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    Clinical Trial Results:
    Long term, single-arm, open-label extension study of protocol AC-055-305 to assess the safety, tolerability and efficacy of macitentan in subjects with Eisenmenger Syndrome

    Summary
    EudraCT number
    2012-004411-31
    Trial protocol
    IT   BG   GB   DE   AT   PT   ES   HU   CZ   RO   PL   GR  
    Global end of trial date
    12 Jan 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    27 Jul 2018
    First version publication date
    27 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055-308
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01739400
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd.
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Clinical Trial Disclosure Desk, Actelion Pharmaceuticals Ltd., clinical-trials-disclosure@its.jnj.com
    Scientific contact
    Clinical Trial Disclosure Desk, Actelion Pharmaceuticals Ltd., clinical-trials-disclosure@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    22 Jan 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jan 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To assess the long-term safety and tolerability of macitentan in subjects with Eisenmenger Syndrome (ES) beyond the treatment of the AC-055-305/MAESTRO double-blind (DB) study (EudraCT number 2012-003335-33), and to assess the long-term efficacy of macitentan in this subject population.
    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 Down Syndrome 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 Down Syndrome, who was not able to personally read and sign the informed consent. Additionally, written assent was obtained from each minor and each Down Syndrome 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
    10 Sep 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 3
    Country: Number of subjects enrolled
    Bulgaria: 5
    Country: Number of subjects enrolled
    Chile: 7
    Country: Number of subjects enrolled
    China: 68
    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
    Malaysia: 3
    Country: Number of subjects enrolled
    Mexico: 29
    Country: Number of subjects enrolled
    Philippines: 2
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Portugal: 7
    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
    Spain: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 5
    Country: Number of subjects enrolled
    Vietnam: 16
    Worldwide total number of subjects
    217
    EEA total number of subjects
    59
    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)
    14
    Adults (18-64 years)
    200
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 51 sites in 19 countries (geographical regions: Asia-Pacific, Eastern Europe, Latin America, North America and Western Europe).

    Pre-assignment
    Screening details
    217 subjects from the AC-055-305/DB study (EudraCT 2012-003335-33) were enrolled in this open-label (OL) study without knowledge of their study treatment allocation (macitentan or placebo) in the DB study. As the DB study did not meet its primary endpoint, the sponsor decided to prematurely terminate this OL study.

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Macitentan
    Arm description
    Macitentan 10 mg, film-coated tablet, oral use, once daily
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    ACT-064992
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Macitentan 10 mg, taken orally once daily

    Number of subjects in period 1
    Macitentan
    Started
    217
    Completed
    191
    Not completed
    26
         Physician decision
    3
         Adverse event, serious fatal
    7
         Consent withdrawn by subject
    14
         Lost to follow-up
    2

    Baseline characteristics

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

    Reporting group values
    Overall study Total
    Number of subjects
    217 217
    Age categorical
    Units: Subjects
        12 - 17 years
    14 14
        18 - 64 years
    200 200
        65 - 84 years
    3 3
        ≥ 85 years
    0 0
    Age continuous
    Units: years
        median (full range (min-max))
    32.0 (12 to 82) -
    Gender categorical
    Units:
        Female
    143 143
        Male
    74 74
    Race
    Units: Subjects
        White
    103 103
        Chinese
    70 70
        Other Asian
    22 22
        Other
    22 22
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    177 177
        Hispanic or Latino
    40 40
    Enrollment by geographical region
    Units: Subjects
        Asia-Pacific
    89 89
        Eastern Europe
    50 50
        Latin America
    36 36
        North America
    5 5
        Western Europe-Israel
    37 37
    WHO functional class
    WHO functional class of subjects Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure
    Units: Subjects
        class I
    0 0
        class II
    131 131
        class III
    86 86
        class IV
    0 0
    Down syndrome status
    Units: Subjects
        Yes
    20 20
        No
    197 197
    Body Mass Index (BMI)
    Units: kg/m2
        median (full range (min-max))
    21.2 (11.9 to 42.2) -
    Subject analysis sets

    Subject analysis set title
    All-enrolled analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The all-enrolled analysis set includes all subjects enrolled in AC-055-308 / OL, whether or not they took at least one dose of macitentan during the OL study.

    Subject analysis set title
    DB-macitentan
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All enrolled subjects treated with macitentan in the AC-055-308 / OL study who received macitentan in the DB study (AC-055-305, EudraCT 2012-003335-33).

    Subject analysis set title
    DB-placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All enrolled subjects treated with macitentan in the AC-055-308 / OL study who received placebo in the DB study (AC-055-305, EudraCT 2012-003335-33).

