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    Clinical Trial Results:
    A Long-term, Multicenter, Single-arm, Open-label Extension of the SERENADE Study, to Assess the Safety and Efficacy of Macitentan in Subjects with Heart Failure with Preserved Ejection Fraction and Pulmonary Vascular Disease

    Summary
    EudraCT number
    		 2018-001603-37
    Trial protocol
    		 BG   DE   HU   DK   SE   RO  
    Global end of trial date
    12 Oct 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Oct 2022
    First version publication date
    28 Oct 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055G203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03714815
    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)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Oct 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to describe the long-term safety of macitentan 10 milligrams (mg) in subjects with heart failure with preserved ejection fraction (HFpEF) and pulmonary vascular disease (PVD).
    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
    21 Dec 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 1
    Country: Number of subjects enrolled
    Austria: 2
    Country: Number of subjects enrolled
    Bulgaria: 8
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Israel: 23
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Romania: 4
    Country: Number of subjects enrolled
    Russian Federation: 14
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    91
    EEA total number of subjects
    34
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    14
    From 65 to 84 years
    69
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Out of the 91 enrolled subjects, 76 subjects 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
    		 Eligible subjects who remained in the main study (2016-003653-15) for at least 24 weeks after randomisation entered this open-label extension study to receive macitentan 10 milligrams (mg) tablet orally once daily until the end of the treatment (treatment exposure ranged from 0.4 to 126 weeks).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    Other name
    JNJ-67896062 ACT-064992
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Macitentan 10 mg tablet was administered once daily until the end of treatment (treatment exposure ranged from 0.4 to 126 weeks).

    Number of subjects in period 1
    		Macitentan 10 mg
    Started
    91
    Completed
    76
    Not completed
    15
         Adverse event, serious fatal
    11
         Physician decision
    2
         Consent withdrawn by subject
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Macitentan 10 mg
    Reporting group description
    		 Eligible subjects who remained in the main study (2016-003653-15) for at least 24 weeks after randomisation entered this open-label extension study to receive macitentan 10 milligrams (mg) tablet orally once daily until the end of the treatment (treatment exposure ranged from 0.4 to 126 weeks).

    Reporting group values
    		 Macitentan 10 mg Total
    Number of subjects
    		 91 91
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 14 14
        From 65 to 84 years
    		 69 69
        85 years and over
    		 8 8
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 72.7 ( 9.21 ) -
    Title for Gender
    Units: subjects
        Female
    		 59 59
        Male
    		 32 32

    End points

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    End points reporting groups
    Reporting group title
    Macitentan 10 mg
    Reporting group description
    		 Eligible subjects who remained in the main study (2016-003653-15) for at least 24 weeks after randomisation entered this open-label extension study to receive macitentan 10 milligrams (mg) tablet orally once daily until the end of the treatment (treatment exposure ranged from 0.4 to 126 weeks).

    Primary: Number of Subjects with All-cause Deaths up to 30 Days After Study Treatment Discontinuation

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    End point title
    		 Number of Subjects with All-cause Deaths up to 30 Days After Study Treatment Discontinuation [1]
    End point description
    Number of subjects with all-cause deaths up to 30 days after study treatment discontinuation were reported. All-cause deaths are defined as all anticipated and unanticipated deaths due to any cause. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 milligrams (mg).
    End point type
    Primary
    End point timeframe
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 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
    91
    Units: subjects
    11
    No statistical analyses for this end point

    Primary: Number of Subjects with All-cause Hospital Admissions up to 30 Days After Study Treatment Discontinuation

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    End point title
    		 Number of Subjects with All-cause Hospital Admissions up to 30 Days After Study Treatment Discontinuation [2]
    End point description
    Number of subjects with all-cause hospital admissions up to 30 days after study treatment discontinuation were reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg.
    End point type
    Primary
    End point timeframe
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 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
    91
    Units: subjects
    42
    No statistical analyses for this end point

