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    Clinical Trial Results:
    A multi-centre, multinational, open-label study to evaluate the long-term safety, tolerability and efficacy of selexipag / ACT 293987 (NS-304) in the treatment of pulmonary arterial hypertension in subjects aged 18 years and over (open-extension study to NS 304/-02)

    Summary
    EudraCT number
    2007-006453-12
    Trial protocol
    HU   AT   FR   BE   GB   IT   DE  
    Global end of trial date
    19 Dec 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Dec 2018
    First version publication date
    30 Dec 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NS-304/-03
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Gewerbestrasse 16, Allschwil, Switzerland, 4123
    Public contact
    Clinical Trial Disclosure Desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@its.jnj.com
    Scientific contact
    Clinical Trial Disclosure Desk, Actelion Pharmaceuticals Ltd, clinical-trials-disclosure@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
    20 Apr 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Dec 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to collect and evaluate long-term safety and tolerability data of selexipag treatment in subjects with pulmonary arterial hypertension (PAH).
    Protection of trial subjects
    The clinical trial was designed and conducted in accordance with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations, including the European Directive 2001/20/EC, and with the ethical principles laid down in the Declaration of Helsinki
    Background therapy
    Oral anticoagulants, calcium channel blockers, diuretics, cardiac glyocsides, supplement oxygen, endothelin receptor antagonists, phosphodiesterase inhibitors and riociguat were allowed.
    Evidence for comparator
    -
    Actual start date of recruitment
    09 Oct 2008
    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
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 5
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 4
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Poland: 7
    Worldwide total number of subjects
    39
    EEA total number of subjects
    39
    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)
    27
    From 65 to 84 years
    12
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    39 subjects (31 previously randomized to selexipag and 8 previously randomized to placebo in the previous NS-304/-02 study) were enrolled into the open-label extension study NS-304/-03, from 7 sites in 7 countries.

    Pre-assignment
    Screening details
    Only the subjects who had completed Visit 7 (Week 17) of the preceding double-blind study NS-304/-02 and who signed the informed consent form to take part in the open-label extension study were eligible to be enrolled in NS-304/-03.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Selexipag
    Arm description
    Subjects who received selexipag during NS-304/-02 continued with their maximal tolerated dose of selexipag. Subjects who received placebo during NS-304/-02 started with 200 μg selexipag b.i.d. from Day 1 to Day 3, then the dose was up-titrated in 200 μg b.i.d. increments up to the maximum tolerated dose (MTD) for each subject but not above 800 µg during the titration phase. Thereafter these subjects continued with their individual maximal tolerated dose. After Week 24, the dose could be adjusted (not exceeding 1600 µg following Amendment 5).
    Arm type
    Experimental

    Investigational medicinal product name
    Selexipag
    Investigational medicinal product code
    ACT-293987, NS-304
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Twice daily administration (b.i.d.) with an interval of approximately 12 hours

    Number of subjects in period 1
    Selexipag
    Started
    39
    Completed
    7
    Not completed
    32
         Death
    10
         Lack of efficacy
    1
         Adverse events
    6
         Treatment goal not reached
    1
         Consent withdrawn by subject
    1
         Disease progression
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    Subjects who received selexipag during NS-304/-02 continued with their maximal tolerated dose of selexipag. Subjects who received placebo during NS-304/-02 started with 200 μg selexipag b.i.d. from Day 1 to Day 3, then the dose was up-titrated in 200 μg b.i.d. increments up to the maximum tolerated dose (MTD) for each subject but not above 800 µg during the titration phase. Thereafter these subjects continued with their individual maximal tolerated dose. After Week 24, the dose could be adjusted (not exceeding 1600 µg following Amendment 5).

