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    Clinical Trial Results:
    Prospective, Multi-center, Single-arm, Open-label Long-term Study Assessing the Safety, Tolerability, and Effectiveness of Macitentan in Fontan-palliated Adult and Adolescent Subjects

    Summary
    EudraCT number
    2018-002821-45
    Trial protocol
    FR   DE   GB   DK   PL   CZ  
    Global end of trial date
    18 Jan 2022

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Jul 2022
    First version publication date
    30 Jul 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055H302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03775421
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Actelion Pharmaceuticals Ltd, ClinicalTrialsEU@its.jnj.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    EMEA-001032-PIP03-19
    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
    18 Jan 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2022
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to assess the long-term safety and tolerability of macitentan in Fontan-palliated adult and adolescent subjects.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    03 May 2019
    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
    Australia: 10
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    China: 5
    Country: Number of subjects enrolled
    Czechia: 16
    Country: Number of subjects enrolled
    Denmark: 17
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    New Zealand: 2
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Taiwan: 6
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    111
    EEA total number of subjects
    63
    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)
    12
    Adults (18-64 years)
    99
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    1 subject was enrolled twice with 2 different subjects IDs but only 111 subjects were enrolled in the study. Of these 111 enrolled subjects, 1 subject completed the study.

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

    Arms
    Arm title
    Macitentan 10 mg
    Arm description
    Subjects received macitentan 10 milligrams (mg) oral tablets once daily with or without food from Day 1 either until the end of the treatment (129 weeks) or when sponsor decided to stop this study.
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    Other name
    ACT-064992 Opsumit JNJ-67896062
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Macitentan 10 mg tablet was administered once daily with or without food from Day 1 until the end of treatment (129 weeks) or when sponsor decided to stop this study.

    Number of subjects in period 1
    Macitentan 10 mg
    Started
    111
    Completed
    1
    Not completed
    110
         Physician decision
    2
         Adverse event, serious non-fatal
    1
         Adverse event, serious fatal
    1
         Study terminated by sponsor
    94
         Consent withdrawn by subject
    10
         Lost to follow-up
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Macitentan 10 mg
    Reporting group description
    Subjects received macitentan 10 milligrams (mg) oral tablets once daily with or without food from Day 1 either until the end of the treatment (129 weeks) or when sponsor decided to stop this study.

    Reporting group values
    Macitentan 10 mg Total
    Number of subjects
    111 111
    Title for AgeCategorical
    Units: subjects
        Adolescents: 12-<18 yrs
    12 12
        Adults: >= 18 yrs
    99 99
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    25.1 ± 7.04 -
    Title for Gender
    Units: subjects
        Female
    34 34
        Male
    77 77

    End points

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    End points reporting groups
    Reporting group title
    Macitentan 10 mg
    Reporting group description
    Subjects received macitentan 10 milligrams (mg) oral tablets once daily with or without food from Day 1 either until the end of the treatment (129 weeks) or when sponsor decided to stop this study.

    Primary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects with Treatment-emergent Adverse Events (TEAEs) [1]
    End point description
    An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Any AE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent. The RUBATO open-label extension set (OLES) included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 milligrams (mg).
    End point type
    Primary
    End point timeframe
    Up to 133 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    111
    Units: subjects
    68
    No statistical analyses for this end point

    Primary: Number of Subjects with Treatment-emergent Serious AEs (SAEs)

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    End point title
    Number of Subjects with Treatment-emergent Serious AEs (SAEs) [2]
    End point description
    An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is life-threatening experience, is a congenital anomaly/birth defect and may jeopardize subject and/or may require medical or surgical intervention to prevent one of the outcomes listed above. Any SAE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg.
    End point type
    Primary
    End point timeframe
    Up to 133 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    111
    Units: subjects
    18
    No statistical analyses for this end point

    Primary: Number of Subjects with TEAEs Leading to Death

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    End point title
    Number of Subjects with TEAEs Leading to Death [3]
    End point description
    An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Any AE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg.
    End point type
    Primary
    End point timeframe
    Up to 133 weeks
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    111
    Units: subjects
    1
    No statistical analyses for this end point

