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    Clinical Trial Results:
    mUlticenter, single-arM, open-laBel, long-teRm safety study with macitEntan in patients with puLmonary hypertension previousLy treated with mAcitentan in clinical studies UMBRELLA

    Summary
    EudraCT number
    2017-003934-10
    Trial protocol
    FR   PL   BE  
    Global end of trial date
    27 Dec 2023

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Jan 2025
    First version publication date
    03 Jan 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-055-314
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03422328
    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
    27 Dec 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this trial was to investigate the long-term safety of macitentan 10 milligrams in subjects with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    25 May 2018
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    50 Months
    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
    Belarus: 6
    Country: Number of subjects enrolled
    France: 120
    Country: Number of subjects enrolled
    Poland: 3
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    Türkiye: 2
    Country: Number of subjects enrolled
    Ukraine: 3
    Worldwide total number of subjects
    147
    EEA total number of subjects
    124
    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)
    1
    Adults (18-64 years)
    100
    From 65 to 84 years
    46
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 147 subjects were enrolled and treated in this study, out of which 90 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
    Subjects with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) who received macitentan therapy in their parent studies (NCT00667823, NCT02112487, NCT02310672, NCT02968901, NCT02558231, NCT02382016, and NCT02060721) were enrolled and received macitentan 10 mg tablet orally once daily from Day 1 up to 49.7 months. Subjects were then followed up for safety up to 30 days after the last dose of study treatment.
    Arm type
    Experimental

    Investigational medicinal product name
    Macitentan 10 mg
    Investigational medicinal product code
    Other name
    JNJ-67896062; ACT-064992
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received macitentan 10 mg orally once daily from Day 1 up to 49.7 months.

    Number of subjects in period 1
    Macitentan 10 milligrams (mg)
    Started
    147
    Completed
    90
    Not completed
    57
         Consent withdrawn by subject
    6
         Physician decision
    26
         Deaths
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Macitentan 10 milligrams (mg)
    Reporting group description
    Subjects with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) who received macitentan therapy in their parent studies (NCT00667823, NCT02112487, NCT02310672, NCT02968901, NCT02558231, NCT02382016, and NCT02060721) were enrolled and received macitentan 10 mg tablet orally once daily from Day 1 up to 49.7 months. Subjects were then followed up for safety up to 30 days after the last dose of study treatment.

    Reporting group values
    Macitentan 10 milligrams (mg) Total
    Number of subjects
    147 147
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    1 1
        Adults (18-64 years)
    100 100
        From 65 to 84 years
    46 46
        85 years and over
    0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    58.8 ( 13.67 ) -
    Title for Gender
    Units: subjects
        Female
    98 98
        Male
    49 49

    End points

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    End points reporting groups
    Reporting group title
    Macitentan 10 milligrams (mg)
    Reporting group description
    Subjects with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) who received macitentan therapy in their parent studies (NCT00667823, NCT02112487, NCT02310672, NCT02968901, NCT02558231, NCT02382016, and NCT02060721) were enrolled and received macitentan 10 mg tablet orally once daily from Day 1 up to 49.7 months. Subjects were then followed up for safety up to 30 days after the last dose of study treatment.

    Primary: Exposure Adjusted Incidence Rate of Treatment-emergent Adverse Events (TEAEs) per 100 Person-years (PY)

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    End point title
    Exposure Adjusted Incidence Rate of Treatment-emergent Adverse Events (TEAEs) per 100 Person-years (PY) [1]
    End point description
    The exposure adjusted incidence rate of TEAE per 100 PY was calculated as the number of subjects who had TEAEs during the study after the first dose of study drug divided by the sum of all subjects years (where a year was 365.25 days) of follow-up while at risk of TEAE during the study. An adverse event (AE) was any untoward medical occurrence in a clinical study subject administered a pharmaceutical (investigational or non-investigational) product. An AE does not necessarily have a causal relationship with the study treatment. TEAEs were those AEs with onset date from signature of informed consent (IC) until 30 days after the last dose of macitentan except for subjects entering a continued access program for whom TEAEs were those AEs with onset date from signature of IC until end of study treatment. The safety analysis set included all subjects who had signed the IC.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 30 days after last dose of study drug (up to 50.7 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 data was planned to be reported for this endpoint.
    End point values
    Macitentan 10 milligrams (mg)
    Number of subjects analysed
    147
    Units: TEAEs per 100 PY
        number (confidence interval 95%)
    41.44 (34.43 to 49.87)
    No statistical analyses for this end point

    Primary: Exposure Adjusted Incidence Rate of Treatment-emergent Serious Adverse Events (TESAEs) per 100 PY