    Subject analysis sets values
    All-enrolled analysis set DB-macitentan DB-placebo
    Number of subjects
    217
    109
    108
    Age categorical
    Units: Subjects
        12 - 17 years
    14
    12
    2
        18 - 64 years
    200
    94
    106
        65 - 84 years
    3
    3
    0
        ≥ 85 years
    0
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    32.0 (12 to 82)
    33.0 (12 to 82)
    31.5 (14 to 62)
    Gender categorical
    Units:
        Female
    143
    77
    66
        Male
    74
    32
    42
    Race
    Units: Subjects
        White
    103
    52
    51
        Chinese
    70
    35
    35
        Other Asian
    22
    11
    11
        Other
    22
    11
    11
    Ethnicity
    Units: Subjects
        Not Hispanic or Latino
    177
    89
    88
        Hispanic or Latino
    40
    20
    20
    Enrollment by geographical region
    Units: Subjects
        Asia-Pacific
    89
    45
    44
        Eastern Europe
    50
    24
    26
        Latin America
    36
    18
    18
        North America
    5
    1
    4
        Western Europe-Israel
    37
    21
    16
    WHO functional class
    WHO functional class of subjects Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (e.g. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure
    Units: Subjects
        class I
    0
    0
    0
        class II
    131
    66
    65
        class III
    86
    43
    43
        class IV
    0
    0
    0
    Down syndrome status
    Units: Subjects
        Yes
    20
    10
    10
        No
    197
    99
    98
    Body Mass Index (BMI)
    Units: kg/m2
        median (full range (min-max))
    21.2 (11.9 to 42.2)
    20.9 (11.9 to 38.9)
    21.4 (14.5 to 42.2)

    End points

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    End points reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    Macitentan 10 mg, film-coated tablet, oral use, once daily

    Subject analysis set title
    All-enrolled analysis set
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The all-enrolled analysis set includes all subjects enrolled in AC-055-308 / OL, whether or not they took at least one dose of macitentan during the OL study.

    Subject analysis set title
    DB-macitentan
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All enrolled subjects treated with macitentan in the AC-055-308 / OL study who received macitentan in the DB study (AC-055-305, EudraCT 2012-003335-33).

    Subject analysis set title
    DB-placebo
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    All enrolled subjects treated with macitentan in the AC-055-308 / OL study who received placebo in the DB study (AC-055-305, EudraCT 2012-003335-33).

    Primary: Change in exercise capacity as measured by 6-minute walking distance (6MWD) Month 6 and 12

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    End point title
    Change in exercise capacity as measured by 6-minute walking distance (6MWD) Month 6 and 12
    End point description
    NOTE: The MAESTRO-OL study was exploratory in nature and no primary efficacy and safety endpoint were defined in the clinical protocol. This exploratory efficacy outcome measure was selected to be reported as a primary safety endpoint here. All efficacy analyses were considered exploratory. The analyses of the exploratory efficacy endpoints focused on the absolute values and on the change from DB baseline to Week 16 in the DB study and to Month 6 and Month 12 in the OL study. For missing 6MWD values in the OL study, the following imputation rules were applied: If the reason for missing data was death, a distance of zero (0) meters was imputed for all 6MWD visits from the date of death. For any other reasons, the last available value was carried forward.
    End point type
    Primary
    End point timeframe
    From baseline in DB study (AC-055-305) up to month 12 in this OL study.
    End point values
    DB-macitentan DB-placebo
    Number of subjects analysed
    109
    108
    Units: meter (m)
    arithmetic mean (standard deviation)
        6MWD at DB study baseline
    370.6 ± 74.1
    381.6 ± 76.7
        6MWD at Week 16 in DB study
    395.1 ± 88.4
    399.9 ± 80.6
        Change in 6MWD from DB study baseline to Week 16
    24.4 ± 71.0
    18.2 ± 53.0
        6MWD at Month 6 in OL study
    396.8 ± 96.5
    425.0 ± 72.1
        Change in 6MWD from DB study baseline to Month 6
    26.2 ± 77.9
    43.4 ± 51.5
        6MWD at Month 12 in OL study
    397.1 ± 103.9
    421.5 ± 76.5
        Change in 6MWD from DB study baseline to Month 12
    26.5 ± 79.8
    39.9 ± 55.1
    Statistical analysis title
    Analysis of exercise capacity
    Statistical analysis description
    The MAESTRO-OL study was exploratory in nature and no primary efficacy and safety endpoint were defined in the clinical protocol. All efficacy analyses are considered exploratory. No hypothesis testing were defined, hence no p-values will be presented.
    Comparison groups
    DB-macitentan v DB-placebo
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    other [1]
    P-value
    = 0
    Method
    no p-value as exploratory analysis
    Confidence interval
    Notes
    [1] - The analyses of the exploratory efficacy endpoints focused on the absolute values and on the change from DB baseline to Week 16 in the DB study and to Month 6 and Month 12 in this OL study.