    Primary: Number of Subjects with Treatment-emergent Marked Laboratory Abnormalities up to 30 Days After Study Treatment Discontinuation

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    End point title
    Number of Subjects with Treatment-emergent Marked Laboratory Abnormalities up to 30 Days After Study Treatment Discontinuation [4]
    End point description
    Number of subjects with treatment-emergent marked laboratory abnormalities (Hemoglobin [gram/Litre{L}], Platelets [10^9/L], Leukocytes [10^9/L], Lymphocytes [10^9/L], Neutrophils [10^9/L], Prothrombin International Normalized Ratio [PINR; Ratio], Aspartate Aminotransferase [Units/L {U/L}], Bilirubin [micromoles/L {mcmol/L}], Alkaline Phosphatase [U/L], Glomerular Filtration Rate [millilitre/minute/1.73 metre square], Glucose [mmol/L], Potassium [mmol/L], Sodium [mmol/L], Triglycerides [mmol/L] were reported. Abnormalities that occurred after study treatment start and up to 30 days after study treatment discontinuation, that were not present at baseline, were treatment-emergent. RUBATO OLES: all subjects who were enrolled in this study and received at least 1 dose of macitentan 10mg. n=subjects who were analysed for specified categories; >=:greater than or equal to; <=:less than or equal to; ULN=upper limit of normal; L=Low, H=High, LLL=lower/worse than LL, HHH=higher/worse than HH.
    End point type
    Primary
    End point timeframe
    Up to 133 weeks
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    111
    Units: subjects
        Hemoglobin: LL<100; n=111
    1
        Platelets: LL (< 75); n=108
    3
        Leukocytes: LLL (< 1.9); n=107
    2
        Leukocytes: LL (< 3.0); n=107
    10
        Lymphocytes: HH (> 4.0); n=106
    1
        Neutrophils: LL (< 1.5); n=106
    3
        PINR: HH (>=1.5 ULN); n=103
    4
        PINR: HHH (>= 2.5 ULN); n=103
    1
        Aspartate Aminotransferase: HH (>=3 ULN); n=111
    1
        Bilirubin: HH (>=2 ULN); n=107
    1
        Alkaline Phosphatase: HH (> 2.5 ULN); n=106
    1
        Glomerular Filtration Rate: LL (< 60); n=106
    1
        Glucose: LL (< 3.0); n=106
    2
        Glucose: HH (> 8.9); n=106
    3
        Potassium: HH (>5.5); n=106
    1
        Sodium: LLL (<130); n=106
    1
        Triglycerides: HH (>3.42); n=106
    3
    No statistical analyses for this end point

    Primary: Number of Subjects with TEAEs Leading to Premature Discontinuation of Study Treatment

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    End point title
    Number of Subjects with TEAEs Leading to Premature Discontinuation of Study Treatment [5]
    End point description
    An adverse event is any untoward medical event that occurs in a subject administered an investigational product, and it does not necessarily indicate only events with clear causal relationship with the relevant investigational product. Any AE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) (limits included) within the analysis set was considered to be treatment-emergent. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg.
    End point type
    Primary
    End point timeframe
    Up to 133 weeks
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    111
    Units: subjects
    2
    No statistical analyses for this end point

    Primary: Change from Baseline in Hemoglobin Over Time

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    End point title
    Change from Baseline in Hemoglobin Over Time [6]
    End point description
    Change from baseline in hemoglobin over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    98
    Units: grams per litre (g/L)
    arithmetic mean (standard deviation)
        Week 26; n=98
    -6.0 ± 9.94
        Week 52; n=75
    -4.0 ± 9.19
        Week 78; n=42
    -5.0 ± 7.20
        Week 104; n=18
    -2.4 ± 10.66
        Week 130; n=3
    5.7 ± 19.35
    No statistical analyses for this end point