    Primary: Number of Subjects with Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) up to 30 Days After Study Treatment Discontinuation

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    End point title
    		 Number of Subjects with Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) up to 30 Days After Study Treatment Discontinuation [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. SAE is any AE that results in: death, persistent or significant disability/incapacity, requires inpatient hospitalization or prolongation of existing hospitalization, is a suspected transmission of any infectious agent via a medicinal product, 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 AE and SAE occurring at or after the study treatment start up to 30 days after end of treatment (EOT) within the analysis set was considered to be treatment-emergent. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg.
    End point type
    Primary
    End point timeframe
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 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
    91
    Units: subjects
        TEAEs
    81
        TESAEs
    49
    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 [4]
    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 EOT within the analysis set was considered to be treatment-emergent. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg.
    End point type
    Primary
    End point timeframe
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 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
    91
    Units: subjects
    25
    No statistical analyses for this end point

    Primary: Change from Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 24

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    End point title
    		 Change from Baseline in Systolic and Diastolic Arterial Blood Pressure (BP) at Week 24 [5]
    End point description
    Change from baseline in systolic and diastolic arterial BP at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    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
    62
    Units: millimeters of mercury (mmHg)
    arithmetic mean (standard deviation)
        Systolic BP
    -5.01 ( 13.152 )
        Diastolic BP
    -3.34 ( 9.903 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Systolic and Diastolic Arterial BP at Week 52

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    End point title
    		 Change from Baseline in Systolic and Diastolic Arterial BP at Week 52 [6]
    End point description
    Change from baseline in systolic and diastolic arterial BP at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    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
    53
    Units: mmHg
    arithmetic mean (standard deviation)
        Systolic BP
    -2.10 ( 20.855 )
        Diastolic BP
    -0.79 ( 11.685 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Pulse Rate at Week 24

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    End point title
    		 Change from Baseline in Pulse Rate at Week 24 [7]
    End point description
    Change from baseline in pulse rate at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    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
    62
    Units: beats per minute (bpm)
        arithmetic mean (standard deviation)
    0.59 ( 9.706 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Pulse Rate at Week 52

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    End point title
    		 Change from Baseline in Pulse Rate at Week 52 [8]
    End point description
    Change from baseline in pulse rate at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    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
    53
    Units: bpm
        arithmetic mean (standard deviation)
    2.62 ( 18.441 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Body Weight at Week 24

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    End point title
    		 Change from Baseline in Body Weight at Week 24 [9]
    End point description
    Change from baseline in body weight at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    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
    64
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    0.25 ( 6.353 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Body Weight at Week 52

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    End point title
    		 Change from Baseline in Body Weight at Week 52 [10]
    End point description
    Change from baseline in body weight at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    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
    56
    Units: kg
        arithmetic mean (standard deviation)
    -0.16 ( 8.200 )
    No statistical analyses for this end point

