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    Clinical Trial Results:
    A Multi-center, Double-blind, Placebo-controlled Phase 2b Study to Evaluate the Efficacy and Safety of Macitentan in Subjects with Heart Failure with Preserved Ejection Fraction and Pulmonary Vascular Disease

    Summary
    EudraCT number
    2016-003653-15
    Trial protocol
    DE   HU   GB   DK   CZ   AT   SE   ES   BG  
    Global end of trial date
    12 Mar 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    24 Mar 2022
    First version publication date
    24 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055G202
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03153111
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, CH-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
    12 Mar 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to evaluate whether macitentan 10 milligrams (mg) reduced N-terminal pro-brain natriuretic peptide (NT-proBNP) versus placebo at Week 24 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 Practice (GCP) and applicable regulatory requirements. Safety assessments included analysis of treatment-emergent adverse events (TEAEs), laboratory analyte values, vital sign measurements, electrocardiogram (ECG) data, all-cause hospital admissions up to 30 days after treatment, estimated Glomerular Filtration Rate (GFR), and heart failure (HF) signs/symptoms of special interest reported during the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    02 Aug 2017
    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: 10
    Country: Number of subjects enrolled
    Brazil: 2
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Denmark: 2
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    France: 6
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    Israel: 27
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    Romania: 7
    Country: Number of subjects enrolled
    Russian Federation: 20
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    United States: 24
    Worldwide total number of subjects
    142
    EEA total number of subjects
    63
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    18
    From 65 to 84 years
    112
    85 years and over
    12

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Out of 143 randomised subjects, 1 subject was randomised by mistake and did not receive any dose of study drug. 142 subjects received the study drug and were analysed.

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Subjects received placebo tablet orally once a day starting from Day 1 up to Week 52.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet was administered orally once a day starting at Day 1 up to Week 52.

    Arm title
    Macitentan
    Arm description
    Subjects received macitentan 10 milligrams (mg) tablet orally once a day starting from Day 1 up to Week 52.
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Macitentan 10 mg tablet was administered orally once a day starting at Day 1 up to Week 52.

    Number of subjects in period 1
    Placebo Macitentan
    Started
    71
    71
    Completed
    62
    60
    Not completed
    9
    11
         Physician decision
    -
    1
         Adverse event, serious non-fatal
    1
    4
         Adverse event, serious fatal
    5
    2
         Adverse event, non-fatal
    -
    2
         Consent withdrawn by subject
    3
    1
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo tablet orally once a day starting from Day 1 up to Week 52.

    Reporting group title
    Macitentan
    Reporting group description
    Subjects received macitentan 10 milligrams (mg) tablet orally once a day starting from Day 1 up to Week 52.

    Reporting group values
    Placebo Macitentan Total
    Number of subjects
    71 71 142
    Title for AgeCategorical
    Units: subjects
        Adults (18-64 years)
    8 10 18
        From 65 to 84 years
    57 55 112
        85 years and over
    6 6 12
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    74.2 ± 8.25 72.9 ± 10.11 -
    Title for Gender
    Units: subjects
        Female
    41 46 87
        Male
    30 25 55

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo tablet orally once a day starting from Day 1 up to Week 52.

    Reporting group title
    Macitentan
    Reporting group description
    Subjects received macitentan 10 milligrams (mg) tablet orally once a day starting from Day 1 up to Week 52.

    Primary: Percent of Baseline N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Assessed at Week 24

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    End point title
    Percent of Baseline N-terminal Pro-brain Natriuretic Peptide (NT-proBNP) Assessed at Week 24
    End point description
    Percent of baseline NT-proBNP assessed at week 24 was reported. Percent of baseline is calculated as the ratio of the Week 24 NT-proBNP value over baseline value, expressed in percentage. NT-proBNP is one of the best established cardiovascular response markers among all available surrogates in heart failure (HF). Full analysis set (FAS) included subjects which were randomized to double-blind study treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24
    End point values
    Placebo Macitentan
    Number of subjects analysed
    71
    71
    Units: percentage of baseline NT-proBNP
        geometric mean (geometric coefficient of variation)
    106.27 ± 0.55
    108.39 ± 0.65
    Statistical analysis title
    Statistical Analysis for Double-blind period
    Comparison groups
    Placebo v Macitentan
    Number of subjects included in analysis
    142
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.7923
    Method
    ANCOVA
    Parameter type
    Geometric mean ratio
    Point estimate
    1.02
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    0.88
         upper limit
    1.19

