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    Clinical Trial Results:
    A Multi-center, Double-blind, Placebo-controlled, Phase 4 Study in Subjects with Pulmonary Arterial Hypertension to Assess the Effect of Selexipag on Daily Life Physical Activity and Subject's Self-reported Symptoms and their Impacts

    Summary
    EudraCT number
    2017-000216-42
    Trial protocol
    GB   IE   SE   DE   AT   PT   FR  
    Global end of trial date
    20 Feb 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Feb 2021
    First version publication date
    22 Feb 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AC-065A404
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03078907
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Actelion Pharmaceuticals Ltd
    Sponsor organisation address
    Keilaranta 16, 02150 Espoo, Finland,
    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
    23 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Feb 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Feb 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to evaluate the effect of selexipag on daily life physical activity (DLPA) of subjects with pulmonary arterial hypertension (PAH).
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety assessment was based on reported adverse events, clinical laboratory tests (such as hematology clinical chemistry, N-terminal pro b-type natriuretic peptide (NT-pro BNP), blood samples for circulating biomarkers, thyroid function test [as hyperthyroidism has been observed with selexipag]), vital sign measurements, and pregnancy tests (for women of childbearing potential).
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    08 Nov 2017
    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: 1
    Country: Number of subjects enrolled
    Switzerland: 1
    Country: Number of subjects enrolled
    Germany: 11
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    United Kingdom: 66
    Country: Number of subjects enrolled
    Ireland: 2
    Country: Number of subjects enrolled
    Norway: 1
    Country: Number of subjects enrolled
    Portugal: 6
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    108
    EEA total number of subjects
    27
    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)
    85
    From 65 to 84 years
    23
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 108 subjects were randomized out of which 96 subjects completed the study treatment.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Selexipag
    Arm description
    Subjects received Selexipag which was up-titrated from Day 1 (Week 1) to Week 12 to the individualized highest tolerated dose (HTD) which ranged from 200 microgram (mcg) to 1600 mcg twice daily (BID) orally. The dose was increased in increments of 200 mcg BID, usually at weekly intervals, depending on the dose tolerability. Up-titration was followed by a stable maintenance treatment period at the highest tolerated dose, from Week 13 to Week 24.
    Arm type
    Experimental

    Investigational medicinal product name
    Selexipag
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Selexipag was administered as tablets of 200 mcg in doses of up to 1600 mcg (8 tablets) orally twice daily.

    Arm title
    Placebo
    Arm description
    Subjects received one to 8 tablets of 200 (mcg) matching placebo, administered up to a maximum dose up-titrated to 1600 mcg orally twice daily. Up-titration was followed by a stable maintenance treatment period at the highest tolerated dose, from Week 13 to Week 24.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered as matching tablets of 200 mcg in doses of up to 1600 mcg (8 tablets) orally twice daily.

    Number of subjects in period 1
    Selexipag Placebo
    Started
    53
    55
    Completed
    50
    54
    Not completed
    3
    1
         Subject decision
    1
    -
         Protocol deviation
    -
    1
         Adverse Event
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    Subjects received Selexipag which was up-titrated from Day 1 (Week 1) to Week 12 to the individualized highest tolerated dose (HTD) which ranged from 200 microgram (mcg) to 1600 mcg twice daily (BID) orally. The dose was increased in increments of 200 mcg BID, usually at weekly intervals, depending on the dose tolerability. Up-titration was followed by a stable maintenance treatment period at the highest tolerated dose, from Week 13 to Week 24.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received one to 8 tablets of 200 (mcg) matching placebo, administered up to a maximum dose up-titrated to 1600 mcg orally twice daily. Up-titration was followed by a stable maintenance treatment period at the highest tolerated dose, from Week 13 to Week 24.

