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    Clinical Trial Results:
    A Phase 2, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled Study of GS-4997 in Subjects with Pulmonary Arterial Hypertension

    Summary
    EudraCT number
    		 2014-002131-34
    Trial protocol
    		 DE   NL   ES   GB   IT  
    Global end of trial date
    13 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    05 Nov 2017
    First version publication date
    05 Nov 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    GS-US-357-1394
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02234141
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd , ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trials Mailbox, Gilead Sciences International Ltd , ClinicalTrialDisclosures@gilead.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
    13 Dec 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Dec 2016
    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 selonsertib (GS-4997) on pulmonary vascular resistance (PVR), as measured by right heart catheterization (RHC) in participants with pulmonary arterial hypertension (PAH).
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Nov 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 6
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Germany: 26
    Country: Number of subjects enrolled
    Italy: 4
    Country: Number of subjects enrolled
    United States: 83
    Country: Number of subjects enrolled
    Canada: 18
    Worldwide total number of subjects
    151
    EEA total number of subjects
    50
    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)
    122
    From 65 to 84 years
    29
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America and Europe. The first participant was screened on 12 November 2014. The last study visit occurred on 13 December 2016.

    Pre-assignment
    Screening details
    		 185 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Selonsertib 2 mg
    Arm description
    		 Selonsertib 2 mg for 24 weeks during the treatment phase (Period 1)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg administered once daily

    Arm title
    		 Selonsertib 6 mg
    Arm description
    		 Selonsertib 6 mg for 24 weeks during the treatment phase (Period 1)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    6 mg administered once daily

    Arm title
    		 Selonsertib 18 mg
    Arm description
    		 Selonsertib 18 mg for 24 weeks during the treatment phase (Period 1)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    18 mg administered once daily

    Arm title
    		 Placebo
    Arm description
    		 Placebo for 24 weeks (Period 1) and may have been rerandomized 1:1:1 to selonsertib 2, 6, or 18 mg during the long-term treatment phase (Period 2)
    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
    Administered once daily

    Number of subjects in period 1 [1]
    		Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Started
    39
    37
    37
    37
    Completed
    33
    31
    33
    32
    Not completed
    6
    6
    4
    5
         Adverse event, serious fatal
    1
    3
    -
    2
         Subject Withdrew Consent
    -
    -
    1
    -
         Adverse event, non-fatal
    5
    1
    3
    2
         Protocol Deviation
    -
    -
    -
    1
         Investigator's discretion
    -
    2
    -
    -
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1 participant who was randomized but not treated is not included in the subject disposition table.
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Selonsertib 2 mg
    Arm description
    		 Participants continued treatment with selonsertib 2 mg during the long-term treatment phase (Period 2)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg administered once daily

    Arm title
    		 Selonsertib 6 mg
    Arm description
    		 Participants continued treatment with selonsertib 6 mg during the long-term treatment phase (Period 2)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    6 mg administered once daily

    Arm title
    		 Selonsertib 18 mg
    Arm description
    		 Participants continued treatment with selonsertib 18 mg during the long-term treatment phase (Period 2)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    18 mg administered once daily

    Arm title
    		 Placebo to Selonsertib 2 mg
    Arm description
    		 Participants were on placebo in Period 1 and were rerandomized to receive selonsertib 2 mg during the long-term treatment phase (Period 2)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 mg administered once daily

    Arm title
    		 Placebo to Selonsertib 6 mg
    Arm description
    		 Participants were on placebo in Period 1 and were rerandomized to receive selonsertib 6 mg during the long-term treatment phase (Period 2)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    6 mg administered once daily

    Arm title
    		 Placebo to Selonsertib 18 mg
    Arm description
    		 Participants were on placebo in Period 1 and were rerandomized to receive selonsertib 18 mg during the long-term treatment phase (Period 2)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Selonsertib
    Investigational medicinal product code
    Other name
    GS-4997
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    18 mg administered once daily

    Number of subjects in period 2
    		Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo to Selonsertib 2 mg Placebo to Selonsertib 6 mg Placebo to Selonsertib 18 mg
    Started
    33
    31
    33
    10
    12
    10
    Completed
    0
    0
    0
    0
    0
    0
    Not completed
    33
    31
    33
    10
    12
    10
         Adverse event, serious fatal
    -
    -
    1
    -
    -
    -
         Subject Withdrew Consent
    -
    1
    1
    -
    -
    -
         Adverse event, non-fatal
    3
    -
    4
    -
    1
    1
         Death
    -
    -
    -
    -
    1
    -
         Study Discontinued by Sponsor
    29
    27
    25
    9
    10
    8
         Investigator's discretion
    1
    3
    2
    1
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Selonsertib 2 mg
    Reporting group description
    		 Selonsertib 2 mg for 24 weeks during the treatment phase (Period 1)

