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    Clinical Trial Results:
    Long term, multicenter, single-arm, open-label extension study of the MERIT-1 study, to assess the safety, tolerability and efficacy of macitentan in subjects with inoperable chronic thromboembolic pulmonary hypertension (CTEPH)

    Summary
    EudraCT number
    		 2013-003457-25
    Trial protocol
    		 CZ   BE   GB   HU   DE   AT   NL   LT   FR  
    Global end of trial date
    21 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Apr 2023
    First version publication date
    02 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055E202
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02060721
    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
    21 Mar 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to evaluate the long-term safety and tolerability of macitentan 10 milligrams (mg) in subjects with inoperable CTEPH.
    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 (GCP) and applicable regulatory requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Feb 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
    Belgium: 1
    Country: Number of subjects enrolled
    China: 23
    Country: Number of subjects enrolled
    Czechia: 2
    Country: Number of subjects enrolled
    Germany: 3
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    United Kingdom: 3
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Lithuania: 2
    Country: Number of subjects enrolled
    Mexico: 2
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Thailand: 4
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    Ukraine: 4
    Worldwide total number of subjects
    76
    EEA total number of subjects
    18
    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)
    48
    From 65 to 84 years
    28
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 76 subjects who completed the double-blind MERIT-1 study, rolled-over to this study (MERIT-2), out of which 38 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 milligrams (mg)
    Arm description
    		 Eligible subjects who were either randomised to macitentan 10 mg or placebo group during 24 weeks double-blind MERIT-1 (2013-002950-56) study, were rolled-over to this open-label extension study and received macitentan 10 mg tablet orally once daily starting from Day 1 to the end of treatment (treatment exposure ranged from 1 to 82 months).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Macitentan 10 mg tablet was administered orally once daily starting from Day 1 to the end of treatment (treatment exposure ranged from 1 to 82 months).

    Number of subjects in period 1
    		Macitentan 10 milligrams (mg)
    Started
    76
    Completed
    38
    Not completed
    38
         Adverse event, serious fatal
    14
         Physician decision
    2
         Consent withdrawn by subject
    2
         Compliance with local regulation:enrolled in China
    19
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Macitentan 10 milligrams (mg)
    Reporting group description
    		 Eligible subjects who were either randomised to macitentan 10 mg or placebo group during 24 weeks double-blind MERIT-1 (2013-002950-56) study, were rolled-over to this open-label extension study and received macitentan 10 mg tablet orally once daily starting from Day 1 to the end of treatment (treatment exposure ranged from 1 to 82 months).

    Reporting group values
    		 Macitentan 10 milligrams (mg) Total
    Number of subjects
    		 76 76
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 48 48
        From 65 to 84 years
    		 28 28
        85 years and over
    		 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.8 ± 13.99 -
    Title for Gender
    Units: subjects
        Female
    		 48 48
        Male
    		 28 28

    End points

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    End points reporting groups
    Reporting group title
    Macitentan 10 milligrams (mg)
    Reporting group description
    		 Eligible subjects who were either randomised to macitentan 10 mg or placebo group during 24 weeks double-blind MERIT-1 (2013-002950-56) study, were rolled-over to this open-label extension study and received macitentan 10 mg tablet orally once daily starting from Day 1 to the end of treatment (treatment exposure ranged from 1 to 82 months).

    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 (AE) is any untoward medical occurrence in a subject participating in a clinical study that does not necessarily have a causal relationship with the pharmaceutical/ biological agent under study. TEAEs are those events that started after administration of the first dose and up to safety follow-up visit/end of study, that is, 30 days after the last dose of study medication. Open-label analysis set (OLAS) included all data from subjects who were enrolled into this open-label extension study, from the time they entered this open-label extension study.
    End point type
    Primary
    End point timeframe
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 1 to 82 months)
    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: Only descriptive statistics were reported. No inferential statistics was planned.
    End point values
    		 Macitentan 10 milligrams (mg)
    Number of subjects analysed
    76
    Units: Subjects
    72
    No statistical analyses for this end point