    Reporting group values
    Selexipag Placebo Total
    Number of subjects
    53 55 108
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0 0
        Adolescents (12-17 years)
    0 0 0
        Adults (18-64 years)
    42 43 85
        From 65 to 84 years
    11 12 23
        85 years and over
    0 0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    49 ± 14.75 49.8 ± 13.63 -
    Title for Gender
    Units: subjects
        Female
    35 42 77
        Male
    18 13 31

    End points

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    End points reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    Subjects received Selexipag which was up-titrated from Day 1 (Week 1) to Week 12 to the individualized highest tolerated dose (HTD) which ranged from 200 microgram (mcg) to 1600 mcg twice daily (BID) orally. The dose was increased in increments of 200 mcg BID, usually at weekly intervals, depending on the dose tolerability. Up-titration was followed by a stable maintenance treatment period at the highest tolerated dose, from Week 13 to Week 24.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received one to 8 tablets of 200 (mcg) matching placebo, administered up to a maximum dose up-titrated to 1600 mcg orally twice daily. Up-titration was followed by a stable maintenance treatment period at the highest tolerated dose, from Week 13 to Week 24.

    Primary: Change from Baseline to Week 24 in Actigraphy Assessed Daily Life Physical Activity (DLPA) for Variables Expressed in Minutes

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    End point title
    Change from Baseline to Week 24 in Actigraphy Assessed Daily Life Physical Activity (DLPA) for Variables Expressed in Minutes
    End point description
    Change from baseline to Week 24 of the DLPA activity parameters for daily time spent in non-sedentary activity (NSA) (as defined by Freedson ’98 and Koster ‘16) and daily time spent in moderate-to-vigorous physical activity (MVPA) as defined by Freedson ‘98 were reported. These variables were assessed by actigraphy and were expressed in minutes. Freedson 1998 established ranges of activity counts obtained from a hip worn accelerometer corresponding to commonly employed MET categories. Based on this work, threshold between sedentary and NSA was defined. This threshold is often referred to as Freedson’s 1998 publication. Koster 2016 defined the threshold between sedentary and NSA based on wrist-worn accelerometers on non-dominant hand, respectively. Positive change from baseline means improvement. The Full Analysis Set (FAS) included all subjects randomly assigned to a study treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
    End point values
    Selexipag Placebo
    Number of subjects analysed
    53
    55
    Units: minutes
    arithmetic mean (standard deviation)
        Daily time spent in NSA (Freedson ‘98)
    -15.2 ± 79.78
    -25.2 ± 72.47
        Daily time spent in MVPA (Freedson '98)
    0.2 ± 34.48
    -1.9 ± 34.26
        Daily time spent in NSA (Koster'16)
    -0.7 ± 72.50
    -15.0 ± 62.27
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Daily time spent in non-sedentary activity (minutes), Freedson ‘98
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    Least Square (LS) mean
    Point estimate
    13.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    13.366
         upper limit
    40.944
    Variability estimate
    Standard error of the mean
    Dispersion value
    13.695
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Daily time spent in MVPA (minutes), Freedson ‘98
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    LS mean
    Point estimate
    2.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10.782
         upper limit
    15.396
    Variability estimate
    Standard error of the mean
    Dispersion value
    6.601
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Daily time spent in non-sedentary activity (minutes), Koster ‘16
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    LS mean
    Point estimate
    17.81
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.003
         upper limit
    41.619
    Variability estimate
    Standard error of the mean
    Dispersion value
    12.008

    Primary: Change from Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Percentage (%)