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    End point title
    Exposure Adjusted Incidence Rate of Treatment-emergent Serious Adverse Events (TESAEs) per 100 PY [2]
    End point description
    Exposure adjusted incidence rate of TESAE per 100 PY was calculated as number of subjects who had TESAEs during the study after the first dose of study drug divided by the sum of all subjects’ years (where a year was 365.25 days) of follow-up while at risk of TESAE during the study. TEAEs were those AEs with onset date from signature of IC until 30 days after last dose of macitentan except for subjects entering a continued access program for whom TEAEs were those AEs with onset date from signature of IC until end of study treatment. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalisation; life-threatening experience (immediately result in death); persistent or significant disability/incapacity; congenital anomaly/birth defect; suspected transmission of any infectious agent via a medicinal product or medically important. Safety analysis set included all subjects who had signed the IC.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 30 days after last dose of study drug (up to 50.7 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 data was planned to be reported for this endpoint.
    End point values
    Macitentan 10 milligrams (mg)
    Number of subjects analysed
    147
    Units: TESAEs per 100 PY
        number (confidence interval 95%)
    20.56 (16.24 to 26.03)
    No statistical analyses for this end point

    Primary: Number of Subjects With Abnormal Pregnancy Outcomes With Maternal Exposure to Macitentan

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    End point title
    Number of Subjects With Abnormal Pregnancy Outcomes With Maternal Exposure to Macitentan [3]
    End point description
    Number of subjects with abnormal pregnancy outcomes with maternal exposure to macitentan was reported. Abnormal pregnancy outcomes (for example, spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancies) wre considered SAEs and must be reported using a SAE reporting form. Any subject who becomes pregnant during the study must discontinue further study treatment. The safety set included all subjects who had signed the IC.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 30 days after last dose of study drug (up to 50.7 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 data was planned to be reported for this endpoint.
    End point values
    Macitentan 10 milligrams (mg)
    Number of subjects analysed
    147
    Units: Subjects
    0
    No statistical analyses for this end point

    Primary: Treatment Exposure Adjusted Incidence Rate of TEAEs Leading to Discontinuation of Study Treatment per 100 PY

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    End point title
    Treatment Exposure Adjusted Incidence Rate of TEAEs Leading to Discontinuation of Study Treatment per 100 PY [4]
    End point description
    Exposure adjusted incidence rate of TEAE leading to discontinuation of study treatment per 100 PY was calculated as number of subjects who had TEAEs leading to discontinuation of study treatment during study after first dose of study drug divided by sum of all subjects years (where a year was 365.25 days) of follow-up while at risk of TEAE during the study. An AE was any untoward medical occurrence in a clinical study subject administered a pharmaceutical (investigational or non-investigational) product. TEAEs were those AEs with onset date from signature of IC until 30 days after last dose of macitentan except for subjects entering a continued access program for whom TEAEs were those AEs with onset date from signature of IC until end of study treatment. Any AE was recorded that leads to premature discontinuation of study treatment and decision may be made by the subject, investigator or sponsor. Safety analysis set included all subjects who had signed the IC.
    End point type
    Primary
    End point timeframe
    From Day 1 up to 30 days after last dose of study drug (up to 50.7 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 data was planned to be reported for this endpoint.
    End point values
    Macitentan 10 milligrams (mg)
    Number of subjects analysed
    147
    Units: TEAEs leading to discontinuation/100PY
        number (confidence interval 95%)
    1.84 (0.92 to 3.68)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 up to 30 days after last dose of study drug (up to 50.7 months)
    Adverse event reporting additional description
    The safety analysis set included all subject who had signed the informed consent.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Macitentan 10 mg
    Reporting group description
    Subjects with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) who received macitentan therapy in their parent studies (NCT00667823, NCT02112487, NCT02310672, NCT02968901, NCT02558231, NCT02382016, and NCT02060721) were enrolled and received macitentan 10 mg tablet orally once daily from Day 1 up to 49.7 months. Subjects were then followed up for safety up to 30 days after the last dose of study treatment.