    Primary: Number of Subjects With AEs Leading to Study Drug Discontinuation

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    End point title
    		 Number of Subjects With AEs Leading to Study Drug Discontinuation [2]
    End point description
    Number of subjects with AEs leading to study drug discontinuation was reported. OLAS included all data from subjects who were enrolled into this open-label extension study, from the time they entered this open-label extension study.
    End point type
    Primary
    End point timeframe
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 1 to 82 months)
    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: Only descriptive statistics were reported. No inferential statistics was planned.
    End point values
    		 Macitentan 10 milligrams (mg)
    Number of subjects analysed
    76
    Units: Subjects
    9
    No statistical analyses for this end point

    Primary: Number of Subjects With Treatment-emergent Serious Adverse Events (SAEs)

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    End point title
    		 Number of Subjects With Treatment-emergent Serious Adverse Events (SAEs) [3]
    End point description
    A serious adverse event (SAE) is any untoward medical occurrence that at any dose resulting in any of following outcomes: results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, is a suspected transmission of any infectious agent via a medicinal product. Treatment-emergent SAEs were those events that started after administration of the first dose and up to safety follow-up visit/end of study, that is, 30 days after the last dose of study medication. OLAS included all data from subjects who were enrolled into this open-label extension study, from the time they entered this open-label extension study.
    End point type
    Primary
    End point timeframe
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 1 to 82 months)
    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: Only descriptive statistics were reported. No inferential statistics was planned.
    End point values
    		 Macitentan 10 milligrams (mg)
    Number of subjects analysed
    76
    Units: Subjects
    44
    No statistical analyses for this end point

    Primary: Number of Subjects With Hemoglobin Abnormalities

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    End point title
    		 Number of Subjects With Hemoglobin Abnormalities [4]
    End point description
    Number of subjects with hemoglobin abnormalities were reported. It included hemoglobin less than (<) 80 grams per litre (g/L), hemoglobin <100 g/L, hemoglobin greater than or equal to (>=) 80 g/L and <100 g/L, hemoglobin <100g/L and a decrease of >20 g/L from baseline, decrease of >20 g/L in hemoglobin from baseline, decrease of >20 g/L and <=50 g/L in hemoglobin from baseline, and decrease of >50 g/L in hemoglobin from baseline. OLAS included all data from subjects who were enrolled into this open-label extension study, from the time they entered this open-label extension study.
    End point type
    Primary
    End point timeframe
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 1 to 82 months)
    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: Only descriptive statistics were reported. No inferential statistics was planned.
    End point values
    		 Macitentan 10 milligrams (mg)
    Number of subjects analysed
    76
    Units: Subjects
        Hemoglobin < 80 g/L
    0
        Hemoglobin <100 g/L
    7
        Hemoglobin >= 80 g/L and <100 g/L
    7
        <100 g/L and a decrease from baseline >20 g/L
    6
        Decrease of >20 g/L in hemoglobin from baseline
    32
        Decrease of >20 g/L and <=50 g/L from baseline
    31
        Decrease of >50 g/L in hemoglobin from baseline
    5
    No statistical analyses for this end point

    Primary: Number of Subjects With Liver Tests Abnormalities

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    End point title
    		 Number of Subjects With Liver Tests Abnormalities [5]
    End point description
    Number of subjects with liver tests abnormalities were reported. It included alanine aminotransferase (ALT) or aspartate aminotransferase (AST): >=3 x Upper limit of the normal range (ULN), >=3 and <5 x ULN, >=5 ULN, and >=5 and <8 x ULN, >= 8 x ULN, and total bilirubin >=2 x ULN. OLAS included all data from subjects who were enrolled into this open-label extension study, from the time they entered this open-label extension study.
    End point type
    Primary
    End point timeframe
    Up to 30 days after study treatment discontinuation (treatment exposure ranged from 1 to 82 months)
    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: Only descriptive statistics were reported. No inferential statistics was planned.
    End point values
    		 Macitentan 10 milligrams (mg)
    Number of subjects analysed
    76
    Units: Subjects
        ALT or AST >=3 x ULN
    2
        ALT or AST >=3 and <5 x ULN
    1
        ALT or AST >=5 x ULN
    1
        ALT or AST >=5 and <8 x ULN
    0
        ALT or AST >=8 x ULN
    1
        Total Bilirubin >=2 x ULN
    8
    No statistical analyses for this end point