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    End point title
    Change from Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Percentage (%)
    End point description
    Change from baseline to Week 24 of the DLPA activity parameters for daily time spent in non-sedentary activity (NSA) (Freedson ‘98), daily time spent in moderate-to-vigorous physical activity (MVPA) (Freedson ‘98) and dailytime spent in NSA (Koster ‘16) were reported. These variables were assessed by actigraphy andwere expressed in percentage (%). Freedson 1998 established ranges of activity counts obtained from a hip worn accelerometer corresponding to commonly employed MET categories. Based on this work, threshold between sedentary and NSA was defined. This threshold is often referred to as Freedson’s 1998 publication. Koster 2016 defined the threshold between sedentary and NSA based on wrist-worn accelerometers on non-dominant hand, respectively. Positive change from baseline means improvement. The FAS included all subjects randomly assigned to a study treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
    End point values
    Selexipag Placebo
    Number of subjects analysed
    53
    55
    Units: Percentage
    arithmetic mean (standard deviation)
        Daily time spent in NSA (%), Freedson ‘98
    0.08 ± 7.265
    -0.10 ± 6.439
        Daily time spent in MVPA (%), Freedson ‘98
    0.23 ± 3.342
    0.32 ± 3.513
        Daily time spent in NSA (%), Koster ‘16
    0.80 ± 7.158
    0.00 ± 6.269
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Percentage of daily time spent in non-sedentary activity (%), Freedson ‘98
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.713
         upper limit
    3.06
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.204
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Percentage of daily time spent in MVPA (%), Freedson ‘98
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    LS mean
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.351
         upper limit
    1.258
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.658
    Statistical analysis title
    Statistical Analysis 3
    Statistical analysis description
    Percentage of daily time spent in non-sedentary activity (%), Koster ‘16
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    LS mean
    Point estimate
    1.26
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.104
         upper limit
    3.618
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.191

    Primary: Change from Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Counts per Minute (Counts/Minute)

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    End point title
    Change from Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Counts per Minute (Counts/Minute)
    End point description
    Change from baseline to Week 24 of the DLPA activity parameter for volume of total daily activities and volume of NSA (Koster ‘16) were reported. These variables were assessed by actigraphy and were expressed in counts/minutes. Koster 2016 defined the threshold between sedentary and NSA based on wrist-worn accelerometers on non-dominant hand, respectively. Positive change from baseline means improvement. The FAS included all subjects randomly assigned to a study treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
    End point values
    Selexipag Placebo
    Number of subjects analysed
    53
    55
    Units: counts/minute
    arithmetic mean (standard deviation)
        Volume of total daily activities
    29.3 ± 337.18
    18.8 ± 342.77
        Volume of NSA, Koster ‘16
    36.1 ± 342.11
    16.8 ± 351.08
    Statistical analysis title
    Statistical Analysis 1
    Statistical analysis description
    Volume of total daily activities (counts / minute)
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    20.66
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -105.632
         upper limit
    146.958
    Variability estimate
    Standard error of the mean
    Dispersion value
    63.695
    Statistical analysis title
    Statistical Analysis 2
    Statistical analysis description
    Volume of non-sedentary activity (counts/minute), Koster ‘16
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    LS mean
    Point estimate
    27.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -101.945
         upper limit
    156.976
    Variability estimate
    Standard error of the mean
    Dispersion value
    65.291

    Primary: Change from Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Counts

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    End point title
    Change from Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Counts
    End point description
    Change from baseline to Week 24 of the DLPA activity parameters for volume of non-sedentary activity (Koster ‘16)were reported. These variables were assessed by actigraphy and were expressed in counts. Koster 2016 defined the threshold between sedentary and NSA based on wrist-worn accelerometers on non-dominant hand, respectively. Positive change from baseline means improvement. The FAS included all subjects randomly assigned to a study treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
    End point values
    Selexipag Placebo
    Number of subjects analysed
    53
    55
    Units: counts
        arithmetic mean (standard deviation)
    3898 ± 345872
    -49187 ± 343402.2
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    58409
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -70444
         upper limit
    187263
    Variability estimate
    Standard error of the mean
    Dispersion value
    64985

    Primary: Change from Baseline to Week 24 in Actigraphy DLPA for Variable Expressed in Step Counts

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    End point title
    Change from Baseline to Week 24 in Actigraphy DLPA for Variable Expressed in Step Counts
    End point description
    Change from baseline to Week 24 of the DLPA activity parameters for number of steps during awake time were reported. These variables were assessed by actigraphy and were expressed in step counts. Positive change from baseline means improvement. The Full Analysis Set (FAS) included all subjects randomly assigned to a study treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
    End point values
    Selexipag Placebo
    Number of subjects analysed
    53
    55
    Units: step counts
        arithmetic mean (standard deviation)
    -32.4 ± 1288.64
    -170.9 ± 1076.87
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    201.59
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -242.977
         upper limit
    646.163
    Variability estimate
    Standard error of the mean
    Dispersion value
    224.212