    Primary: Change from Baseline in Hematocrit Over Time

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    End point title
    Change from Baseline in Hematocrit Over Time [7]
    End point description
    Change from baseline in hematocrit over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    100
    Units: Litre/Litre (L/L)
    arithmetic mean (standard deviation)
        Week 26; n=100
    -0.016 ± 0.0323
        Week 52; n=74
    -0.007 ± 0.0288
        Week 78; n=42
    -0.011 ± 0.0247
        Week 104; n=18
    -0.008 ± 0.0285
        Week 130; n=3
    0.010 ± 0.0624
    No statistical analyses for this end point

    Primary: Change from Baseline in Leukocytes, Neutrophils, Lymphocytes, and Platelets Over Time

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    End point title
    Change from Baseline in Leukocytes, Neutrophils, Lymphocytes, and Platelets Over Time [8]
    End point description
    Change from baseline in leukocytes, neutrophils, lymphocytes, and platelets over time were reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    100
    Units: 10^9/L
    arithmetic mean (standard deviation)
        Leukocytes: Week 26; n=100
    -0.358 ± 1.2966
        Leukocytes: Week 52; n=75
    -0.222 ± 1.3677
        Leukocytes: Week 78; n=42
    -0.300 ± 1.2868
        Leukocytes: Week 104; n=18
    -0.255 ± 1.2914
        Leukocytes: Week 130; n=3
    -0.560 ± 1.1186
        Neutrophils: Week 26; n=98
    -0.185 ± 1.0712
        Neutrophils: Week 52; n=75
    -0.074 ± 1.0624
        Neutrophils: Week 78; n=42
    -0.233 ± 1.0569
        Neutrophils: Week 104; n=18
    -0.105 ± 1.1060
        Neutrophils: Week 130; n=3
    -0.400 ± 1.0130
        Lymphocytes: Week 26; n=98
    -0.153 ± 0.3176
        Lymphocytes: Week 52; n=75
    -0.098 ± 0.5366
        Lymphocytes: Week 78; n=42
    -0.016 ± 0.3046
        Lymphocytes: Week 104; n=18
    -0.089 ± 0.3181
        Lymphocytes: Week 130; n=3
    -0.113 ± 0.2223
        Platelets: Week 26; n=100
    -9.2 ± 24.94
        Platelets: Week 52; n=74
    -4.3 ± 30.54
        Platelets: Week 78; n=42
    -8.1 ± 24.18
        Platelets: Week 104; n=18
    -11.1 ± 25.08
        Platelets: Week 130; n=3
    6.7 ± 12.74
    No statistical analyses for this end point

    Primary: Change from Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) Over Time

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    End point title
    Change from Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) Over Time [9]
    End point description
    Change from baseline in systolic and diastolic arterial BP over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    101
    Units: millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Systolic BP: Week 26; n=101
    -0.7 ± 13.00
        Systolic BP: Week 52; n=75
    -1.7 ± 14.81
        Systolic BP: Week 78; n=43
    -0.7 ± 14.79
        Systolic BP: Week 104; n=18
    0.7 ± 6.49
        Systolic BP: Week 130; n=3
    -12 ± 8.72
        Diastolic BP: Week 26; n=101
    -2.9 ± 12.63
        Diastolic BP: Week 52; n=75
    -0.9 ± 12.56
        Diastolic BP: Week 78; n=43
    -1.6 ± 11.61
        Diastolic BP: Week 104; n=18
    2.6 ± 9.65
        Diastolic BP: Week 130; n=3
    -0.7 ± 7.23
    No statistical analyses for this end point

    Primary: Change from Baseline in Pulse Rate Over Time

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    End point title
    Change from Baseline in Pulse Rate Over Time [10]
    End point description
    Change from baseline in pulse rate over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    101
    Units: beats per minute (bpm)
    arithmetic mean (standard deviation)
        Week 26; n=101
    -2.1 ± 10.48
        Week 52; n=75
    0.9 ± 10.95
        Week 78; n=43
    -1.3 ± 10.12
        Week 104; n=18
    -1.7 ± 8.78
        Week 130; n=3
    -0.3 ± 13.05
    No statistical analyses for this end point