    Secondary: Change from Baseline to Week 24 in the Clinical Summary Score Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) Score

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    End point title
    Change from Baseline to Week 24 in the Clinical Summary Score Assessed by Kansas City Cardiomyopathy Questionnaire (KCCQ) Score
    End point description
    The KCCQ is a validated health related quality of life measure for heart failure. The KCCQ is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Clinical summary score is one of the quality of life variable of interest derived from KCCQ. Clinical summary score is the mean of domains: physical limitations score (6 items) and total symptom score (2 items [symptoms frequency and symptom burden]). The score is calculated by summing domain responses and then transforming scores to a 0-100 unit scale with higher scores indicating better health status. FAS included subjects which were randomized to double-blind study treatment. Here, 'N' (number of subjects analyzed) specifies all subjects who were evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo Macitentan
    Number of subjects analysed
    71
    69
    Units: score on a scale
        arithmetic mean (standard deviation)
    0.89 ± 17.72
    -2.37 ± 16.12
    Statistical analysis title
    Statistical Analysis for Double-blind period
    Comparison groups
    Placebo v Macitentan
    Number of subjects included in analysis
    140
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.2172
    Method
    ANCOVA
    Parameter type
    Least square mean
    Point estimate
    -3.5
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -8.17
         upper limit
    1.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.82

    Secondary: Change from Baseline to Week 24 in Accelerometer-assessed Proportion of Time Spent in Light to Vigourous Physical Activity

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    End point title
    Change from Baseline to Week 24 in Accelerometer-assessed Proportion of Time Spent in Light to Vigourous Physical Activity
    End point description
    Physical activity is assessed by accelerometer as the proportion of time spent in light to vigorous physical activity based on a threshold of greater than (>)100 activity counts per minute and expressed as change from baseline to Week 24. FAS included subjects which were randomized to double-blind study treatment. Here, 'N' (number of participants analyzed) specifies all subjects who were evaluated for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 24
    End point values
    Placebo Macitentan
    Number of subjects analysed
    31
    30
    Units: proportion of time spent
        arithmetic mean (standard deviation)
    -0.005 ± 0.098
    -0.024 ± 0.084
    Statistical analysis title
    Statistical Analysis for Double-blind period
    Comparison groups
    Placebo v Macitentan
    Number of subjects included in analysis
    61
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.3665
    Method
    ANCOVA
    Parameter type
    Least square mean
    Point estimate
    -0.02
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    -0.05
         upper limit
    0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02

    Secondary: Number of Subjects with Worsening of Heart Failure (WHF) Events Over 52 Weeks

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    End point title
    Number of Subjects with Worsening of Heart Failure (WHF) Events Over 52 Weeks
    End point description
    Number of subjects with WHF events were reported. A WHF event includes HF death, hospitalization for WHF or an urgent visit for WHF. FAS included subjects which were randomized to double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Weeks 16, 24, 36, 52
    End point values
    Placebo Macitentan
    Number of subjects analysed
    71
    71
    Units: subjects
        Week 16
    5
    12
        Week 24
    6
    14
        Week 36
    9
    17
        Week 52
    13
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 17 months
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Macitentan
    Reporting group description
    Subjects received macitentan 10 milligrams (mg) tablet orally once a day starting at Day 1 up to Week 52.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received placebo tablet orally once a day starting at Day 1 up to Week 52.