    Primary: Change from Baseline in Blood Pressure at Month 6

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    End point title
    		 Change from Baseline in Blood Pressure at Month 6 [6]
    End point description
    Change from baseline in blood pressure (both systolic blood pressure [SBP] and diastolic blood pressure [DBP]) at Month 6 was reported. OLAS included all data from subjects who were enrolled into this open-label extension study, from the time they entered this open-label extension study. Here, 'N' (number of subjects analysed) signifies subjects evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Month 6
    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: Only descriptive statistics were reported. No inferential statistics was planned.
    End point values
    		 Macitentan 10 milligrams (mg)
    Number of subjects analysed
    70
    Units: Millimetres of mercury (mmHg)
    arithmetic mean (standard deviation)
        SBP
    -0.4 ± 13.15
        DBP
    -2.8 ± 9.51
    No statistical analyses for this end point

    Primary: Change from Baseline in Pulse Rate at Month 6

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    End point title
    		 Change from Baseline in Pulse Rate at Month 6 [7]
    End point description
    Change from baseline in pulse rate at Month 6 was reported. OLAS included all data from subjects who were enrolled into this open-label extension study, from the time they entered this open-label extension study. Here, 'N' (number of subjects analysed) signifies subjects evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Month 6
    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: Only descriptive statistics were reported. No inferential statistics was planned.
    End point values
    		 Macitentan 10 milligrams (mg)
    Number of subjects analysed
    70
    Units: Beats per minute
        arithmetic mean (standard deviation)
    -1.1 ± 8.76
    No statistical analyses for this end point

    Primary: Change from Baseline in Body Weight at Month 6

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    End point title
    		 Change from Baseline in Body Weight at Month 6 [8]
    End point description
    Change from baseline in body weight at Month 6 was reported. OLAS included all data from subjects who were enrolled into this open-label extension study, from the time they entered this open-label extension study. Here, 'N' (number of subjects analysed) signifies subjects evaluated for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline and Month 6
    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: Only descriptive statistics were reported. No inferential statistics was planned.
    End point values
    		 Macitentan 10 milligrams (mg)
    Number of subjects analysed
    70
    Units: kilograms (kg)
        arithmetic mean (standard deviation)
    -0.35 ± 2.871
    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 1 to 82 months)
    Adverse event reporting additional description
    Open-label analysis set (OLAS) included all data from subjects who were enrolled into this open-label extension study, from the time they entered this open-label extension study.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Macitentan 10 milligrams (mg)
    Reporting group description
    		 Eligible subjects who were either randomised to macitentan 10 mg or placebo group during 24 weeks double-blind MERIT-1 (2013-002950-56) study, were rolled-over to this open-label extension study and received macitentan 10 mg tablet orally once daily starting from Day 1 to the end of treatment (treatment exposure ranged from 1 to 82 months).