    Reporting group title
    Selonsertib 6 mg
    Reporting group description
    		 Selonsertib 6 mg for 24 weeks during the treatment phase (Period 1)

    Reporting group title
    Selonsertib 18 mg
    Reporting group description
    		 Selonsertib 18 mg for 24 weeks during the treatment phase (Period 1)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo for 24 weeks (Period 1) and may have been rerandomized 1:1:1 to selonsertib 2, 6, or 18 mg during the long-term treatment phase (Period 2)

    Reporting group values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo Total
    Number of subjects
    		 39 37 37 37 150
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 50 ( 13.9 ) 49 ( 13.7 ) 48 ( 14.1 ) 55 ( 15.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 30 27 32 30 119
        Male
    		 9 10 5 7 31
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 2 1 0 0 3
        Asian
    		 0 3 0 2 5
        Black
    		 1 0 0 0 1
        White
    		 35 33 36 35 139
        Not Permitted
    		 1 0 1 0 2
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 6 5 3 2 16
        Not Hispanic or Latino
    		 31 31 32 35 129
        Not Permitted
    		 2 1 2 0 5
    WHO Functional Class
    Units: Subjects
        Class II
    		 24 23 19 24 90
        Class III
    		 15 14 18 13 60
    6 Minute Walk Distance
    Units: meter
        arithmetic mean (standard deviation)
    		 452 ( 111.9 ) 449 ( 85.3 ) 437 ( 102.7 ) 412 ( 109.3 ) -
    NT-proBNP
    Units: pg/mL
        geometric mean (inter-quartile range (Q1-Q3))
    		 385 (86 to 1177) 431 (174 to 1134) 352 (135 to 822) 492 (158 to 1424) -
    Borg Dyspnea Index
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 3.5 ( 2.13 ) 3.7 ( 2.41 ) 3.5 ( 1.53 ) 3.6 ( 1.94 ) -
    RVFAC
    Units: percentage
        arithmetic mean (standard deviation)
    		 34.7 ( 8.00 ) 33.6 ( 9.68 ) 37.3 ( 8.47 ) 32.3 ( 9.59 ) -
    TAPSE
    Units: centimeter
        arithmetic mean (standard deviation)
    		 1.5 ( 0.31 ) 1.5 ( 0.37 ) 1.5 ( 0.29 ) 1.5 ( 0.31 ) -
    mRAP
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 8 ( 4.3 ) 9 ( 4.4 ) 9 ( 4.3 ) 8 ( 3.5 ) -
    mPAP
    Units: mm Hg
        arithmetic mean (standard deviation)
    		 53.4 ( 15.28 ) 56.7 ( 10.79 ) 55.0 ( 12.51 ) 51.3 ( 9.94 ) -
    PVR
    Units: dyn*sec/cm^5
        arithmetic mean (standard deviation)
    		 734 ( 313.4 ) 806 ( 381.2 ) 809 ( 366.1 ) 743 ( 268.2 ) -
    Cardiac Index
    Units: L/min/m^2
        arithmetic mean (standard deviation)
    		 2.87 ( 0.818 ) 2.86 ( 0.679 ) 2.69 ( 0.649 ) 2.64 ( 0.501 ) -

    End points

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    End points reporting groups
    Reporting group title
    Selonsertib 2 mg
    Reporting group description
    		 Selonsertib 2 mg for 24 weeks during the treatment phase (Period 1)

    Reporting group title
    Selonsertib 6 mg
    Reporting group description
    		 Selonsertib 6 mg for 24 weeks during the treatment phase (Period 1)

    Reporting group title
    Selonsertib 18 mg
    Reporting group description
    		 Selonsertib 18 mg for 24 weeks during the treatment phase (Period 1)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo for 24 weeks (Period 1) and may have been rerandomized 1:1:1 to selonsertib 2, 6, or 18 mg during the long-term treatment phase (Period 2)
    Reporting group title
    Selonsertib 2 mg
    Reporting group description
    		 Participants continued treatment with selonsertib 2 mg during the long-term treatment phase (Period 2)