    Primary: Change in WHO functional class (FC) at Month 6 and 12

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    End point title
    Change in WHO functional class (FC) at Month 6 and 12
    End point description
    NOTE: The MAESTRO-OL study was exploratory in nature and no primary efficacy and safety endpoint were defined in the clinical protocol. This exploratory efficacy outcome measure was selected to be reported as a primary efficacy endpoint here. For missing WHO FC values in the OL study, the following imputation rules were applied: If the reason for missing data was death, class IV was imputed for all WHO visits from the date of death. For any other reasons, the last available value was carried forward. Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (e.g. short of breath with climbing stairs). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest and inability to carry out any physical activity without symptoms. Patients in class IV manifest signs of right heart failure.
    End point type
    Primary
    End point timeframe
    From baseline in DB study (AC-055-305) up to month 12 in this OL study.
    End point values
    DB-macitentan DB-placebo
    Number of subjects analysed
    109
    108
    Units: subjects
        WHO functional class I at DB study baseline
    0
    0
        WHO functional class II at DB study baseline
    66
    65
        WHO functional class III at DB study baseline
    43
    43
        WHO functional class IV at DB study baseline
    0
    0
        WHO functional class I at Week 16 in DB study
    3
    1
        WHO functional class II at Week 16 in DB study
    70
    77
        WHO functional class III at Week 16 in DB study
    36
    30
        WHO functional class IV at Week 16 in DB study
    0
    0
        Improvement from DB study baseline to Week 16
    10
    15
        Worsening from DB study baseline to Week 16
    0
    1
        WHO functional class I at Month 6 in OL study
    5
    7
        WHO functional class II at Month 6 in OL study
    74
    79
        WHO functional class III at Month 6 in OL study
    28
    22
        WHO functional class IV at Month 6 in OL study
    2
    0
        Improvement from DB study baseline to Month 6
    19
    27
        Worsening from DB study baseline to Month 6
    3
    1
        WHO functional class I at Month 12 in OL study
    5
    7
        WHO functional class II at Month 12 in OL study
    74
    79
        WHO functional class III at Month 12 in OL study
    28
    22
        WHO functional class IV at Month 12 in OL study
    2
    0
        Improvement from DB study baseline to Month 12
    20
    31
        Worsening from DB study baseline to Month 12
    4
    3
    Statistical analysis title
    Analysis of change in WHO functional class
    Statistical analysis description
    The MAESTRO-OL study was exploratory in nature and no primary efficacy and safety endpoint were defined in the clinical protocol. All efficacy analyses are considered exploratory. No hypothesis testing were defined, hence no p-values will be presented.
    Comparison groups
    DB-macitentan v DB-placebo
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    other [2]
    P-value
    = 0
    Method
    no p-value as exploratory analysis
    Confidence interval
    Notes
    [2] - The analyses of the exploratory efficacy endpoints focused on the absolute values and on the change from DB baseline to Week 16 in the DB study and to Month 6 and Month 12 in this OL study.

    Primary: Change in Borg dyspnea score at Month 6 and 12

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    End point title
    Change in Borg dyspnea score at Month 6 and 12
    End point description
    The Borg dyspnea score rates the severity of dyspnea (difficult or labored breathing) on a scale from 0 (‘Nothing at all’) to 10 (‘Very, very severe – maximal’). NOTE: The MAESTRO-OL study was exploratory in nature and no primary efficacy and safety endpoint were defined in the clinical protocol. This exploratory efficacy outcome measure was selected to be reported as a primary safety endpoint here. For missing Borg dyspnea index values in the OL study, the following imputation rules were applied: If the reason for missing data was death, a value of 10 was imputed for all Borg visits from the date of death. For any other reasons, the last available value was carried forward.
    End point type
    Primary
    End point timeframe
    From baseline in DB study (AC-055-305) up to month 12 in this OL study.
    End point values
    DB-macitentan DB-placebo
    Number of subjects analysed
    109
    108
    Units: Score on a scale
    arithmetic mean (standard deviation)
        Borg dyspnea score at DB study baseline
    3.0 ± 1.9
    2.9 ± 1.8
        Borg dyspnea score at Week 16 in DB study
    2.7 ± 1.9
    1.9 ± 1.6
        Change from DB study baseline to Week 16
    -0.3 ± 1.4
    -0.2 ± 1.5
        Borg dyspnea score at Month 6 in OL study
    2.8 ± 2.0
    2.5 ± 1.8
        Change from DB study baseline to Month 6
    -0.1 ± 2.0
    -0.4 ± 1.5
        Borg dyspnea score at Month 12 in OL study
    2.9 ± 2.0
    2.6 ± 1.9
        Change from DB study baseline to Month 12
    -0.1 ± 2.1
    -0.3 ± 1.6
    Statistical analysis title
    Analysis of Borg dyspnea score
    Statistical analysis description
    The MAESTRO-OL study was exploratory in nature and no primary efficacy and safety endpoint were defined in the clinical protocol. All efficacy analyses are considered exploratory. No hypothesis testing were defined, hence no p-values will be presented.
    Comparison groups
    DB-macitentan v DB-placebo
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    = 0
    Method
    no p-value as exploratory analysis
    Confidence interval
    Notes
    [3] - The analyses of the exploratory efficacy endpoints focused on the absolute values and on the change from DB baseline to Week 16 in the DB study and to Month 6 and Month 12 in this OL study.