    Primary: Change from Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Step Counts/Minute

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    End point title
    Change from Baseline to Week 24 in Actigraphy DLPA for Variables Expressed in Step Counts/Minute
    End point description
    Change from baseline to Week 24 of the DLPA activity parameters for number of steps during awake time were reported. These variables were assessed by actigraphy and were expressed in step counts/minute. Positive change from baseline means improvement. The Full Analysis Set (FAS) included all subjects randomly assigned to a study treatment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
    End point values
    Selexipag Placebo
    Number of subjects analysed
    53
    55
    Units: step counts/minute
        arithmetic mean (standard deviation)
    0 ± 1.25
    0.0 ± 1.04
    Statistical analysis title
    Statistical Analysis
    Comparison groups
    Selexipag v Placebo
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    other
    Method
    ANCOVA
    Parameter type
    LS mean
    Point estimate
    0.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.366
         upper limit
    0.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.221

    Primary: Change from Baseline to Week 24 in Total Sleep Time (TST)

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    End point title
    Change from Baseline to Week 24 in Total Sleep Time (TST) [1]
    End point description
    TST (in minutes) was assessed by actigraphy. Mean value from the last 14 days period on study treatment was evaluated and mean change from baseline was calculated. The FAS included all subjects randomly assigned to a study treatment. Data was not reported because the sleep episodes were not identified due to unexpected inaccuracy in automated sleep detection algorithm which resulted in missing/unreliable sleep data which would mislead the design of future trials and the interpretation of sleep results.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
    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 inferential statistical hypothesis testing was planned for this endpoint.
    End point values
    Selexipag Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: minutes
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [2] - Data was not reported for reason stated above.
    [3] - Data was not reported for reason stated above.
    No statistical analyses for this end point

    Primary: Change from Baseline to Week 24 in Wake After Sleep Onset (WASO)

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    End point title
    Change from Baseline to Week 24 in Wake After Sleep Onset (WASO) [4]
    End point description
    WASO (in minutes) was assessed by actigraphy. Mean value from the last 14 days period on study treatment was evaluated and mean change from baseline was calculated. The FAS included all participants randomly assigned to a study treatment. Data was not reported because the sleep episodes were not identified due to unexpected inaccuracy in automated sleep detection algorithm which resulted in missing/unreliable sleep data which would mislead the design of future trials and the interpretation of sleep results.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
    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 inferential statistical hypothesis testing was planned for this endpoint.
    End point values
    Selexipag Placebo
    Number of subjects analysed
    0 [5]
    0 [6]
    Units: minutes
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [5] - Data was not reported for reason stated above.
    [6] - Data was not reported for reason stated above.
    No statistical analyses for this end point

    Primary: Change from Baseline to Week 24 in Number of Awakenings

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    End point title
    Change from Baseline to Week 24 in Number of Awakenings [7]
    End point description
    Number of awakenings was assessed by actigraphy. Mean value from the last 14 days period on study treatment was evaluated and mean change from baseline was calculated. The FAS included all subjects randomly assigned to a study treatment. Data was not reported because the sleep episodes were not identified due to unexpected inaccuracy in automated sleep detection algorithm which resulted in missing/unreliable sleep data which would mislead the design of future trials and the interpretation of sleep results.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for 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 inferential statistical hypothesis testing was planned for this endpoint.
    End point values
    Selexipag Placebo
    Number of subjects analysed
    0 [8]
    0 [9]
    Units: per night
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [8] - Data was not reported for reason stated above.
    [9] - Data was not reported for reason stated above.
    No statistical analyses for this end point

    Primary: Change from Baseline to Week 24 in Sleep Efficiency (SE)