    Reporting group values
    Selexipag Total
    Number of subjects
    39
    Age categorical
    Units: Subjects
    Age continuous
    Age at baseline is the age reported when subjects were enrolled in the NS-304/-02 study.
    Units: years
        median (full range (min-max))
    54 (19 to 80) -
    Gender categorical
    Units:
        Male
    5 5
        Female
    34 34
    Ethnicity
    Units: Subjects
        Caucasian
    36 36
        Asian
    2 2
        Other
    1 1
    PAH etiology
    PAH etiology at baseline is the PAH etiology reported when subjects were enrolled in the NS-304/-02 study
    Units: Subjects
        Idiopathic PAH
    28 28
        Familial PAH
    2 2
        PAH associated with CTD
    5 5
        PAH associated with corrected CHD
    2 2
        PAH associated with anorexigen use
    2 2
    WHO Functional class (FC)
    WHO FC for each subject in the open-label extension study was collected on Day 1 of study NS-304/-03, before starting the open-label treatment.
    Units: Subjects
        WHO FC I
    3 3
        WHO FC II
    17 17
        WHO FC III
    19 19
    PAH-specific concomitant therapy
    PAH-specific concomitant therapy means PAH-specific therapies reported as ongoing on Day 1 of study NS-304/-03, before starting the open-label treatment.
    Units: Subjects
        Endothelin receptor antagonist (ERA)
    13 13
        Phosphodiesterase-5 inhibitor (PDE5i)
    12 12
        ERA + PDE5i
    14 14
    Time since PAH diagnosis
    This is the time since pulmonary arterial hypertension diagnosis at Day 1 of study NS-304/-03, before starting the open-label treatment.
    Units: Days
        median (full range (min-max))
    1071 (251 to 10062) -

    End points

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    End points reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    Subjects who received selexipag during NS-304/-02 continued with their maximal tolerated dose of selexipag. Subjects who received placebo during NS-304/-02 started with 200 μg selexipag b.i.d. from Day 1 to Day 3, then the dose was up-titrated in 200 μg b.i.d. increments up to the maximum tolerated dose (MTD) for each subject but not above 800 µg during the titration phase. Thereafter these subjects continued with their individual maximal tolerated dose. After Week 24, the dose could be adjusted (not exceeding 1600 µg following Amendment 5).

    Primary: Number of subjects with any treatment-emergent adverse events (TEAEs)

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    End point title
    Number of subjects with any treatment-emergent adverse events (TEAEs) [1]
    End point description
    A treatment emergent adverse event (TEAE) was defined as any AE with an onset on the first day of selexipag intake in NS-304/-03 up to 3 days after treatment discontinuation (EOT + 3 days), whether or not considered related to the study treatment.
    End point type
    Primary
    End point timeframe
    From Day 1 to EOT + 3 days
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables.
    End point values
    Selexipag
    Number of subjects analysed
    39
    Units: Subjects
    38
    No statistical analyses for this end point

    Primary: Number of subjects with TEAEs of mild, moderate or severe intensity

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    End point title
    Number of subjects with TEAEs of mild, moderate or severe intensity [2]
    End point description
    Treatment-emergent adverse events (TEAEs) were classified into three intensity categories: mild AE (usually transient and do not interfere with the subject daily's activities), moderate AE (low level of inconvenience to the subject and may interfere with daily's activities), severe AE (interruption of the subject's usual daily activities). The number of subjects with at least one adverse event of mild, moderate or severe intensity was reported.
    End point type
    Primary
    End point timeframe
    from Day 1 to EOT + 3 days
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables.
    End point values
    Selexipag
    Number of subjects analysed
    39
    Units: Subjects
        Mild intensity
    33
        Moderate intensity
    37
        Severe intensity
    27
    No statistical analyses for this end point

    Primary: Number of subjects with TEAEs causally related to the study treatment

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    End point title
    Number of subjects with TEAEs causally related to the study treatment [3]
    End point description
    The causal relationship between the study treatment (selexipag) and the adverse event (TEAE) was characterized as unrelated (no reasonable possibility that the study treatment caused the AE), unlikely (only a remote connection exists between the study treatment and the AE; other conditions appear to explain the AE), possible (the association of the AE with the study treatment is unknown; however the AE is not reasonably supported by other conditions) or probable (a reasonable temporal sequence of the AE with the study treatment administration exists). The number of subjects with at least one TEAE characterized as "possible" or "probable" by the investigator was reported as causally related to the study treatment.
    End point type
    Primary
    End point timeframe
    From day 1 to EOT + 3 days
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables.
    End point values
    Selexipag
    Number of subjects analysed
    39
    Units: Subjects
    28
    No statistical analyses for this end point