    Serious adverse events
    Macitentan Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 71 (40.85%)
    23 / 71 (32.39%)
         number of deaths (all causes)
    2
    5
         number of deaths resulting from adverse events
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral Ischaemia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon Cancer
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatic Carcinoma
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Superficial Spreading Melanoma Stage Iv
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Organ Dysfunction Syndrome
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Delirium
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental Status Changes
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine Polyp
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle Fracture
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road Traffic Accident
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Ammonia Increased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Lactic Acid Increased
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemoglobin Decreased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute Left Ventricular Failure
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina Unstable
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular Block Complete
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Acute
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac Failure Congestive
         subjects affected / exposed
    5 / 71 (7.04%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Right Ventricular Failure
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left Ventricular Failure
         subjects affected / exposed
    3 / 71 (4.23%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    6 / 71 (8.45%)
    6 / 71 (8.45%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Sinus Node Dysfunction
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Pulmonary Oedema
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumopathy
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural Effusion
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary Congestion
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood Loss Anaemia
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebral Ischaemia
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Encephalopathy
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Diabetic Retinopathy
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oliguria
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Congestive Hepatopathy
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash Pruritic
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 71 (1.41%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle Twitching
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid Overload
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid Retention
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Gangrene
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 71 (2.82%)
    3 / 71 (4.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pyelonephritis Acute
         subjects affected / exposed
    1 / 71 (1.41%)
    0 / 71 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic Shock
         subjects affected / exposed
    0 / 71 (0.00%)
    1 / 71 (1.41%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urinary Tract Infection
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Macitentan Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 71 (80.28%)
    54 / 71 (76.06%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 71 (2.82%)
    2 / 71 (2.82%)
         occurrences all number
    2
    3
    Hypotension
         subjects affected / exposed
    3 / 71 (4.23%)
    3 / 71 (4.23%)
         occurrences all number
    3
    3
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin Cancer
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 71 (4.23%)
    1 / 71 (1.41%)
         occurrences all number
    3
    1
    Fatigue
         subjects affected / exposed
    5 / 71 (7.04%)
    6 / 71 (8.45%)
         occurrences all number
    5
    6
    Non-Cardiac Chest Pain
         subjects affected / exposed
    1 / 71 (1.41%)
    2 / 71 (2.82%)
         occurrences all number
    1
    2
    Oedema Peripheral
         subjects affected / exposed
    9 / 71 (12.68%)
    4 / 71 (5.63%)
         occurrences all number
    13
    5
    Reproductive system and breast disorders
    Gynaecomastia
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
         occurrences all number
    0
    2
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 71 (1.41%)
    4 / 71 (5.63%)
         occurrences all number
    1
    4
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Blood Creatinine Increased
         subjects affected / exposed
    3 / 71 (4.23%)
    2 / 71 (2.82%)
         occurrences all number
    3
    2
    Blood Potassium Increased
         subjects affected / exposed
    1 / 71 (1.41%)
    2 / 71 (2.82%)
         occurrences all number
    1
    2
    Blood Urea Increased
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 71 (1.41%)
         occurrences all number
    4
    1
    Blood Uric Acid Increased
         subjects affected / exposed
    1 / 71 (1.41%)
    3 / 71 (4.23%)
         occurrences all number
    1
    3
    Glomerular Filtration Rate Decreased
         subjects affected / exposed
    2 / 71 (2.82%)
    2 / 71 (2.82%)
         occurrences all number
    2
    2
    Brain Natriuretic Peptide Increased
