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    Clinical Trial Results:
    Prospective, Multicenter, Open-label Study Evaluating the Effects of First-line Oral Combination Therapy of Macitentan and TadalafIl in Patients with Newly Diagnosed Pulmonary Arterial Hypertension

    Summary
    EudraCT number
    2015-002078-19
    Trial protocol
    FR  
    Global end of trial date
    10 Sep 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    21 Sep 2019
    First version publication date
    21 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055-405
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02968901
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals
    Sponsor organisation address
    21 Boulevard De La Madeleine, Paris, France, 75001
    Public contact
    Clinical Registry Group, Actelion Pharmaceuticals, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Actelion Pharmaceuticals, 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 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Sep 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main objective of this study was to document the effect of first line dual oral combination therapy with macitentan 10 milligram (mg) and tadalafil 40 mg on pulmonary vascular resistance (PVR) in treatment-naïve subjects with newly diagnosed pulmonary arterial hypertension (PAH).
    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. Safety evaluations included monitoring of adverse events (AEs), serious adverse events (SAEs), clinical laboratory parameters (liver function tests [LFTs], creatinine, hemoglobin and biomarkers of myocardial stress), vital signs, electrocardiograms (ECG), weight, height and physical examination.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Nov 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    25
    From 65 to 84 years
    21
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 46 subjects were enrolled and treated with macitentan and tadalafil. Of these, 2 subjects discontinued the study and 44 subjects entered the extension period of whom 39 subjects completed this OPTIMA study and were enrolled into the UMBRELLA (AC-055-314 [NCT03422328]) 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 / Tadalafil 40 mg
    Arm description
    Subjects received macitentan 10 mg film-coated tablets and tadalafil 40 mg (2*20 mg) tablets administered orally once daily starting on Day 1 of Open-label period up to Day 15. Subject were then continued to Maintenence treatment period (Day 15 to End of treatment 1 [EOT1]) and then to Extension period (EOT1 to End of treatment 2 (EOT2). EOT1, defined as the earliest of the followings: a. Visit 3 at Week 16 ± 1 week; b. Pulmonary arterial hypertension (PAH) progression requiring intake of other PAH-specific drug(s); c. Sponsor decision to stop the trial;d. Subject or investigator decision to discontinue both study treatments. EOT2, defined as the earliest time at which one of the following occurred: a. Commercial availability and reimbursement of macitentan in France; b. Sponsor decision to stop the trial; c. Subject or investigator decision to discontinue both study treatments.
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan 10 mg
    Investigational medicinal product code
    Other name
    Opsumit®
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received macitentan 10 mg once daily.

    Investigational medicinal product name
    Tadalafil 40 mg
    Investigational medicinal product code
    Other name
    Adcirca®)
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received tadalafil 40 mg once daily.

    Number of subjects in period 1
    Macitentan 10 mg / Tadalafil 40 mg
    Started
    46
    Completed
    39
    Not completed
    7
         Physician decision
    2
         Adverse event, serious fatal
    3
         Consent withdrawn by subject
    1
         Sponsor decision
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Macitentan 10 mg / Tadalafil 40 mg
    Reporting group description
    Subjects received macitentan 10 mg film-coated tablets and tadalafil 40 mg (2*20 mg) tablets administered orally once daily starting on Day 1 of Open-label period up to Day 15. Subject were then continued to Maintenence treatment period (Day 15 to End of treatment 1 [EOT1]) and then to Extension period (EOT1 to End of treatment 2 (EOT2). EOT1, defined as the earliest of the followings: a. Visit 3 at Week 16 ± 1 week; b. Pulmonary arterial hypertension (PAH) progression requiring intake of other PAH-specific drug(s); c. Sponsor decision to stop the trial;d. Subject or investigator decision to discontinue both study treatments. EOT2, defined as the earliest time at which one of the following occurred: a. Commercial availability and reimbursement of macitentan in France; b. Sponsor decision to stop the trial; c. Subject or investigator decision to discontinue both study treatments.