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

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    End point title
    		 Number of Subjects with Treatment-emergent Marked Laboratory Abnormalities (MLAs) up to 30 Days After Study Treatment Discontinuation [11]
    End point description
    Number of subjects with treatment-emergent MLAs (Hemoglobin [grams/Litre{L}], Hematocrit [L/L], Leukocytes [10^9cells/L], Lymphocytes [10^9cells/L], Alanine Aminotransferase [Units/L {U/L}], Aspartate Aminotransferase [U/L], Bilirubin [micromoles/L {mcmol/L}], Alkaline Phosphatase [U/L], Creatinine [mcmol/L], Urea Nitrogen [mmol/L], Urate [mcmol/L], Potassium [mmol/L], Sodium [mmol/L], Magnesium [mmol/L], Calcium [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. SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. N=subjects evaluable for this endpoint; >:greater than; <:less than; ULN=upper limit of normal; L=Low, H=High, LL=low/low, HH=high/high LLL=lower/worse than LL, HHH=higher/worse than HH.
    End point type
    Primary
    End point timeframe
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
    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
    85
    Units: subjects
        Hemoglobin:LL<100
    10
        Hematocrit: LL(<0.28-females;<0.32-males)
    5
        Leukocytes: HH (>20.0)
    1
        Lymphocytes: LLL (<0.5)
    1
        Lymphocytes: LL (<0.8)
    10
        Alanine Aminotransferase: HH (>3 ULN)
    1
        Aspartate Aminotransferase: HH (>3 ULN)
    1
        Alkaline Phosphatase: HH (>2.5 ULN)
    1
        Bilirubin: HH (>2 ULN)
    1
        Bilirubin: HHH (>5 ULN)
    1
        Creatinine: HH (>1.5 ULN)
    2
        Urea Nitrogen: HH (>2.5 ULN)
    3
        Urate: HH (>590)
    15
        Urate: HHH (>720)
    3
        Sodium: LLL (<130)
    3
        Potassium: LLL (<3.0)
    1
        Potassium: LL (<3.2)
    5
        Potassium: HH (>5.5)
    5
        Magnesium: HHH (>1.23)
    1
        Calcium: LLL (<1.75)
    1
        Calcium: LL (<2.0)
    2
    No statistical analyses for this end point

    Primary: Change from Baseline in Hemoglobin at Week 24

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    End point title
    		 Change from Baseline in Hemoglobin at Week 24 [12]
    End point description
    Change from baseline in hemoglobin at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    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
    59
    Units: grams per litre (g/L)
        arithmetic mean (standard deviation)
    -4.13 ( 11.324 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Leukocytes and Platelets at Week 24

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    End point title
    		 Change from Baseline in Leukocytes and Platelets at Week 24 [13]
    End point description
    Change from baseline in leukocytes and platelets at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    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
    59
    Units: 10^9 cells/L
    arithmetic mean (standard deviation)
        Leukocytes
    -0.078 ( 1.6871 )
        Platelets
    1.39 ( 36.102 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Hemoglobin at Week 52

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    End point title
    		 Change from Baseline in Hemoglobin at Week 52 [14]
    End point description
    Change from baseline in hemoglobin at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    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
    51
    Units: g/L
        arithmetic mean (standard deviation)
    -1.10 ( 13.241 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Leukocytes and Platelets at Week 52

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    End point title
    		 Change from Baseline in Leukocytes and Platelets at Week 52 [15]
    End point description
    Change from baseline in leukocytes and platelets at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    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
    51
    Units: 10^9 cells/L
    arithmetic mean (standard deviation)
        Leukocytes
    -0.503 ( 1.5090 )
        Platelets
    -9.02 ( 37.285 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 24

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    End point title
    		 Change from Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 24 [16]
    End point description
    Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who 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 for specified categories.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    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
    59
    Units: units per litre (U/L)
    arithmetic mean (standard deviation)
        Alanine Aminotransferase; n=59
    -0.49 ( 7.590 )
        Aspartate Aminotransferase; n=58
    -0.2 ( 7.76 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 52

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    End point title
    		 Change from Baseline in Alanine Aminotransferase and Aspartate Aminotransferase at Week 52 [17]
    End point description
    Change from baseline in alanine aminotransferase and aspartate aminotransferase at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    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
    51
    Units: U/L
    arithmetic mean (standard deviation)
        Alanine Aminotransferase
    0.10 ( 7.529 )
        Aspartate Aminotransferase
    1.2 ( 6.52 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Bilirubin at Week 24

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    End point title
    		 Change from Baseline in Bilirubin at Week 24 [18]
    End point description
    Change from baseline in bilirubin at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    Notes
    [18] - 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
    58
    Units: micromoles per litre (mcmol/L)
        arithmetic mean (standard deviation)
    -0.0970 ( 4.20548 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Bilirubin at Week 52