    Primary: Change from Baseline in Oxygen Saturation (SpO2) Over Time

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    End point title
    Change from Baseline in Oxygen Saturation (SpO2) Over Time [11]
    End point description
    Change from baseline in SpO2 over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analyzed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    99
    Units: percentage of SpO2 (%)
    arithmetic mean (standard deviation)
        Week 26; n=99
    0.2 ± 3.22
        Week 52; n=75
    0.2 ± 2.79
        Week 78; n=43
    -0.5 ± 2.52
        Week 104; n=18
    0.3 ± 2.44
        Week 130; n=3
    3.3 ± 2.31
    No statistical analyses for this end point

    Primary: Change from Baseline in Body Weight Over Time

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    End point title
    Change from Baseline in Body Weight Over Time [12]
    End point description
    Change from baseline in body weight over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    102
    Units: kilograms (kg)
    arithmetic mean (standard deviation)
        Week 26; n=102
    0.8 ± 2.89
        Week 52; n=75
    0.9 ± 4.23
        Week 78; n=43
    1.7 ± 3.65
        Week 104; n=18
    2.0 ± 4.17
        Week 130; n=3
    2.6 ± 5.54
    No statistical analyses for this end point

    Primary: Change from Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP), and Gamma Glutamyl Transferase (GGT) Over Time

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    End point title
    Change from Baseline in Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), Alkaline Phosphatase (AP), and Gamma Glutamyl Transferase (GGT) Over Time [13]
    End point description
    Change from baseline in ALT, AST, AP, and GGT over time were reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    103
    Units: units per litre (U/L)
    arithmetic mean (standard deviation)
        ALT: Week 26; n=101
    -2.0 ± 8.57
        ALT: Week 52; n=75
    -2.1 ± 10.40
        ALT: Week 78; n=43
    -2.7 ± 11.32
        ALT: Week 104; n=18
    -6.8 ± 15.72
        ALT: Week 130; n=3
    -13.7 ± 23.69
        AST: Week 26; n=100
    -1.3 ± 8.39
        AST: Week 52; n=75
    -1.7 ± 9.60
        AST: Week 78; n=42
    -3.0 ± 11.39
        AST: Week 104; n=18
    -6.1 ± 17.03
        AST: Week 130; n=3
    -21.3 ± 41.43
        AP: Week 26; n=103
    -7.7 ± 36.04
        AP: Week 52; n=75
    -1.9 ± 25.25
        AP: Week 78; n=43
    -6.6 ± 28.02
        AP: Week 104; n=18
    -21.8 ± 53.46
        AP: Week 130; n=3
    6.7 ± 6.03
        GGT: Week 26; n=103
    -1.2 ± 14.85
        GGT: Week 52; n=75
    1.2 ± 15.74
        GGT: Week 78; n=43
    -2.2 ± 18.26
        GGT: Week 104; n=18
    -3.2 ± 18.13
        GGT: Week 130; n=3
    1.0 ± 13.23
    No statistical analyses for this end point

    Primary: Change from Baseline in Bilirubin, Direct Bilirubin, and Creatinine Over Time

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    End point title
    Change from Baseline in Bilirubin, Direct Bilirubin, and Creatinine Over Time [14]
    End point description
    Change from baseline in bilirubin, direct bilirubin, and creatinine over time were reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    103
    Units: micromoles per litre (mcmol/L)
    arithmetic mean (standard deviation)
        Bilirubin: Week 26; n=103
    -0.9 ± 6.62
        Bilirubin: Week 52; n=75
    -1.1 ± 10.41
        Bilirubin: Week 78; n=43
    -0.5 ± 5.68
        Bilirubin: Week 104; n=18
    -0.8 ± 6.13
        Bilirubin: Week 130; n=3
    -1.3 ± 2.89
        Direct Bilirubin: Week 26; n=101
    -0.1 ± 1.14
        Direct Bilirubin: Week 52; n=72
    0.0 ± 1.29
        Direct Bilirubin: Week 78; n=41
    0.0 ± 1.00
        Direct Bilirubin: Week 104; n=18
    -0.2 ± 1.25
        Direct Bilirubin: Week 130; n=3
    -1.0 ± 1.00
        Creatinine: Week 26; n=102
    0.2 ± 9.27
        Creatinine: Week 52; n=75
    0.9 ± 9.16
        Creatinine: Week 78; n=42
    0.8 ± 8.22
        Creatinine: Week 104; n=18
    0.1 ± 8.10
        Creatinine: Week 130; n=3
    -0.7 ± 5.51
    No statistical analyses for this end point