    Primary: Number of subjects with fatal treatment-emergent adverse events

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    End point title
    Number of subjects with fatal treatment-emergent adverse events [4]
    End point description
    The number of subjects with at least one treatment-emergent adverse event leading to death was reported
    End point type
    Primary
    End point timeframe
    From Day 1 to EOT + 3 days
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables.
    End point values
    Selexipag
    Number of subjects analysed
    39
    Units: Subjects
    12
    No statistical analyses for this end point

    Primary: Number of subjects with adverse events leading to study treatment discontinuation

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    End point title
    Number of subjects with adverse events leading to study treatment discontinuation [5]
    End point description
    Subjects with at least one AE leading to permanent withdrawal of the study treatment (selexipag) were reported
    End point type
    Primary
    End point timeframe
    From day 1 up to treatment discontinuation
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables.
    End point values
    Selexipag
    Number of subjects analysed
    39
    Units: Subjects
    18
    No statistical analyses for this end point

    Primary: Number of subjects with treatment-emergent adverse events of special interest (AESI)

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    End point title
    Number of subjects with treatment-emergent adverse events of special interest (AESI) [6]
    End point description
    AESI were defined based on the selexipag European Risk Management Plan (EU RMP) and included the following: Hypotension, Anemia / decrease in hemoglobin concentration, Hyperthyroidism, Major adverse cardiac event (MACE), Acute renal failure and renal impairment, Bleeding events, Light-dependent non-melanoma skin tumors, Ophthalmological effects associated with retinal vascular system, Gastrointestinal disturbances denoting intestinal intussusception.
    End point type
    Primary
    End point timeframe
    From Day 1 to EOT + 3 days
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables.
    End point values
    Selexipag
    Number of subjects analysed
    39
    Units: Subjects
        Hypotension
    5
        Anemia, decrease in hemoglobin
    8
        MACE
    8
        Acute renal failure and renal impairment
    3
        Bleeding events
    11
        Overall (any categories)
    23
    No statistical analyses for this end point

    Primary: Incidence of marked laboratory tests abnormalities

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    End point title
    Incidence of marked laboratory tests abnormalities [7]
    End point description
    The number of subjects enrolled in NS-304/-03 with marked abnormalities in hematology or chemistry variables were to be reported. Marked abnormality was considered for subjects who presented an abnormality post-baseline which was not present at baseline.
    End point type
    Primary
    End point timeframe
    From Day 1 to Week 24
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables.
    End point values
    Selexipag
    Number of subjects analysed
    39
    Units: Subjects
        Hemoglobin decrease (<100 g/L)
    2
        Creatinine increase (> 1.5 x ULN)
    1
        Sodium increase (>150 mmol/L)
    1
        Potassium increase (> 5.5 mmol/L)
    2
        Potassium decrease (< 3 mmol/L)
    1
    No statistical analyses for this end point

    Primary: Incidence of marked abnormalities in vital signs

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    End point title
    Incidence of marked abnormalities in vital signs [8]
    End point description
    The number of subjects enrolled in NS-304/-03 with marked abnormalities in systolic / diastolic blood pressure (SBP/DBP) or pulse rate were to be reported. Marked abnormality was considered for subjects who presented an abnormality post-baseline which was not present at baseline.
    End point type
    Primary
    End point timeframe
    From Day 1 up to the last study visit
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables.
    End point values
    Selexipag
    Number of subjects analysed
    39
    Units: Subjects
        SBP < 90 mmHg
    6
        SBP decrease > 40 mmHg from Baseline
    1
        DBP < 50 mmHg
    1
        DBP decrease > 20 mmHg from baseline
    5
    No statistical analyses for this end point