    Reporting group values
    Macitentan 10 mg / Tadalafil 40 mg Total
    Number of subjects
    46 46
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    25 25
        From 65 to 84 years
    21 21
        85 years and over
    0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    57.4 ± 14.89 -
    Title for Gender
    Units: subjects
        Female
    30 30
        Male
    16 16

    End points

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    End points reporting groups
    Reporting group title
    Macitentan 10 mg / Tadalafil 40 mg
    Reporting group description
    Subjects received macitentan 10 mg film-coated tablets and tadalafil 40 mg (2*20 mg) tablets administered orally once daily starting on Day 1 of Open-label period up to Day 15. Subject were then continued to Maintenence treatment period (Day 15 to End of treatment 1 [EOT1]) and then to Extension period (EOT1 to End of treatment 2 (EOT2). EOT1, defined as the earliest of the followings: a. Visit 3 at Week 16 ± 1 week; b. Pulmonary arterial hypertension (PAH) progression requiring intake of other PAH-specific drug(s); c. Sponsor decision to stop the trial;d. Subject or investigator decision to discontinue both study treatments. EOT2, defined as the earliest time at which one of the following occurred: a. Commercial availability and reimbursement of macitentan in France; b. Sponsor decision to stop the trial; c. Subject or investigator decision to discontinue both study treatments.

    Primary: Pulmonary Vascular Resistance (PVR) Ratio between Baseline and Week 16 as Assessed by Right Heart Catheterization (RHC)

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    End point title
    Pulmonary Vascular Resistance (PVR) Ratio between Baseline and Week 16 as Assessed by Right Heart Catheterization (RHC) [1]
    End point description
    PVR was calculated and assessed by RHC. PVR [dyn.sec/cm−5] was calculated as mPAP-PCWP/CO*80 (If PCWP was missing, LVEDP was used instead). Here, mPAP, PCWP, CO and LVEDP means Mean pulmonary arterial pressure, Pulmonary capillary wedge pressure, Cardiac output and Left ventricular end-diastolic pressure respectively. A geometric mean ratio of Week 16 to baseline <1 corresponded to an improvement (reduction in PVR from baseline). The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
    End point type
    Primary
    End point timeframe
    Baseline and Week 16
    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: Descriptive statistics were done, no inferential statistical analyses were performed.
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    46
    Units: Ratio
        geometric mean (confidence interval 95%)
    0.53 (0.47 to 0.59)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Clinically Meaningful Improvement in PVR at Week 16 (decrease of >=30 Percent [%] from Baseline to Week 16)

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    End point title
    Percentage of Subjects with Clinically Meaningful Improvement in PVR at Week 16 (decrease of >=30 Percent [%] from Baseline to Week 16)
    End point description
    Percentage of subjects with clinically meaningful improvement in PVR at Week 16 (decrease of >=30% from baseline to Week 16) were reported. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    46
    Units: Percentage of subjects
        number (confidence interval 95%)
    86.96 (73.74 to 95.06)
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 16 in Mean Right Atrial Pressure (mRAP)

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    End point title
    Change from Baseline to Week 16 in Mean Right Atrial Pressure (mRAP)
    End point description
    Change from baseline to Week 16 in mRAP was reported. mRAP is the mean blood pressure in the right atrium of the heart. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    46
    Units: millimeter of mercury (mmHg)
        arithmetic mean (standard deviation)
    -0.28 ± 5.56
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 16 in Mean Pulmonary Arterial Pressure (mPAP)

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    End point title
    Change from Baseline to Week 16 in Mean Pulmonary Arterial Pressure (mPAP)
    End point description
    Change from baseline to Week 16 in mean pulmonary arterial pressure (mPAP) was reported. mPAP is the mean blood pressure inside the pulmonary artery which moves the blood from the heart to the lungs. Monitoring of mPAP can detect small changes in the function of the heart. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    46
    Units: mmHg
        arithmetic mean (standard deviation)
    -7.83 ± 13.07
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 16 in Cardiac Index (CI)

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    End point title
    Change from Baseline to Week 16 in Cardiac Index (CI)
    End point description
    Change from Baseline to Week 16 in cardiac index (CI) was reported. The cardiac index is an assessment of the function of the heart and relates the cardiac output to the subject's body size (the patient's body surface area). The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    46
    Units: Liter per minute per meter^2 (L/min/m^2)
        arithmetic mean (standard deviation)
    0.91 ± 0.66
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 16 in Total Pulmonary Resistance (TPR)