    Primary: Change from Baseline in Glomerular Filtration Rate (GFR) Over Time

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    End point title
    Change from Baseline in Glomerular Filtration Rate (GFR) Over Time [15]
    End point description
    Change from baseline in GFR over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    102
    Units: millilitres/minute/1.73 metre square
    arithmetic mean (standard deviation)
        Week 26; n=102
    -0.9 ± 15.43
        Week 52; n=75
    -2.0 ± 15.22
        Week 78; n=42
    -0.5 ± 13.26
        Week 104; n=17
    0.4 ± 17.00
        Week 130; n=3
    -1.7 ± 7.57
    No statistical analyses for this end point

    Primary: Change from Baseline in Prothrombin Time Over Time

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    End point title
    Change from Baseline in Prothrombin Time Over Time [16]
    End point description
    Change from baseline in prothrombin time over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    98
    Units: seconds
    arithmetic mean (standard deviation)
        Week 26; n=98
    -0.31 ± 3.523
        Week 52; n=73
    -0.05 ± 4.038
        Week 78; n=42
    -0.38 ± 2.293
        Week 104; n=18
    -1.12 ± 3.317
        Week 130; n=3
    -0.57 ± 0.651
    No statistical analyses for this end point

    Primary: Change from Baseline in Prothrombin International Normalized Ratio Over Time

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    End point title
    Change from Baseline in Prothrombin International Normalized Ratio Over Time [17]
    End point description
    Change from baseline in prothrombin international normalized ratio over time was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Primary
    End point timeframe
    Baseline up to Week 130
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No inferential statistics was planned for this primary endpoint.
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    98
    Units: ratio
    arithmetic mean (standard deviation)
        Week 26; n=98
    -0.06 ± 0.401
        Week 52; n=73
    -0.06 ± 0.456
        Week 78; n=42
    -0.12 ± 0.245
        Week 104; n=18
    -0.16 ± 0.379
        Week 130; n=3
    -0.07 ± 0.058
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Count per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac)

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    End point title
    Change from Baseline in Mean Count per Minute of Daily Physical Activity Measured by Accelerometer (PA-Ac)
    End point description
    Change from baseline in mean count per minute of daily PA-Ac was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 26, Week 52, Week 78, and Week 104
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    42
    Units: mean count per minute
    arithmetic mean (standard deviation)
        Week 26; n=42
    19.74 ± 131.622
        Week 52; n=20
    44.58 ± 153.196
        Week 78; n=10
    99.14 ± 165.965
        Week 104; n=2
    -62.87 ± 189.264
    No statistical analyses for this end point

    Secondary: Change from Baseline in Peak Oxygen Uptake/Consumption (VO2)

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    End point title
    Change from Baseline in Peak Oxygen Uptake/Consumption (VO2)
    End point description
    Change from baseline in peak VO2 was reported. The RUBATO OLES included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint; "n" specifies those subjects who were analysed at specified timepoints.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 52, and Week 104
    End point values
    Macitentan 10 mg
    Number of subjects analysed
    71
    Units: Millilitres/kilogram/minute (mL/kg/min)
    arithmetic mean (standard deviation)
        Week 52; n=71
    -0.82 ± 2.724
        Week 104; n=12
    -0.93 ± 1.968
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 133 weeks
    Adverse event reporting additional description
    The RUBATO open-label extension set (OLES) included all subjects who were enrolled in this study and received at least 1 dose of macitentan 10 milligrams (mg).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Macitentan 10 mg
    Reporting group description
    Subjects received macitentan 10 milligrams (mg) oral tablets once daily with or without food from Day 1 either until the end of the treatment (129 weeks) or when sponsor decided to stop this study.