    Primary: Incidence of QTcF abnormalities

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    End point title
    Incidence of QTcF abnormalities [9]
    End point description
    The number of subjects enrolled in NS-304/-03 with QTcF abnormalities as assessed by ECG were to be reported. Marked abnormality was considered for subjects who presented a QTcF prolongation post-baseline which was not present at baseline.
    End point type
    Primary
    End point timeframe
    From Day 1 to Week 24
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal statistical analyses were planned for this study. Only descriptive analyses were performed for all variables.
    End point values
    Selexipag
    Number of subjects analysed
    39
    Units: Subjects
        QTcF > 450 ms
    21
        QTcF > 480 ms
    5
        QTcF > 500 ms
    2
        QTcF increase from baseline > 30 ms
    5
        QTcF increase from baseline > 60 ms
    1
        QTcF > 450 ms and increase from baseline > 30 ms
    4
        QTcF > 450 ms and increase from baseline > 60 ms
    1
    No statistical analyses for this end point

    Secondary: Change from baseline in 6-minute walk distance over time

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    End point title
    Change from baseline in 6-minute walk distance over time
    End point description
    Walk distance is measured during the 6-minute walk test (6MWT). 6MWT is a non-encouraged test, which measures the distance (in meters) covered by the subject during a 6-minute walk in a flat corridor. Change from baseline in 6MWT was analyzed at various timepoints during the study. Thirty-nine subjects had a 6MWT measure available at baseline. If the number of subjects included in the analysis for a specific timepoint was less than 10 this timepoint was not reported here.
    End point type
    Secondary
    End point timeframe
    From Day 1 to the last study visit
    End point values
    Selexipag
    Number of subjects analysed
    39
    Units: meters
    median (full range (min-max))
        Week 12 (N=34)
    1.0 (-100 to 125)
        Week 24 (N=34)
    -0.5 (-172 to 115)
        Month 12 (N=30)
    -15.0 (-195 to 167)
        Month 18 (N=29)
    -10.0 (-233 to 147)
        Month 24 (N=26)
    -19.5 (-256 to 185)
        Month 30 (N=25)
    -27 (-208 to 114)
        Month 36 (N=23)
    -45 (-121 to 178)
        Month 42 (N=21)
    -30 (-247 to 247)
        Month 48 (N=19)
    -27 (-228 to 330)
        Month 54 (N=18)
    -34.5 (-150 to 270)
        Month 60 (N=18)
    -20.5 (-342 to 355)
        Month 66 (N=16)
    -31 (-172 to 371)
        Month 72 (N=15)
    -50 (-256 to 370)
        Month 78 (N=15)
    -29 (-268 to 357)
        Month 84 (N=10)
    -20.5 (-114 to 359)
        Month 90 (N=11)
    -25 (-96 to 373)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 to EOT + 3 days for non-serious and serious AEs and up to EOT + 30 days for deaths (all causes)
    Adverse event reporting additional description
    Day 1 is the first day of enrollment in the open-label phase (NS-304/-03)
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    A total of 39 subjects received selexipag during NS-304/-03 for a median duration of 1712 days (range: 11-3347 days), with 20 and 8 subjects receiving selexipag for a cumulative duration of at least 48 months and 96 months, respectively.