    Serious adverse events
    Macitentan 10 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    69 / 147 (46.94%)
         number of deaths (all causes)
    25
         number of deaths resulting from adverse events
    25
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bone Cancer
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Glioblastoma
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Breast Cancer
         subjects affected / exposed
    4 / 147 (2.72%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Cholangiocarcinoma
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gallbladder Cancer
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric Cancer
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Squamous Cell Carcinoma of the Hypopharynx
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Squamous Cell Carcinoma of Pharynx
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Small Cell Lung Cancer
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Renal Neoplasm
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Prostate Cancer
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oesophageal Squamous Cell Carcinoma
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Malignant Neoplasm Progression
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Lung Adenocarcinoma
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Vascular disorders
    Raynaud's Phenomenon
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Appendicectomy
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial Septal Defect Repair
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Catheterisation Venous
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tumour Ablation
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung Transplant
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Inguinal Hernia Repair
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatectomy
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Drug Therapy
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cholecystectomy
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    General Physical Health Deterioration
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Death
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Cyst
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Oedema Peripheral
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Puncture Site Haematoma
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden Death
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Dyspnoea
         subjects affected / exposed
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Pulmonary Arterial Hypertension
         subjects affected / exposed
    10 / 147 (6.80%)
         occurrences causally related to treatment / all
    0 / 12
         deaths causally related to treatment / all
    0 / 4
    Pulmonary Artery Aneurysm
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Pulmonary Embolism
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Respiratory Failure
         subjects affected / exposed
    3 / 147 (2.04%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 1
    Psychiatric disorders
    Cardiovascular Somatic Symptom Disorder
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Alcohol Withdrawal Syndrome
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Product issues
    Device Malfunction
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Weight Decreased
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular Resistance Pulmonary Increased
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Brain Contusion
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Craniocerebral Injury
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fat Embolism
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Femur Fracture
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Shoulder Fracture
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Spinal Fracture
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural Haematoma
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Angina Pectoris
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Atrial Fibrillation
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Arrhythmia Supraventricular
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac Failure
         subjects affected / exposed
    4 / 147 (2.72%)
         occurrences causally related to treatment / all
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardiopulmonary Failure
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac Failure Acute
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Cardiac Tamponade
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardio-Respiratory Arrest
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Pericardial Effusion
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    9 / 147 (6.12%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 3
    Tachycardia
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Brain Compression
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cerebral Haemorrhage
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Syncope
         subjects affected / exposed
    4 / 147 (2.72%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Hepatic Encephalopathy
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    Haemorrhagic Stroke
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Anaemia
         subjects affected / exposed
    4 / 147 (2.72%)
         occurrences causally related to treatment / all
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Acute Abdomen
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Rectal Haemorrhage
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal Haemorrhage
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Sjogren's Syndrome
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neck Pain
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Back Pain
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Arthritis Bacterial
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Covid-19
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Device Related Infection
         subjects affected / exposed
    2 / 147 (1.36%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia Bacterial
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 147 (3.40%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Ear, Nose and Throat Infection
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Streptococcal Infection
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Suspected Covid-19
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Fluid Retention
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Diabetic Metabolic Decompensation
         subjects affected / exposed
    1 / 147 (0.68%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Macitentan 10 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 147 (12.24%)
    Infections and infestations
    Covid-19
         subjects affected / exposed
    18 / 147 (12.24%)
         occurrences all number
    19

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Mar 2018
    This amendment was planned for exclusion criterion 1 was relaxed to include subjects with hemoglobin lower than 80 grams per litre (g/L), with treatment starting as soon as hemoglobin was higher than 80 g/L.
    06 Jun 2018
    This amendment was planned to include the list of parent studies was expanded to include patients who were treated with macitentan in study AC-055-404 (PORTICO).
    03 Dec 2018
    This amendment was panned to include the all adverse events (AEs) and serious AEs (SAEs) leading to permanent discontinuation of study treatment must be reported to Actelion drug safety. Laboratory results within 7 days prior to Visit 1 were acceptable for eligibility assessment. Concomitant therapies no longer need to be documented in the case report form (CRF). For patients temporarily ineligible for UMBRELLA at the end of the parent study, an interruption of macitentan treatment was acceptable if not longer than 4 weeks.
    23 Jan 2019
    This amendment was planned to include the inclusion of patients exiting from SERAPHIN OL in additional European countries, Asia and in Latin America, who do not have access to reimbursed macitentan in their country. The number of patients and sites was updated. References to France/French were generalized to cover affected regions. Changes were made on the study medication bottle labels. The definitions of the full analysis set and safety set were clarified. It was clarified that Actelion could decide to terminate the study at country or site level.
    17 Jul 2020
    This amendment was planned to include exclusion criterion 8 was added to exclude subjects who, were currently receiving treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor. A new section (5.1.10.3) was introduced to add the treatment with moderate dual CYP3A4/cytochrome P450 family 2 subfamily C member 9 (CYP2C9) inhibitors or coadministration of moderate CYP3A4- and moderate CYP2C9 inhibitors to the list of “Study-specific criteria for interruption/premature discontinuation of study treatment”. Section 5.2.5 was modified to include new information on concomitant administration of CYP34A and CYP2C9 inhibitors was added. A new reference (Food and Drug Administration 2020) was added to the reference list and Section 5.2.5.
    15 Oct 2020
    This amendment was planned to include the long term data of macitentan in subjects with pulmonary arterial hypertension (PAH) and MERIT-1 studies have been updated. These data show that subjects with chronic thromboembolic pulmonary hypertension (CTEPH) can be included in this study in addition to the PAH subjects; therefore, the primary objective of the study was updated to also includes subjects with CTEPH and allow subjects rolling over from the MERIT-2 open-label study in European and Asian countries where access to a post-trial program was not available. In addition, the food and drug administration (FDA) post marketing requirement to assess serious hepatic AEs of interest by an Independent Liver Safety Data Review Board (ILSDRB) was fulfilled in September 2019 and consequently, mention to ILSDRB was removed. Moreover, the purpose of this amendment was to adapt internal safety reporting processes, clarify the Child-Pugh assessments as needed for exclusion criterion 3, make minor corrections, and perform editorial document formatting revisions.
    05 Aug 2021
    This amendment was planned for to clarify how to manage the roll-over of UMBRELLA subjects into a continued access program (post-trial access [PTA] program or other open-label extension study). Also the number of subjects and sites was revised.

    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.
    None reported
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