    Primary: Change in peripheral oxygen saturation (SpO2) at rest at Month 6 and 12

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    End point title
    Change in peripheral oxygen saturation (SpO2) at rest at Month 6 and 12
    End point description
    NOTE: The MAESTRO-OL study was exploratory in nature and no primary efficacy and safety endpoint were defined in the clinical protocol. This exploratory efficacy outcome measure was selected to be reported as a primary efficacy endpoint here. No imputation of missing data for SpO2 was applied. Oxygen saturation assessed by pulse oximetry: peripheral oxygen saturation (SpO2) at rest before the 6-minute walk test (6MWT)
    End point type
    Primary
    End point timeframe
    From baseline in DB study (AC-055-305) up to month 12 in this OL study.
    End point values
    DB-macitentan DB-placebo
    Number of subjects analysed
    109 [4]
    108 [5]
    Units: percent (%)
    arithmetic mean (standard deviation)
        SpO2 at DB study baseline
    84.2 ± 5.6
    85.4 ± 5.0
        SpO2 at Week 16 in DB study
    85.3 ± 5.8
    85.6 ± 5.4
        Change in SpO2 from DB study baseline to Week 16
    1.1 ± 4.0
    0.2 ± 4.5
        SpO2 at Month 6 in OL study
    85.9 ± 5.9
    87.4 ± 5.4
        Change in SpO2 from DB study baseline to Month 6
    1.5 ± 4.9
    2.0 ± 4.3
        SpO2 at Month 12 in OL study
    86.4 ± 6.3
    87.1 ± 5.0
        Change in SpO2 from DB study baseline to Month 12
    2.0 ± 4.4
    1.6 ± 4.9
    Notes
    [4] - Out of 109 subjects 104 subjects were analyzed at month 6 and 92 subjects at month 12.
    [5] - Out of 109 subjects 103 subjects were analyzed at month 6 and 84 subjects at month 12.
    Statistical analysis title
    Analysis of peripheral oxygen saturation (SpO2)
    Statistical analysis description
    The MAESTRO-OL study was exploratory in nature and no primary efficacy and safety endpoint were defined in the clinical protocol. All efficacy analyses are considered exploratory. No hypothesis testing were defined, hence no p-values will be presented.
    Comparison groups
    DB-macitentan v DB-placebo
    Number of subjects included in analysis
    217
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    = 0
    Method
    no p-value as exploratory analysis
    Confidence interval
    Notes
    [6] - The analyses of the exploratory efficacy endpoints focused on the absolute values and on the change from DB baseline to Week 16 in the DB study and to Month 6 and Month 12 in this OL study.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From OL 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
    20
    Reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    Mactientan 10 mg to be taken daily, film-coated tablet, oral use