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    End point title
    Change from Baseline to Week 16 in Total Pulmonary Resistance (TPR)
    End point description
    Change from Baseline to Week 16 in total pulmonary resistance (TPR) was reported. TPR is the resistance the pulmonary circulation that must be overcome in order for the blood flow to occur. It takes into account the blood pressure in the pulmonary arteries and the cardiac output. It is an important measurement to monitor the function of the pulmonary circulation and detect disease progression or improvement. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    46
    Units: dyn*sec/cm^−5
        arithmetic mean (standard deviation)
    -431.97 ± 308.3
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 16 in Mixed Venous Oxygen Saturation (SvO2)

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    End point title
    Change from Baseline to Week 16 in Mixed Venous Oxygen Saturation (SvO2)
    End point description
    Change from baseline to Week 16 in mixed venous oxygen saturation (SvO2) was reported. SVO2 help assess tissue oxygen delivery. It describes the percentage of oxygen bound to hemoglobin in the blood which returns to the heart. This reflects the amount of residual oxygen in the blood after oxygen extraction by the tissues throughout the body. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement. Here 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    29
    Units: Percentage of Oxygen saturation
        arithmetic mean (standard deviation)
    5.53 ± 7.19
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 16 in 6-Minute Walk Distance (6MWD)

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    End point title
    Change from Baseline to Week 16 in 6-Minute Walk Distance (6MWD)
    End point description
    Change from baseline to Week 16 in 6-minute walk distance (6MWD) was reported. The purpose of the six minute walk is to test exercise tolerance and capacity. The test measures the distance an individual is able to walk over a total of six minutes on a hard, flat surface. The goal is for the individual to walk as far as possible in six minutes. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    46
    Units: Meters
        arithmetic mean (standard deviation)
    35.8 ± 67.7
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 16 in World Health Organization Functional Class (WHO-FC) (Change from WHO-FC III to WHO-FC I, from WHO-FC III to WHO-FC II, and WHO-FC II to WHO-FC I)

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    End point title
    Change from Baseline to Week 16 in World Health Organization Functional Class (WHO-FC) (Change from WHO-FC III to WHO-FC I, from WHO-FC III to WHO-FC II, and WHO-FC II to WHO-FC I)
    End point description
    Changes from baseline to Week 16 in WHO FC were dichotomized as worsening (that is, change > 0) versus no change or improvement (change <= 0). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (example. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (example. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Subjects in class IV manifest signs of right heart failure. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement. Here 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    36
    Units: Percentage of subjects
    number (not applicable)
        Change at Week 16: WHO-FC III to WHO-FC I
    5.56
        Change at Week 16: WHO-FC III to WHO-FC II
    55.56
        Change at Week 16: WHO-FC II to WHO-FC I
    70.00
    No statistical analyses for this end point

    Secondary: Percentage of Subjects with Improvement or Worsening of WHO-FC from Baseline to Week 16

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    End point title
    Percentage of Subjects with Improvement or Worsening of WHO-FC from Baseline to Week 16
    End point description
    Percentage of subjects with improvement/worsening of WHO-FC from Baseline to Week 16 were reported. WHO FC were dichotomized as worsening (that is, change > 0) versus no change or improvement (change <= 0). Class I: no symptoms with exercise or at rest. No limitation of activity. Class II: No symptoms at rest but slight limitation with ordinary activities causing symptoms (example. short of breath with climbing a flight of stairs, grocery shopping, or making the bed). Class III: may not have symptoms at rest but activities greatly limited by shortness of breath, fatigue, or near fainting. Class IV: symptoms at rest (example. dyspnea and/or fatigue) and inability to carry out any physical activity without symptoms. Subjects in class IV manifest signs of right heart failure. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement. Here 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Week 16
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    36
    Units: Percentage of subjects
    number (not applicable)
        Week 16: Subjects with Improvement in WHO-FC
    63.04
        Week 16: Subjects with Worsening in WHO-FC
    0
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 16 in N-terminal pro B-type Natriuretic Peptide (NT-proBNP)