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
         occurrences all number
    0
    2
    Haemoglobin Decreased
         subjects affected / exposed
    3 / 71 (4.23%)
    3 / 71 (4.23%)
         occurrences all number
    4
    4
    Weight Increased
         subjects affected / exposed
    2 / 71 (2.82%)
    3 / 71 (4.23%)
         occurrences all number
    2
    3
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    4 / 71 (5.63%)
    5 / 71 (7.04%)
         occurrences all number
    4
    5
    Angina Pectoris
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences all number
    2
    0
    Atrial Flutter
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Cardiac Failure Congestive
         subjects affected / exposed
    3 / 71 (4.23%)
    1 / 71 (1.41%)
         occurrences all number
    3
    1
    Left Ventricular Failure
         subjects affected / exposed
    5 / 71 (7.04%)
    0 / 71 (0.00%)
         occurrences all number
    6
    0
    Palpitations
         subjects affected / exposed
    0 / 71 (0.00%)
    2 / 71 (2.82%)
         occurrences all number
    0
    2
    Right Ventricular Failure
         subjects affected / exposed
    5 / 71 (7.04%)
    2 / 71 (2.82%)
         occurrences all number
    6
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 71 (2.82%)
    4 / 71 (5.63%)
         occurrences all number
    2
    6
    Dyspnoea
         subjects affected / exposed
    8 / 71 (11.27%)
    7 / 71 (9.86%)
         occurrences all number
    9
    10
    Nasal Congestion
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Pleural Effusion
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    5 / 71 (7.04%)
    3 / 71 (4.23%)
         occurrences all number
    6
    3
    Blood Loss Anaemia
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Hypochromic Anaemia
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences all number
    2
    0
    Iron Deficiency Anaemia
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 71 (1.41%)
         occurrences all number
    4
    1
    Normocytic Anaemia
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Nervous system disorders
    Cerebral Ischaemia
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences all number
    2
    0
    Dizziness
         subjects affected / exposed
    3 / 71 (4.23%)
    3 / 71 (4.23%)
         occurrences all number
    3
    3
    Headache
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 71 (1.41%)
         occurrences all number
    4
    1
    Lethargy
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Syncope
         subjects affected / exposed
    1 / 71 (1.41%)
    2 / 71 (2.82%)
         occurrences all number
    1
    2
    Gastrointestinal disorders
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences all number
    2
    0
    Ascites
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Diarrhoea
         subjects affected / exposed
    2 / 71 (2.82%)
    2 / 71 (2.82%)
         occurrences all number
    3
    3
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    5 / 71 (7.04%)
    2 / 71 (2.82%)
         occurrences all number
    5
    3
    Renal Failure
         subjects affected / exposed
    2 / 71 (2.82%)
    4 / 71 (5.63%)
         occurrences all number
    2
    4
    Renal Impairment
         subjects affected / exposed
    5 / 71 (7.04%)
    1 / 71 (1.41%)
         occurrences all number
    5
    1
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences all number
    2
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 71 (4.23%)
    0 / 71 (0.00%)
         occurrences all number
    3
    0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    2 / 71 (2.82%)
    3 / 71 (4.23%)
         occurrences all number
    2
    3
    Muscle Spasms
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 71 (1.41%)
         occurrences all number
    4
    2
    Pain in Extremity
         subjects affected / exposed
    1 / 71 (1.41%)
    4 / 71 (5.63%)
         occurrences all number
    1
    5
    Neck Pain
         subjects affected / exposed
    0 / 71 (0.00%)
    3 / 71 (4.23%)
         occurrences all number
    0
    3
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 71 (1.41%)
    2 / 71 (2.82%)
         occurrences all number
    1
    2
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 71 (1.41%)
    2 / 71 (2.82%)
         occurrences all number
    1
    2
    Fluid Retention
         subjects affected / exposed
    2 / 71 (2.82%)
    1 / 71 (1.41%)
         occurrences all number
    2
    1
    Gout
         subjects affected / exposed
    6 / 71 (8.45%)
    2 / 71 (2.82%)
         occurrences all number
    6
    2
    Hyperkalaemia
         subjects affected / exposed
    3 / 71 (4.23%)
    4 / 71 (5.63%)
         occurrences all number
    4
    4
    Hyperuricaemia
         subjects affected / exposed
    2 / 71 (2.82%)
    2 / 71 (2.82%)
         occurrences all number
    2
    2
    Hypokalaemia
         subjects affected / exposed
    3 / 71 (4.23%)
    3 / 71 (4.23%)
         occurrences all number
    3
    3
    Hypomagnesaemia
         subjects affected / exposed
    1 / 71 (1.41%)
    2 / 71 (2.82%)
         occurrences all number
    2
    2
    Iron Deficiency
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences all number
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    4 / 71 (5.63%)
    2 / 71 (2.82%)
         occurrences all number
    4
    2
    Conjunctivitis
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences all number
    3
    0
    Lower Respiratory Tract Infection