    Serious adverse events
    Selexipag
    Total subjects affected by serious adverse events
         subjects affected / exposed
    29 / 39 (74.36%)
         number of deaths (all causes)
    13
         number of deaths resulting from adverse events
    Vascular disorders
    Phlebitis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Surgical and medical procedures
    Balloon atrial septostomy
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Cardiac ablation
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cranioplasty
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung transplant
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Mastectomy
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transurethral prostatectomy
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Benign gastrointestinal neoplasm
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Myelodysplastic syndrome
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Pregnancy
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Euthanasia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sudden death
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences causally related to treatment / all
    0 / 3
         deaths causally related to treatment / all
    0 / 3
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Mental disorder
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Alcohol poisoning
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Investigations
    Catheterisation cardiac
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute right ventricular failure
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Atrial fibrillation
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Atrial flutter
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Cardiac arrest
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Palpitations
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences causally related to treatment / all
    0 / 10
         deaths causally related to treatment / all
    0 / 2
    Tachycardia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Hypochromic anaemia
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    12 / 39 (30.77%)
         occurrences causally related to treatment / all
    0 / 13
         deaths causally related to treatment / all
    0 / 1
    Pulmonary hypertension
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Peripheral sensory neuropathy
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 39 (2.56%)
         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 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatic congestion
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Pain of skin
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 39 (2.56%)
         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
    Selexipag
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    38 / 39 (97.44%)
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Flushing
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    Hot flush
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Hypotension
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    5
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Chest pain
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    10
    Fatigue
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    7
    Malaise
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Oedema peripheral
         subjects affected / exposed
    11 / 39 (28.21%)
         occurrences all number
    14
    Pain
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Pyrexia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Depression
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Insomnia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Fall
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    4
    Ligament sprain
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Blood uric acid increased
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Weight decreased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Weight increased
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    7
    Right ventricular failure
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Sinus tachycardia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Tachycardia
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    7
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    7
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Cough
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    9
    Dyspnoea
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    7
    Epistaxis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Haemoptysis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Oropharyngeal pain
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Pulmonary arterial hypertension
         subjects affected / exposed
    12 / 39 (30.77%)
         occurrences all number
    13
    Respiratory disorder
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Rhinitis allergic
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Sleep apnoea syndrome
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Throat irritation
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 39 (20.51%)
         occurrences all number
    11
    Headache
         subjects affected / exposed
    19 / 39 (48.72%)
         occurrences all number
    31
    Somnolence
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Syncope
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    10
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Vertigo
         subjects affected / exposed
    8 / 39 (20.51%)
         occurrences all number
    9
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Abdominal pain
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Abdominal pain upper
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    4
    Constipation
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    17 / 39 (43.59%)
         occurrences all number
    18
    Dry mouth
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Dyspepsia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Gastritis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    5
    Nausea
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    10
    Vomiting
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    6
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Proteinuria
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Erythema
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Pruritus
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Back pain
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    6
    Bone pain
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Bursitis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Musculoskeletal pain
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Myalgia
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Osteoporosis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Pain in extremity
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    11
    Pain in jaw
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    7
    Polyarthritis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Tendonitis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    5
    Hyponatraemia
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    22
    Conjunctivitis
         subjects affected / exposed
    1 / 39 (2.56%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    6
    Influenza
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Pharyngitis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    3
    Pneumonia
         subjects affected / exposed
    3 / 39 (7.69%)
         occurrences all number
    3
    Respiratory tract infection
         subjects affected / exposed
    7 / 39 (17.95%)
         occurrences all number
    16
    Rhinitis
         subjects affected / exposed
    2 / 39 (5.13%)
         occurrences all number
    2
    Sinusitis
         subjects affected / exposed
    4 / 39 (10.26%)
         occurrences all number
    7
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 39 (12.82%)
         occurrences all number
    6
    Urinary tract infection
         subjects affected / exposed
    6 / 39 (15.38%)
         occurrences all number
    6
    Viral upper respiratory tract infection
         subjects affected / exposed
    9 / 39 (23.08%)
         occurrences all number
    21