    Reporting group title
    Selonsertib 6 mg
    Reporting group description
    		 Participants continued treatment with selonsertib 6 mg during the long-term treatment phase (Period 2)

    Reporting group title
    Selonsertib 18 mg
    Reporting group description
    		 Participants continued treatment with selonsertib 18 mg during the long-term treatment phase (Period 2)

    Reporting group title
    Placebo to Selonsertib 2 mg
    Reporting group description
    		 Participants were on placebo in Period 1 and were rerandomized to receive selonsertib 2 mg during the long-term treatment phase (Period 2)

    Reporting group title
    Placebo to Selonsertib 6 mg
    Reporting group description
    		 Participants were on placebo in Period 1 and were rerandomized to receive selonsertib 6 mg during the long-term treatment phase (Period 2)

    Reporting group title
    Placebo to Selonsertib 18 mg
    Reporting group description
    		 Participants were on placebo in Period 1 and were rerandomized to receive selonsertib 18 mg during the long-term treatment phase (Period 2)

    Primary: Change from Baseline in Pulmonary Vascular Resistance (PVR) at Week 24, as Measured by Right Heart Catheterization

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    End point title
    		 Change from Baseline in Pulmonary Vascular Resistance (PVR) at Week 24, as Measured by Right Heart Catheterization
    End point description
    Full Analysis Set: all randomized participants who received ≥ 1 dose of study drug.
    End point type
    Primary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    35
    34
    36
    31
    Units: dyne.sec/cm^5
        arithmetic mean (standard error)
    35 ( 35.4 )
    -28 ( 30.2 )
    -21 ( 37.9 )
    6 ( 28.0 )
    Statistical analysis title
    		 Change in PVR - Selonsertib 2 mg vs Placebo
    Comparison groups
    Selonsertib 2 mg v Placebo
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.214 [2]
    Method
    		 gvE/vE
    Confidence interval
    Notes
    [1] - Statistical comparison
    [2] - P-value was calculated using the generalized van Elteren test/van Elteren test (gvE/vE; stratified Wilcoxon rank sum test).
    Statistical analysis title
    		 Change in PVR - Selonsertib 6 mg vs Placebo
    Comparison groups
    Selonsertib 6 mg v Placebo
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.27 [4]
    Method
    		 gvE/vE
    Confidence interval
    Notes
    [3] - Statistical comparison
    [4] - P-value was calculated using the generalized van Elteren test/van Elteren test (gvE/vE; stratified Wilcoxon rank sum test).
    Statistical analysis title
    		 Change in PVR - Selonsertib 18 mg vs Placebo
    Comparison groups
    Selonsertib 18 mg v Placebo
    Number of subjects included in analysis
    67
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.604 [6]
    Method
    		 gvE/vE
    Confidence interval
    Notes
    [5] - Statistical comparison
    [6] - P-value was calculated using the generalized van Elteren test/van Elteren test (gvE/vE; stratified Wilcoxon rank sum test).

    Secondary: Change from Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Cardiac Index (CI)

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    End point title
    		 Change from Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Cardiac Index (CI)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    35
    34
    36
    31
    Units: L/min/m^2
        arithmetic mean (standard error)
    -0.1 ( 0.10 )
    0.1 ( 0.09 )
    0.0 ( 0.09 )
    0.0 ( 0.09 )
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mean Pulmonary Artery Pressure (mPAP)

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    End point title
    		 Change from Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mean Pulmonary Artery Pressure (mPAP)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    36
    34
    36
    31
    Units: mm Hg
        arithmetic mean (standard error)
    1 ( 1.3 )
    -1 ( 1.1 )
    -3 ( 1.4 )
    0 ( 1.2 )
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mean Right Atrial Pressure (mRAP)

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    End point title
    		 Change from Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mean Right Atrial Pressure (mRAP)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    36
    34
    36
    31
    Units: mm Hg
        arithmetic mean (standard error)
    1 ( 0.5 )
    0 ( 0.7 )
    -1 ( 0.5 )
    1 ( 0.5 )
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mixed Venous Oxygen Saturation (SVO2)