    Serious adverse events
    		 Macitentan 10 milligrams (mg)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 76 (57.89%)
         number of deaths (all causes)
    14
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast Cancer
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric Cancer Stage Iv
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast Cancer Metastatic
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Air Embolism
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reperfusion Injury
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Angioplasty
         subjects affected / exposed
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    Arterial Angioplasty
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences causally related to treatment / all
    0 / 23
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Endarterectomy
         subjects affected / exposed
    1 / 76 (1.32%)
         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
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    General Physical Health Deterioration
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Peripheral Swelling
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pyrexia
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Obstructive Airways Disorder
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pickwickian Syndrome
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    Sleep Apnoea Syndrome
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Hypertension
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    Investigations
    Catheterisation Cardiac
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Chest X-Ray Abnormal
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Haemoglobin Decreased
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Head Injury
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Fall
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Chemical Burns of Eye
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lumbar Vertebral Fracture
         subjects affected / exposed
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Congenital, familial and genetic disorders
    Arteriovenous Malformation
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Aortic Valve Stenosis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Atrial Flutter
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial Tachycardia
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac Failure
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 3
    Right Ventricular Failure
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 2
    Coronary Artery Disease
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    3 / 76 (3.95%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Nervous system disorders
    Haemorrhage Intracranial
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Diplegia
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ear and labyrinth disorders
    Deafness Neurosensory
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Vision Blurred
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Gastric Polyps
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal Motility Disorder
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Peritoneal Adhesions
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Hepatitis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal Failure
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Systemic Lupus Erythematosus
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Appendiceal Abscess
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Covid-19 Pneumonia
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia Parainfluenzae Viral
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Neutropenic Sepsis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis Chronic
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Sepsis
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Septic Shock
         subjects affected / exposed
    2 / 76 (2.63%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Streptococcal Sepsis
         subjects affected / exposed
    1 / 76 (1.32%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Hypernatraemia
         subjects affected / exposed
    1 / 76 (1.32%)
         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 milligrams (mg)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 76 (88.16%)
    Investigations
    Blood Bilirubin Increased
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    6
    Blood Creatinine Increased
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    C-Reactive Protein Increased
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    6
    Haemoglobin Decreased
         subjects affected / exposed
    13 / 76 (17.11%)
         occurrences all number
    17
    Weight Decreased
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    8
    Cardiac disorders
    Cardiac Failure
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    5
    Nervous system disorders
    Headache
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    10
    Dizziness
         subjects affected / exposed
    8 / 76 (10.53%)
         occurrences all number
    15
    Syncope
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    8
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 76 (13.16%)
         occurrences all number
    11
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    5
    Oedema Peripheral
         subjects affected / exposed
    11 / 76 (14.47%)
         occurrences all number
    13
    Eye disorders
    Cataract
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    7
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    11
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 76 (11.84%)
         occurrences all number
    11
    Haemoptysis
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    7
    Dyspnoea
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    7
    Pulmonary Hypertension
         subjects affected / exposed
    11 / 76 (14.47%)
         occurrences all number
    12
    Musculoskeletal and connective tissue disorders
    Osteoarthritis
         subjects affected / exposed
    5 / 76 (6.58%)
         occurrences all number
    5
    Back Pain
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    7
    Arthralgia
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    9
    Pain in Extremity
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    6
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 76 (11.84%)
         occurrences all number
    14
    Respiratory Tract Infection Viral
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4
    Nasopharyngitis
         subjects affected / exposed
    9 / 76 (11.84%)
         occurrences all number
    15
    Covid-19
         subjects affected / exposed
    6 / 76 (7.89%)
         occurrences all number
    7
    Urinary Tract Infection
         subjects affected / exposed
    7 / 76 (9.21%)
         occurrences all number
    14
    Upper Respiratory Tract Infection
         subjects affected / exposed
    12 / 76 (15.79%)
         occurrences all number
    21
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    8
    Hyperuricaemia
         subjects affected / exposed
    4 / 76 (5.26%)
         occurrences all number
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jul 2020
    The purpose of this amendment was to update the study specific criteria for drug interruption/ permanent discontinuation and forbidden concomitant medication sections to prohibit strong Cytochrome P-450 (CYP) 3A4 inhibitors, moderate dual CYP3A4/CYP2C9 inhibitors, and concomitant administration of moderate CYP3A4 and CYP2C9 inhibitors.
    28 Sep 2020
    The purpose of this amendment was to update the description of the investigational medicinal product used in this study from debossed on one side to debossed on either one or both sides.
    22 Jun 2021
    The purpose of this amendment was to clarify how to manage the roll-over of MERIT-2 subjects into a continued access program (post-trial access program or other open-label extension study). In addition, the forbidden concomitant medications section was updated to clarify that macitentan 10 mg is not considered as an investigational treatment.

    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.
    Study limitations included the open-label (OL), uncontrolled design, and small sample size.
    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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