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    End point title
    Change from Baseline to Week 16 in N-terminal pro B-type Natriuretic Peptide (NT-proBNP)
    End point description
    Change from baseline to Week 16 in NT-proBNP was reported. The Haemodynamic Set included all subjects from the safety set who had a baseline PVR measurement. Here 'N' (number of subjects analysed) signifies those subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 16
    End point values
    Macitentan 10 mg / Tadalafil 40 mg
    Number of subjects analysed
    43
    Units: Nanogram per Litre (ng/L)
        arithmetic mean (standard deviation)
    -1086.5 ± 2004.9
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 34 months
    Adverse event reporting additional description
    Safety analysis set included all subjects who received at least one dose of any of the two study treatments.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Macitentan 10 mg / Tadalafil 40 mg
    Reporting group description
    Subjects received macitentan 10 mg and tadalafil 40 mg once daily.

    Serious adverse events
    Macitentan 10 mg / Tadalafil 40 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    13 / 46 (28.26%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Venoocclusive Disease
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Therapy Change
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest Pain
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug Effect Incomplete
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug Ineffective
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Oedema Peripheral
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences causally related to treatment / all
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Treatment Failure
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Head Injury
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Investigations
    White Blood Cell Count Increased
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arteriosclerosis Coronary Artery
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    1 / 2
         deaths causally related to treatment / all
    1 / 1
    Cardiac Failure
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Hepatojugular Reflux
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Left Ventricular Failure
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    2 / 46 (4.35%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    1 / 1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea Exertional
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Arterial Hypertension
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Nervous system disorders
    Presyncope
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatic Pain
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device Breakage
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Fluid Retention
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal Bacteraemia
         subjects affected / exposed
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Macitentan 10 mg / Tadalafil 40 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 46 (76.09%)
    Investigations
    Weight Decreased
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    4
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    5
    Dyspnoea
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    6
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    4
    Headache
         subjects affected / exposed
    11 / 46 (23.91%)
         occurrences all number
    15
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 46 (10.87%)
         occurrences all number
    6
    Face Oedema
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Influenza Like Illness
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Oedema Peripheral
         subjects affected / exposed
    11 / 46 (23.91%)
         occurrences all number
    13
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    9 / 46 (19.57%)
         occurrences all number
    11
    Nausea
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    4
    Back Pain
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    6
    Pain in Extremity
         subjects affected / exposed
    4 / 46 (8.70%)
         occurrences all number
    5
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3
    Nasopharyngitis
         subjects affected / exposed
    3 / 46 (6.52%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Oct 2015
    The overall reason for global amendment 1 was to clarify the eligibility criterias. Inclusion criterion 6 was clarified: only congenital heart disease corrected with simple systemic-to-pulmonary shunt (atrial septal defect, ventricular septal defect, patent ductus arteriosus), with persistent PAH >= 1 year after surgical repair.
    29 Mar 2016
    The overall reason for the amendment was to clarify the eligibility criteria and include new committee. An adjudication committee has been set up to determine if a subject can be included despite of a Diffusing capacity of the lung for carbon monoxide (DLCO) greater than (<) 40 percentage (%). Exclusion criterion 2 was changed: Subjects who changed the dose or discontinued calcium channel blockers within 1 week prior to Day 1. Exclusion criterion 9 was clarified: Significant aortic and mitral valve disease treated with a specific treatment. Exclusion criterion 11 (Significant left ventricular dysfunction in the opinion of the investigator) was deleted. Exclusion criterion 20 was created [DLCO < 40% of predicted value (eligible only if no sign of enoocclusive disease according to adjudication committee]. DLCO < 40% of predicted value was deleted from Exclusion criteria 21. Calcium channel blocker were authorized if present at a stable dose for at least 1 week before Day 1 instead of 3 months. Assessment of NT-proBNP were changed: Laboratory assessment were done on blood samples collected at inclusion visit and at Week 16. Finally, laboratory tests for screening and Day 1 can be performed on the same day.

    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 early due to a slow recruitment rate.
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