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    End point title
    		 Change from Baseline in Bilirubin at Week 52 [19]
    End point description
    Change from baseline in bilirubin at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    Notes
    [19] - 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
    49
    Units: mcmol/L
        arithmetic mean (standard deviation)
    0.2041 ( 4.65018 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24

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    End point title
    		 Change from Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 24 [20]
    End point description
    Change from baseline in eGFR rate at Week 24 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    Notes
    [20] - 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
    59
    Units: millilitres/minute/1.73 metre square
        arithmetic mean (standard deviation)
    -4.05 ( 11.766 )
    No statistical analyses for this end point

    Primary: Change from Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52

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    End point title
    		 Change from Baseline in Estimated Glomerular Filtration Rate (eGFR) at Week 52 [21]
    End point description
    Change from baseline in eGFR rate at Week 52 was reported. The SERENADE OL safety analysis set included all subjects who received at least 1 dose of macitentan 10 mg. Here, "N" (number of subjects analysed) specifies number of subjects evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Week 52
    Notes
    [21] - 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
    51
    Units: millilitres/minute/1.73 metre square
        arithmetic mean (standard deviation)
    -1.80 ( 13.510 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 0.4 to 126 weeks)
    Adverse event reporting additional description
    The SERENADE OL safety analysis set included all subjects who 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
    		 Eligible subjects who remained in the main study (2016-003653-15) for at least 24 weeks after randomisation entered this open-label extension study to receive macitentan 10 milligrams (mg) tablet orally once daily until the end of the treatment (treatment exposure ranged from 0.4 to 126 weeks).

    Serious adverse events
    		 Macitentan 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    49 / 91 (53.85%)
         number of deaths (all causes)
    11
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon Cancer
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Malignant Neoplasm of Unknown Primary Site
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Plasma Cell Myeloma
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metastases to Peritoneum
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small Intestine Carcinoma
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Uterine Neoplasm
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Cardiac Pacemaker Replacement
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small Intestinal Resection
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Thyroidectomy
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest Pain
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    No Adverse Event
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ulcer Haemorrhage
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea Exertional
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Blood Potassium Increased
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    International Normalised Ratio Increased
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sars-Cov-2 Test Positive
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Limb Injury
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subcutaneous Haematoma
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wound Dehiscence
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute Left Ventricular Failure
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure Chronic
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    6 / 91 (6.59%)
         occurrences causally related to treatment / all
    3 / 10
         deaths causally related to treatment / all
    0 / 1
    Left Ventricular Failure
         subjects affected / exposed
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Sinus Node Dysfunction
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    5 / 91 (5.49%)
         occurrences causally related to treatment / all
    2 / 5
         deaths causally related to treatment / all
    1 / 1
    Nervous system disorders
    Cerebrovascular Accident
         subjects affected / exposed
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Ischaemic Stroke
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Radiculopathy
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Retinal Vein Thrombosis
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal Incarcerated Hernia
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Duodenal Ulcer Haemorrhage
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Hepatobiliary disorders
    Cholecystitis Acute
         subjects affected / exposed
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    5 / 91 (5.49%)
         occurrences causally related to treatment / all
    1 / 5
         deaths causally related to treatment / all
    0 / 1
    Urinary Retention
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal Impairment
         subjects affected / exposed
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral Disc Protrusion
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Covid-19
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Herpes Zoster
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 91 (3.30%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Pneumonia Viral
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 91 (2.20%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Metabolism and nutrition disorders
    Fluid Retention
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 91 (1.10%)
         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
    45 / 91 (49.45%)
    Investigations
    Weight Increased
         subjects affected / exposed
    5 / 91 (5.49%)
         occurrences all number
    6
    Haemoglobin Decreased
         subjects affected / exposed
    5 / 91 (5.49%)
         occurrences all number
    5
    Vascular disorders
    Hypotension
         subjects affected / exposed
    5 / 91 (5.49%)
         occurrences all number
    5
    Cardiac disorders
    Right Ventricular Failure
         subjects affected / exposed
    6 / 91 (6.59%)
         occurrences all number
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 91 (7.69%)
         occurrences all number
    9
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 91 (6.59%)
         occurrences all number
    6
    General disorders and administration site conditions
    Oedema Peripheral
         subjects affected / exposed
    7 / 91 (7.69%)
         occurrences all number
    13
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    6 / 91 (6.59%)
         occurrences all number
    6
    Nausea
         subjects affected / exposed
    5 / 91 (5.49%)
         occurrences all number
    6
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    11 / 91 (12.09%)
         occurrences all number
    12
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    7 / 91 (7.69%)
         occurrences all number
    7
    Pain in Extremity
         subjects affected / exposed
    6 / 91 (6.59%)
         occurrences all number
    7
    Infections and infestations
    Upper Respiratory Tract Infection
         subjects affected / exposed
    5 / 91 (5.49%)
         occurrences all number
    5
    Urinary Tract Infection
         subjects affected / exposed
    9 / 91 (9.89%)
         occurrences all number
    9

