type
    		 Macitentan - Placebo
    Point estimate
    3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 7.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.2
    Statistical analysis title
    		 SF-36 VITALITY
    Statistical analysis description
    Statistical model is an ANCOVA (analysis of covariance) adjusting for randomized treatment group and location of cardiac defect (as factors), and baseline score (as covariate).
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Macitentan - Placebo
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.1
         upper limit
    		 5.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1
    Statistical analysis title
    		 SF-36 SOCIAL FUNCTIONING
    Statistical analysis description
    Statistical model is an ANCOVA (analysis of covariance) adjusting for randomized treatment group and location of cardiac defect (as factors), and baseline score (as covariate).
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Macitentan - Placebo
    Point estimate
    -1.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.2
         upper limit
    		 4.4
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.9
    Statistical analysis title
    		 SF-36 ROLE-EMOTIONAL
    Statistical analysis description
    Statistical model is an ANCOVA (analysis of covariance) adjusting for randomized treatment group and location of cardiac defect (as factors), and baseline score (as covariate).
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Macitentan - Placebo
    Point estimate
    -2.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.7
         upper limit
    		 3
    Variability estimate
    Standard error of the mean
    Dispersion value
    3
    Statistical analysis title
    		 SF-36 MENTAL HEALTH INDEX
    Statistical analysis description
    Statistical model is an ANCOVA (analysis of covariance) adjusting for randomized treatment group and location of cardiac defect (as factors), and baseline score (as covariate).
    Comparison groups
    Macitentan v Placebo
    Number of subjects included in analysis
    200
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Macitentan - Placebo
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.4
         upper limit
    		 1.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From study treatment initiation up to 30 days after study treatment discontinuation
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 112 subjects were exposed to Placebo for 15.96 weeks on average

    Reporting group title
    Macitentan_10_mg
    Reporting group description
    		 114 subjects were exposed to Macitentan 10mg for 15.93 weeks on average

    Serious adverse events
    		 Placebo Macitentan_10_mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 112 (1.79%)
    7 / 114 (6.14%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    1 / 112 (0.89%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    1 / 112 (0.89%)
    0 / 114 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    0 / 112 (0.00%)
    3 / 114 (2.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Endocarditis
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 112 (0.00%)
    2 / 114 (1.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 112 (0.00%)
    1 / 114 (0.88%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Macitentan_10_mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 112 (26.79%)
    31 / 114 (27.19%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 112 (4.46%)
    13 / 114 (11.40%)
         occurrences all number
    5
    15
    Respiratory, thoracic and mediastinal disorders
    Haemoptysis
         subjects affected / exposed
    6 / 112 (5.36%)
    0 / 114 (0.00%)
         occurrences all number
    8
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 112 (2.68%)
    6 / 114 (5.26%)
         occurrences all number
    3
    6
    Nasopharyngitis
         subjects affected / exposed
    14 / 112 (12.50%)
    3 / 114 (2.63%)
         occurrences all number
    16
    4
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 112 (6.25%)
    11 / 114 (9.65%)
         occurrences all number
    10
    12

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Apr 2013
    Amendment 1 - Changes included: - Efficacy as well as safety and tolerability endpoints sections were revised; - The main efficacy analysis plan was updated - The alternative analysis methods described initially for the main analysis, in case assumptions of normality and homogeneity of variance are not met following an assessment, were changed to a sensitivity analysis. - The overall study design and plan were modified to allow those subjects who did not meet the eligibility criteria for the sub-study to be considered for the main study on a case-by-case basis. - Exclusion criterion 5 concerning systolic blood pressure was updated - Other changes.
    13 Mar 2014
    Global Amendment 2 - Changes included: - The study design and eligibility criteria were modified to allow the participation of additional subjects with more complex cardiac defects, including those with Down Syndrom, - Inclusion criterion 3 was revised; - Cardiac catheterization requirements (inclusion criterion 4) were updated; - The limit of variance between the 2 6MWT at screening was increased to 15% (inclusion criterion 6). - Exclusion criterion 1 was revised to rule out (1) other causes of pulmonary hypertension - Other changes.

    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.
    There were no significant limitations of the trial.
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