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    End point title
    Change from Baseline to Week 24 in Sleep Efficiency (SE) [10]
    End point description
    SE (in percentage) was assessed by actigraphy. Mean value from the last 14 days period on study treatment was evaluated and mean change from baseline was calculated. The FAS included all subjects randomly assigned to a study treatment. Data was not reported because the sleep episodes were not identified due to unexpected inaccuracy in automated sleep detection algorithm which resulted in missing/unreliable sleep data which would mislead the design of future trials and the interpretation of sleep results.
    End point type
    Primary
    End point timeframe
    Baseline and Week 24 (data collection was done during 14-Days each for Baseline and for Week 24)
    Notes
    [10] - 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 inferential statistical hypothesis testing was planned for this endpoint.
    End point values
    Selexipag Placebo
    Number of subjects analysed
    0 [11]
    0 [12]
    Units: percentage per night
        arithmetic mean (standard deviation)
    ±
    ±
    Notes
    [11] - Data was not reported for reason stated above.
    [12] - Data was not reported for reason stated above.
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 in Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Score

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    End point title
    Change from Baseline to Week 24 in Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Score
    End point description
    The PAH-SYMPACT has two main parts: symptoms (cardiopulmonary and cardiovascular)and impact (physical impacts and cognitive/emotional). The symptom part is a questionnaire completed daily for 7 consecutive days and contains 11 items. The impact part has a 7-day recall period and is completed on the seventh day of the symptoms questionnaire data collection period. It contains 11 items pertaining to the impact of PAH. The average Cardiopulmonary Symptoms and cardiovascular symptoms domain scores are determined based on the daily scores of the 6 and 5 items, respectively, reported on a 5-point Likert scale (from 0 to 4). The score ranges from 0=best to 4=worst. Mean value on each of the 7-day period was calculated for each specific domain score and corresponding mean change from baseline was determined. The FAS included all subjects randomly assigned to a study treatment. Here, 'n' (number of subjects analyzed) signifies the number of subjects evaluable for a specified category.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Selexipag Placebo
    Number of subjects analysed
    53
    55
    Units: units on a scale
    arithmetic mean (standard deviation)
        Cardiopulmonary symptom (n=44, 52)
    -0.030 ± 0.4160
    -0.080 ± 0.2564
        Cardiovascular symptom (n=44, 52)
    0.010 ± 0.3522
    -0.045 ± 0.3029
        Physical impact (n=40, 50)
    -0.043 ± 0.5932
    -0.074 ± 0.5470
        Cognitive/emotional impact (n=40, 50)
    0.000 ± 0.5311
    -0.090 ± 0.5992
    No statistical analyses for this end point

    Secondary: Number of Subjects with Change from Baseline to Week 24 in World Health Organization Functional Class (WHO FC)

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    End point title
    Number of Subjects with Change from Baseline to Week 24 in World Health Organization Functional Class (WHO FC)
    End point description
    The WHO FC of pulmonary hypertension is a physical activity rating scale as follows: Class I (No limitation of physical activity); Class II (Slight limitation of physical activity); Class III (Marked limitation of physical activity); and Class IV (Inability to carry out any physical activity without symptoms). The change from baseline in WHO FC was classified into "Improved", "No change" and "Worsened" compared to baseline. Deterioration, No Change, and Improvement are based on shift of risk category (I, II, III, IV) from baseline in WHO Functional Class. The FAS included all subjects randomly assigned to a study treatment. Here 'N' (number of subjects analyzed) included all subjects who were with assessments at both baseline and post-baseline time point.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Selexipag Placebo
    Number of subjects analysed
    44
    54
    Units: subjects
        Deterioration
    2
    1
        No change
    33
    43
        Improvement
    9
    10
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 in 6-Minute Walk Distance (6MWD)