    Serious adverse events
    Macitentan 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    18 / 111 (16.22%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular Carcinoma
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Depression
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental Disorder
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic Stenosis
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Spermatozoa Progressive Motility Decreased
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Sperm Concentration Decreased
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleurisy
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Clonic Convulsion
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Colitis Ulcerative
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Incarcerated Inguinal Hernia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic Mass
         subjects affected / exposed
    1 / 111 (0.90%)
         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 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cytomegalovirus Infection
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 111 (0.90%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Covid-19
         subjects affected / exposed
    1 / 111 (0.90%)
         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 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 111 (25.23%)
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    7 / 111 (6.31%)
         occurrences all number
    7
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 111 (7.21%)
         occurrences all number
    15
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    7 / 111 (6.31%)
         occurrences all number
    8
    Infections and infestations
    Covid-19
         subjects affected / exposed
    13 / 111 (11.71%)
         occurrences all number
    13

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Feb 2019
    The purpose of this amendment was to harmonize the RUBATO open-label (OL) protocol with the recently amended RUBATO double blind (DB) study. Changes were introduced to the RUBATO study to implement recommendations from the Fontan Advisory Board (meeting held on 19 September 2018) on ways to improve recruitment and compliance with study examinations. These measures were expected to reduce study subject burden while preserving the scientific and medical merit of the RUBATO study. Reducing the burden on subjects resulted in increased subject compliance with the evaluation and monitoring visits, hence enhanced the completeness of the efficacy and safety assessments.
    16 Jul 2020
    The purpose of this amendment was to update the exclusion criteria, initiation of forbidden medication and concomitant therapy sections pertaining to newly identified drug-drug interactions (DDI) between macitentan and fluconazole (a dual moderate inhibitor of cytochrome P450 [CYP]3A4 and CYP2C9) from a preclinical study on implications of role of CYP2C9 in the metabolism of macitentan.
    21 Jul 2020
    The purpose of this amendment was a preclinical study newly identified DDI between macitentan and fluconazole (a dual moderate inhibitor of CYP3A4 and CYP2C9), and concluded that there were implications on the role of CYP2C9 in the metabolism of macitentan. This led to the need for an amendment for an urgent safety measure (USM). At the time of the USM, there were sites who had implemented protocol version 1 and others were already on protocol version 2. As USM updates could not be combined with other updates to the protocol, a version 1.1 had to be created for regulatory submission and approval (for those on version 1) before transitioning those sites to version 3 (which combined version 2 and the USM information) as well.
    19 Nov 2020
    The purpose of this amendment was to align the study protocol with updates made for the AC-055H301 RUBATO double-blind study. a. Countries that did not enroll candidates for RUBATO open-label (OL) during the RUBATO study were removed from the section on acceptable methods of contraception; b. Study treatment supply and storage information was simplified was part of the Actelion and Janssen integration; c. The study duration was adapted to help ensure treatment with macitentan was available after the expected treatment duration of 2 years per subject; d. Global safety updates were made to align the protocol with Janssen processes as part of the Janssen and Actelion integration; e. Based on recent literature on the potential prognostic value of cardiopulmonary exercise testing (CPET) in Fontan-palliated subjects, the sponsor added 2 new exploratory efficacy endpoint variables that were not collected thus far but were already part of CPET assessments evaluated by the central leading facility. One of these variables, oxygen update/consumption at ventilatory anaerobic threshold, had also been claimed to be of interest in a recently completed study with a phosphodiesterase 5 inhibitor. Finally, an appendix was added to facilitate evaluation of exclusion criterion 3.3.

    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.
    The study was stopped prematurely because the main double-blind (DB) study did not meet the primary and secondary efficacy endpoints.
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