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Aug 2018
    The purpose of this amendment was to correct the description of the investigational medicinal product used in the study.
    16 May 2019
    The purpose of this amendment was to: introduce a new efficacy endpoint, the 6-minute walk distance (6MWD), assessed by the 6-minute walk test (6MWT), as part of a substudy to assess the change from baseline in exercise capacity; include the collection of mid-regional pro-atrial natriuretic peptide (MR-proANP) and a research biomarker (optional) sample at scheduled visits and at the time of a fluid retention or worsening heart failure event to continue the analysis from the main study; include the collection of N-terminal pro-brain natriuretic peptide (NT-proBNP) at the time of fluid retention or worsening heart failure event to support the clinical event committee (CEC) review.
    06 Feb 2020
    The purpose of this amendment was to: align the strategy for subject enrollment into this open-label (OL) extension study due to premature termination of recruitment into the main study (AC-055G202/ SERENADE)-eligible subjects could enroll into this OL extension study after remaining in the main study for at least 24 weeks; remove evaluation of the efficacy assessments (that is, Kansas City cardiomyopathy questionnaire, accelerometry, echocardiography, and blood sample collection for NT-proBNP, MR-proANP, and biomarkers) in an effort to simplify the study and reduce assessment burden for subjects and study site personnel; stop the substudy assessments (6MWT and Borg Dyspnea Index), as number of subjects participating in the substudy was too low to allow for meaningful interpretation of results; remove CEC adjudication in line with the main study global protocol Version 6. The CEC was appointed to review and adjudicate in a blinded fashion worsening heart failure event, the reasons for hospitalization, and causes of death. The rationale was based on the reduction of the double-blind treatment period from 52 weeks to 24 weeks coupled with the low occurrence of clinical events, which did not allow meaningful conclusions to be drawn. However, the investigator assessment of worsening heart failure events was continued. Removal of the CEC did not affect safety monitoring and therefore, the decision was also endorsed by the independent data monitoring committee; created a single version of the SERENADE OL AC-055G203 protocol by incorporating voluntary harmonization procedure (VHP)-mandated changes into the global protocol version.
    16 Jul 2020
    The purpose of this amendment was to update the exclusion criteria and concomitant therapy sections pertaining to new information regarding a drug-drug-interaction of macitentan with moderate dual cytochrome P450 (CYP)3A4 and CYP2C9 inhibitors or co-administration of a combination of moderate CYP3A4 inhibitors and moderate CYP2C9 inhibitors.
    26 Nov 2020
    The purpose of this amendment was to adapt to changed internal safety language and reporting processes to align with TransCelerate template, to update information about post-treatment access program, study treatment storage conditions, forbidden medications, Actelion’s policy for study data disclosure, and to make minor editorial revisions and corrections.

    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.
    Limited number of efficacy parameters were assessed in an exploratory manner. Study was stopped prematurely as main double-blind study did not meet the primary efficacy endpoint.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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