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    End point title
    Change from Baseline to Week 24 in 6-Minute Walk Distance (6MWD)
    End point description
    The 6MWD was the total distance walked during 6 minutes. Mean change from baseline (distance walked at Week 24 minus distance walked at baseline) was reported. The Full Analysis Set (FAS) included all subjects randomly assigned to a study treatment. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Selexipag Placebo
    Number of subjects analysed
    50
    54
    Units: meters
        arithmetic mean (standard deviation)
    18.3 ± 54.47
    9.8 ± 60.72
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 in Borg Dyspnea Score

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    End point title
    Change from Baseline to Week 24 in Borg Dyspnea Score
    End point description
    The Borg dyspneas score was a self-rating scale to evaluate the severity of dyspnea (from 0 "no shortness of breath at all" to 10 "very, very severe / maximal shortness of breath"). It was completed immediately after the 6-minute walk test at Week 24 and at baseline. Mean change from baseline in scoring was reported. The Full Analysis Set (FAS) included all subjects randomly assigned to a study treatment. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Selexipag Placebo
    Number of subjects analysed
    50
    54
    Units: units on a scale
        arithmetic mean (standard deviation)
    -0.25 ± 2.122
    0.37 ± 1.869
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 24 in N-Terminal Pro B-type Natriuretic Peptide (NT-proBNP)

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    End point title
    Change from Baseline to Week 24 in N-Terminal Pro B-type Natriuretic Peptide (NT-proBNP)
    End point description
    Change from baseline to Week 24 in NT-pro BNP levels was reported. The negative change from baseline means improvement. The Full Analysis Set (FAS) included all subjects randomly assigned to a study treatment. Here, N (Number of Subjects Analyzed) signifies number of subjects evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 24
    End point values
    Selexipag Placebo
    Number of subjects analysed
    51
    53
    Units: nanogram per liter (ng/L)
        geometric mean (confidence interval 95%)
    0.91 (0.768 to 1.073)
    0.98 (0.828 to 1.149)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 28 weeks
    Adverse event reporting additional description
    Safety Analysis Set included the subjects who were who were randomized and received at least 1 dose of study treatment.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.0
    Reporting groups
    Reporting group title
    Selexipag
    Reporting group description
    Subjects received Selexipag which was up-titrated from Day 1 (Week 1) to Week 12 to the individualized highest tolerated dose (HTD) which ranged from 200 microgram (mcg) to 1600 mcg twice daily (BID) orally. The dose was increased in increments of 200 mcg BID, usually at weekly intervals, depending on the dose tolerability. Up-titration was followed by a stable maintenance treatment period at the highest tolerated dose, from Week 13 to Week 24.

    Reporting group title
    Placebo
    Reporting group description
    Subjects received one to 8 tablets of 200 (mcg), administered in doses of up to 1600 mcg, matching placebo orally twice daily up-titrated for 24 weeks.