    Serious adverse events
    Macitentan
    Total subjects affected by serious adverse events
         subjects affected / exposed
    62 / 217 (28.57%)
         number of deaths (all causes)
    7
         number of deaths resulting from adverse events
    1
    Vascular disorders
    Arterial perforation
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Peripheral ischaemia
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Drug therapy
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgery
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    1 / 1
    Immune system disorders
    Allergy to arthropod sting
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    3 / 217 (1.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 217 (1.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst ruptured
         subjects affected / exposed
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Hip fracture
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Antineutrophil cytoplasmic antibody positive
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure
         subjects affected / exposed
    3 / 217 (1.38%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    6 / 217 (2.76%)
         occurrences causally related to treatment / all
    3 / 7
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ventricular extrasystoles
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Bronchiectasis
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    9 / 217 (4.15%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    4 / 217 (1.84%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    Pulmonary embolism
         subjects affected / exposed
    3 / 217 (1.38%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    Pulmonary haemorrhage
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary infarction
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic transformation stroke
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Retinal artery embolism
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyschezia
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Spinal disorder
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Brain abscess
         subjects affected / exposed
    2 / 217 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bronchitis viral
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 217 (2.30%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tuberculous pleurisy
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral pharyngitis
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 217 (0.46%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Macitentan
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    152 / 217 (70.05%)
    Investigations
    Haemoglobin decreased
         subjects affected / exposed
    20 / 217 (9.22%)
         occurrences all number
    29
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 217 (10.60%)
         occurrences all number
    28
    Haemoptysis
         subjects affected / exposed
    24 / 217 (11.06%)
         occurrences all number
    42
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    18 / 217 (8.29%)
         occurrences all number
    20
    Headache
         subjects affected / exposed
    29 / 217 (13.36%)
         occurrences all number
    34
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    13 / 217 (5.99%)
         occurrences all number
    13
    Fatigue
         subjects affected / exposed
    11 / 217 (5.07%)
         occurrences all number
    11
    Oedema peripheral
         subjects affected / exposed
    14 / 217 (6.45%)
         occurrences all number
    15
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    18 / 217 (8.29%)
         occurrences all number
    20
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    20 / 217 (9.22%)
         occurrences all number
    27
    Upper respiratory tract infection
         subjects affected / exposed
    61 / 217 (28.11%)
         occurrences all number
    119
    Viral upper respiratory tract infection
         subjects affected / exposed
    21 / 217 (9.68%)
         occurrences all number
    35

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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 resulting in Global Protocol Version 2. Changes included: - A summary of the potential risks associated with macitentan and the methodology for risk management were added. - Sections related to study assessments (for e.g., review of the documents, order of assessments, 6MWT and Borg dyspnea index, etc.) were slightly modified in^order to clarify the instructions relevant to the investigators. - The “risks” section of the ICF was revised to account for the possibility of interruption or permanent discontinuation of study medication based on specific decreases in hemoglobin levels. -The ICF was revised to include additional information about the potential risk of macitentan to align with updates to the Macitentan IB for non-oncology indications. The ICF was also updated to clarify the duties of the trial subjects following a change in the sponsor's insurance company.
    19 Sep 2013
    Amendment 2 resulting in Global Protocol Version 3. Changes included: - The number of study sites was increased to improve the rate of recruitment. - Results of all protocol-mandated laboratory assessments to be collected in the database. A Central Laboratory was to be used for the analysis of all laboratory variables requested in the protocol. - Monthly laboratory and safety monitoring at a site visit was added in order to improve sponsor oversight. - The reason for permanent discontinuation was now documented in the eCRF. - Throughout the protocol, upper limits for liver abnormality were updated to reflect the FDA guidance on DILI. - For hemoglobin monitoring, clarification on re-tests for assessing hemoglobin change was provided. - Collection of information on concomitant medication was extended to all visits. - Instructions for collection and handling of local laboratory samples and, where applicable, reporting of results within the eCRF of local analyses of local laboratory samples were added. - Instructions on performing and recording unscheduled visits were added. - Updated definitions of alert flags for abnormal laboratory values were included in the appropriate appendix. - The ICF was updated to reflect the increased number of planned study sites. - The ICF was updated to reflect the expanded instructions for unscheduled visits. - The risk section of the ICF was updated to account for the latest results of controlled studies.
    16 May 2014
    Amendment 3 resulting in Global Protocol Version 4. Changes included: - The recruitment period was made consistent with the updated study planned duration of the AC-055-305 / MAESTRO study. - The number of study centers selected for the AC-055-305 / MAESTRO study was increased to improve recruitment speed. The same change was implemented in the MAESTRO-OL protocol. - Eligibility criteria was opened up to females of childbearing potential truly abstinent and to subjects with Down Syndrome (if they had support from a caregiver or family member). - To address anticipated difficulties in Down Syndrome subjects, adaptations were made to the 6MWT to accommodate these subjects and to safeguard study outcome. - Clarification regarding which prohibited concomitant treatments must lead to study treatment discontinuation was added. - Clarifications were added on when to perform the requested laboratory re-tests for hemoglobin monitoring. - The timeline to review the laboratory report was shortened in order to identify any potential clinically significant abnormality as early as possible. - Clarifications on medication errors and pre-existing medical conditions were added. - The ICF was updated to reflect the protocol 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.
    None reported
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