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences all number
    4
    0
    Nasopharyngitis
         subjects affected / exposed
    4 / 71 (5.63%)
    1 / 71 (1.41%)
         occurrences all number
    4
    1
    Pneumonia
         subjects affected / exposed
    2 / 71 (2.82%)
    5 / 71 (7.04%)
         occurrences all number
    2
    5
    Respiratory Tract Infection Viral
         subjects affected / exposed
    2 / 71 (2.82%)
    2 / 71 (2.82%)
         occurrences all number
    3
    2
    Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 71 (2.82%)
    4 / 71 (5.63%)
         occurrences all number
    2
    5
    Urinary Tract Infection
         subjects affected / exposed
    2 / 71 (2.82%)
    5 / 71 (7.04%)
         occurrences all number
    2
    8
    Viral Upper Respiratory Tract Infection
         subjects affected / exposed
    2 / 71 (2.82%)
    0 / 71 (0.00%)
         occurrences all number
    2
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2017
    The overall reason for the amendment 1 was implementation of additional safety monitoring measures after first dose of macitentan, as requested by the Food and Drug Administration (FDA).
    12 Apr 2017
    The overall reason for the amendment 2 was addition of medications mainly transported by breast-cancer resistant protein to the list of forbidden medications, as requested by the FDA.
    10 Apr 2018
    The overall reason for the amendment 3 was added description of transition to the SERENADE Open-label (OL) extension study, revision of the eligibility and run-in failure criteria, and introduction of a Clinical Event Committee (CEC). Changes made to the statistical methods to allow N-terminal pro-brain natriuretic peptide values measured at screening to be used for stratification at time of treatment assignment and to the definitions of the placebo run-in and macitentan analysis sets.
    08 Mar 2019
    The overall reason for the amendment 4 was Addition of the 6-minute walk distance (6MWD) substudy to assess the change in exercise capacity from baseline and removal of the 8-hour safety monitoring period after first dose of macitentan at the start of macitentan run-in. Addition of 2 telephone calls to ensure adequate safety follow-up is established during the run-in phase. Reordered testing hierarchy of the key secondary efficacy endpoints: Kansas City Cardiomyopathy Questionnaire was moved to the first secondary endpoint and accelerometry moved to the second position. Added new hierarchical composite exploratory efficacy endpoint which combined hard (death, hospitalizations) and soft (functional capacity, quality of life) endpoints to allow for a more complete and broader assessment of clinical benefit.
    06 Feb 2020
    Overall reason for amendment 5 was early termination of enrollment. Subject recruitment targets not met and completion of study within reasonable timeline not realistic. Updated sample size to reflect early termination of recruitment. Reduced length of double-blind treatment (DBT) period to 24 weeks. Week 24 was pre-defined timepoint to assess primary as well as key secondary endpoints. Secondary endpoint of time to worsening HF event however was planned to be assessed up to Week 52 to gather meaningful information for preparation of pivotal clinical trial development program. Due to reduced sample size, number of worsening HF events was expected to be too low for meaningful analysis of time to worsening HF. DBT period was to be stopped at Week 24, and eligible subjects were to be transitioned to SERENADE OL at that timepoint. Subjects who completed Week 24 visit, were scheduled to come back for an EoT visit within 60 days and enroll in OL study, if eligible. Not all sites participated in OL study. Removed CEC which was appointed to review and adjudicate in blinded fashion worsening HF events, reasons for hospitalization, and causes of death, did not affect safety monitoring and therefore decision was also endorsed by IDMC. DBT period reduced from 52 to 24 weeks, low occurrence of worsening HF events which would not allow for meaningful conclusions to be drawn. Investigator assessment of worsening HF events continued. Re-scheduled accelerometry to be performed 9 consecutive days prior to Week 24 for subjects completing Week 24 to ensure assessment performed on DBT. Stopped sub study assessments (6MWD and Borg Dyspnea Index), due to low count of subjects participating in sub study to allow for meaningful interpretation of results. Planned analysis of sub study data amended to reflect above amendment to protocol. Removed new hierarchical composite exploratory efficacy endpoint that was added in prior amendment due to reduced sample size and stopping of 6MWT sub study.
    16 Jul 2020
    Overall reason for amendment 6 was updated the 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. Data from clinical trials with macitentan 10 mg were reviewed, identifying cases where macitentan 10 mg was administered concomitantly with dual CYP3A4/CYP2C9 inhibitors, such as fluconazole and amiodarone. The review indicated that co-administration of fluconazole or amiodarone with macitentan was not common (between 1% to 3% of subjects). No safety concerns were identified with concurrent administration of fluconazole or amiodarone and macitentan 10 mg.

    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.
    Recruitment was stopped prematurely in December 2019 due to slow enrollment which resulted in an underpowered study and impacted the meaningful interpretation of the results.
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