    Serious adverse events
    Selexipag Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 53 (5.66%)
    6 / 55 (10.91%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Surgical and medical procedures
    Thyroid Nodule Removal
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Flutter
         subjects affected / exposed
    1 / 53 (1.89%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Right Ventricular Failure
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pleural Effusion
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    1 / 53 (1.89%)
    0 / 55 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple Sclerosis Relapse
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Vision Blurred
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Glossitis
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 53 (0.00%)
    1 / 55 (1.82%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Selexipag Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    52 / 53 (98.11%)
    52 / 55 (94.55%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    5 / 53 (9.43%)
    6 / 55 (10.91%)
         occurrences all number
    7
    6
    Hot Flush
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    3
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    2 / 53 (3.77%)
    4 / 55 (7.27%)
         occurrences all number
    2
    5
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 55 (5.45%)
         occurrences all number
    4
    3
    Dyspnoea
         subjects affected / exposed
    4 / 53 (7.55%)
    6 / 55 (10.91%)
         occurrences all number
    4
    6
    Epistaxis
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 55 (5.45%)
         occurrences all number
    4
    3
    Nasal Congestion
         subjects affected / exposed
    5 / 53 (9.43%)
    2 / 55 (3.64%)
         occurrences all number
    5
    2
    Oropharyngeal Pain
         subjects affected / exposed
    2 / 53 (3.77%)
    4 / 55 (7.27%)
         occurrences all number
    2
    5
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    7 / 53 (13.21%)
    7 / 55 (12.73%)
         occurrences all number
    8
    8
    Headache
         subjects affected / exposed
    41 / 53 (77.36%)
    26 / 55 (47.27%)
         occurrences all number
    76
    49
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 53 (9.43%)
    4 / 55 (7.27%)
         occurrences all number
    5
    4
    Non-Cardiac Chest Pain
         subjects affected / exposed
    2 / 53 (3.77%)
    7 / 55 (12.73%)
         occurrences all number
    2
    9
    Oedema Peripheral
         subjects affected / exposed
    3 / 53 (5.66%)
    3 / 55 (5.45%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    Abdominal Distension
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 55 (5.45%)
         occurrences all number
    1
    5
    Abdominal Pain Upper
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 55 (5.45%)
         occurrences all number
    2
    3
    Diarrhoea
         subjects affected / exposed
    28 / 53 (52.83%)
    23 / 55 (41.82%)
         occurrences all number
    37
    36
    Dyspepsia
         subjects affected / exposed
    6 / 53 (11.32%)
    0 / 55 (0.00%)
         occurrences all number
    7
    0
    Nausea
         subjects affected / exposed
    22 / 53 (41.51%)
    15 / 55 (27.27%)
         occurrences all number
    31
    21
    Vomiting
         subjects affected / exposed
    13 / 53 (24.53%)
    4 / 55 (7.27%)
         occurrences all number
    22
    4
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 55 (5.45%)
         occurrences all number
    4
    4
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 53 (20.75%)
    8 / 55 (14.55%)
         occurrences all number
    15
    9
    Back Pain
         subjects affected / exposed
    4 / 53 (7.55%)
    6 / 55 (10.91%)
         occurrences all number
    4
    6
    Myalgia
         subjects affected / exposed
    6 / 53 (11.32%)
    3 / 55 (5.45%)
         occurrences all number
    7
    3
    Pain in Extremity
         subjects affected / exposed
    11 / 53 (20.75%)
    1 / 55 (1.82%)
         occurrences all number
    15
    1
    Pain in Jaw
         subjects affected / exposed
    20 / 53 (37.74%)
    5 / 55 (9.09%)
         occurrences all number
    29
    5
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    4 / 53 (7.55%)
    1 / 55 (1.82%)
         occurrences all number
    6
    1
    Infections and infestations
    Lower Respiratory Tract Infection
         subjects affected / exposed
    2 / 53 (3.77%)
    3 / 55 (5.45%)
         occurrences all number
    2
    3
    Nasopharyngitis
         subjects affected / exposed
    5 / 53 (9.43%)
    14 / 55 (25.45%)
         occurrences all number
    6
    16
    Respiratory Tract Infection
         subjects affected / exposed
    1 / 53 (1.89%)
    3 / 55 (5.45%)
         occurrences all number
    1
    4
    Tonsillitis
         subjects affected / exposed
    0 / 53 (0.00%)
    3 / 55 (5.45%)
         occurrences all number
    0
    3
    Upper Respiratory Tract Infection
         subjects affected / exposed
    6 / 53 (11.32%)
    6 / 55 (10.91%)
         occurrences all number
    7
    6
    Urinary Tract Infection
         subjects affected / exposed
    0 / 53 (0.00%)
    4 / 55 (7.27%)
         occurrences all number
    0
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Dec 2018
    The global amendment was considered substantial and included the following changes: a change to the dosing instructions for study drug (selexipag/placebo) based on a drug-drug interaction study for clopidogrel; the pulmonary function test could be performed in the presence or absence of bronchodilation, whereby the eligible subject population remained unchanged; and the list of assessments was modified without affecting the endpoint variables.

    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.
    No hypothesis testing planned for this exploratory study. Sleep data not reported as sleep episodes not identified due to inaccuracy in algorithm resulting in unreliable data that would mislead design of future trials and interpretation of results.
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