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Oct 2008
    Main reasons for amendment: Operation and sponsorship of the study was changed from Nippon Shinyaku Ltd to Actelion Pharmaceuticals Ltd; Study drug number NS-304 changed to ACT-293987
    25 Nov 2008
    Main reasons for amendment: Because the results of an in vitro phototoxicity study suggested that selexipag and its active metabolite have phototoxic potential, this information was added as well as information on the precautions to be taken regarding sun exposure. A new inclusion criteria was introduced to include only subjects who were willing and able to refrain from sunbathing, prolonged exposure to sun and artificial sunlight (such as solarium), or UV-A/UV-B treatment, and to limit skin and eye exposure to sunlight by taking appropriate precautions (protective clothing, sunscreen, and sunglasses) from the first dose until 14 days after study treatment discontinuation.
    10 Feb 2009
    Main reasons for amendment: Study duration was extended from the existing 24 weeks until the earliest of one of the following: approval of marketing authorization for selexipag in PAH, decision by Actelion Pharmaceuticals Ltd to stop the study, or decision by the subject or investigator to discontinue study treatment.
    25 Jun 2009
    Main reasons for amendment: Activities previously managed by the CRO (Quintiles) were taken over by Actelion Pharmaceuticals Ltd
    03 Nov 2010
    Main reasons for amendment: -In accordance with the other ongoing studies (AC-065A302 and AC-065A303), the maximum dose of selexipag allowed in the present study was increased from 800 μg b.i.d. to 1600 μg b.i.d.; -change in the manufacturer of the selexipag tablets from Nippon Shinyaku Ltd to Excella Pharma GmbH - addition of new phase 1 study results.
    17 Jun 2012
    Main reasons for amendment: -A phase 1 clinical trial studying the phototoxicity of selexipag did not indicate a clinically relevant phototoxic potential of selexipag at doses of 800 and 1200 µg b.i.d. after UV-A and UV-B irradiation in healthy male subjects. Therefore, a footnote was added to the inclusion criterion on sun exposure to indicate that no extra precautions were necessary regarding sun exposure; - New findings from toxicologic studies in animals were added (retinal toxicity, nonmalignant neoplastic changes in the thyroid) -Change in selexipag packager and packaging.
    16 Jan 2014
    Main reasons for amendment: - ACT-293987 replaced by Selexipag in the protocol; - new findings from non clinical studies were added (effects on platelet aggregation in vitro; effects liver drug metabolizin enzymes and thyroid hormones in mice) as well as update on Phase 1 and Phase 2 studies. - Addition of an exclusion criteria: Females who were breast-feeding, pregnant or planned to become pregnant during the study and females who were not using a highly effective method of birth control with a failure rate of less than 1% per year, were to be excluded - Specification on how to manage subjects with liver impairment (based on the results of a Phase 1 study): If, during the course of the study, a subject developed or progressed to Child-Pugh B liver impairment, it was the responsibility of the investigator to assess the benefit-risk of maintaining the subject on study treatment; if a subject developed or progressed to Child Pugh C liver impairment, study treatment was to be discontinued. - ʻTime to aggravation of PAHʼ was added as a tertiary efficacy endpoint.
    10 Apr 2015
    Main reasons for amendment: -The condition that the site should inform the sponsor before a subject’s dose was up titrated to a maximum of 1600 µg b.i.d. after Visit 5 was removed. However, it was clarified that the assessment/decision to up titrate was to be made only after a site visit (scheduled/unscheduled) was performed; -In order to avoid any treatment interruption if there was a lag period between the time when marketing authorization was granted and the time when selexipag could be commercially available to the subjects, the duration of NS-304/-03 study was set up to commercial availability of selexipag in the subject’s country; - A new discontinuation criterion was introduced for subjects who were diagnosed with PVOD; - The concomitant use of selexipag and i.v., s.c., or inhaled prostacyclin and prostacyclin analogs was allowed temporarily when deemed medically justified; - The process of temporarily switching a subject from oral selexipag to another IP receptor with a more convenient route of administration with regard to the subjectʼs medical condition and subsequently restarting selexipag was included in the protocol; -Riociguat was added as an allowed concomitant PAH medication: - because hyperthyroidism has been observed with selexipag and other IP receptor agonists, thyroid function tests were to be performed locally for individual subjects if deemed clinically indicated by the investigator.
    24 Jan 2017
    Main reasons for amendment: - Concomitant administration of strong CYP2C8 inhibitors such as gemfibrozil was to be avoided and selxipag dose adjustment could be required following concomitant administration of moderate CYP2C8 inducer such as rifampicin . These recommendations were added taking into account the results of a phase 1 study.
    30 Jun 2017
    Main reasons for amendment: - To include guidance for concomitant administration of selexipag and strong CYP2C8 inhibitors: concomitant administration of selexipag and strong CYP2C8 inhibitors such as gemfibrozil is prohibited until end-of-study in NS-304/-03. – To include information on other potential drug-drug interactions: ʻThe effect of moderate inhibitors of CYP2C8, and strong inhibitors of UGT1A3 and UGT2B7 on the exposure to selexipag or its active metabolite has not been studied. Concomitant administration may result in a significant increase in exposure to selexipag or its active metaboliteʼ.

    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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