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    End point title
    		 Change from Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Mixed Venous Oxygen Saturation (SVO2)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    36
    34
    35
    31
    Units: percentage
        arithmetic mean (standard error)
    0.0 ( 0.85 )
    0.1 ( 2.13 )
    1.1 ( 2.07 )
    -2.0 ( 1.00 )
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Right Ventricular Cardiac Power (RVCP)

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    End point title
    		 Change from Baseline at Week 24 in Other Cardiopulmonary Hemodynamic Measures: Right Ventricular Cardiac Power (RVCP)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    35
    34
    36
    31
    Units: watts
        arithmetic mean (standard error)
    -0.01 ( 0.026 )
    0.00 ( 0.024 )
    -0.03 ( 0.028 )
    -0.01 ( 0.027 )
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in 6-minute Walk Distance (6MWD)

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    End point title
    		 Change from Baseline at Week 24 in 6-minute Walk Distance (6MWD)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    39
    37
    37
    37
    Units: meter
        arithmetic mean (standard error)
    4.7 ( 6.63 )
    3.5 ( 8.27 )
    -15.9 ( 8.01 )
    -15.0 ( 8.60 )
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in Borg Dyspnea index (BDI) after the 6MWT

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    End point title
    		 Change from Baseline at Week 24 in Borg Dyspnea index (BDI) after the 6MWT
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    39
    37
    37
    37
    Units: units on a scale
        arithmetic mean (standard error)
    -0.1 ( 0.24 )
    0.1 ( 0.26 )
    0.1 ( 0.23 )
    0.3 ( 0.27 )
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in World Health Organization (WHO) Functional Class

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    End point title
    		 Change from Baseline at Week 24 in World Health Organization (WHO) Functional Class
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    39
    37
    37
    37
    Units: participants
    number (not applicable)
        Improved
    7
    6
    5
    1
        Unchanged
    27
    24
    28
    29
        Worsened
    2
    3
    4
    2
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)

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    End point title
    		 Change from Baseline at Week 24 in N-terminal Pro-brain Natriuretic Peptide (NT-proBNP)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    39
    37
    37
    37
    Units: pg/mL
        geometric mean (standard error)
    1.17 ( 0.093 )
    1.01 ( 0.093 )
    1.01 ( 0.082 )
    1.25 ( 0.103 )
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in SF-36 Physical Functioning Scale

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    End point title
    		 Change from Baseline at Week 24 in SF-36 Physical Functioning Scale
    End point description
    Quality of life was assessed using the SF-36 questionnaire. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    37
    35
    36
    36
    Units: units on a scale
        arithmetic mean (standard error)
    0 ( 0.8 )
    2 ( 0.9 )
    0 ( 0.8 )
    0 ( 0.9 )
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in emPHasis-10 Questionnaire Score

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    End point title
    		 Change from Baseline at Week 24 in emPHasis-10 Questionnaire Score
    End point description
    Quality of life was assessed using the emPHasis-10 questionnaire. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    37
    35
    37
    36
    Units: units on a scale
        arithmetic mean (standard error)
    0 ( 1.1 )
    -1 ( 1.2 )
    1 ( 1.1 )
    -1 ( 1 )
    No statistical analyses for this end point

    Secondary: Change from Baseline at Week 24 in Heart Rate Recovery After the 6MWT

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    End point title
    		 Change from Baseline at Week 24 in Heart Rate Recovery After the 6MWT
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    39
    37
    37
    37
    Units: bpm
        arithmetic mean (standard error)
    4.0 ( 2.42 )
    0.1 ( 2.52 )
    -3.0 ( 3.07 )
    2.4 ( 2.08 )
    No statistical analyses for this end point

    Secondary: Time to Clinical Worsening (TTCW) Evaluated in Period 1

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    End point title
    		 Time to Clinical Worsening (TTCW) Evaluated in Period 1
    End point description
    TTCW was defined as time to the first occurrence of: death (all-cause), hospitalization for worsening PAH (any hospitalization for worsening PAH, lung or heart/lung transplant, atrial septostomy, or initiation of continuously infused prostanoid therapy), or disease progression (defined as both > 15% decrease from baseline in 6MWD and WHO class III or IV symptoms at two consecutive postbaseline clinic visits separated by ≥ 14 days). Participants in the Full Analysis Set with available data were analyzed. 9999 = Not applicable; not reached due to insufficient number of events
    End point type
    Secondary
    End point timeframe
    Up to 24 weeks
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    39
    37
    37
    37
    Units: day
        median (inter-quartile range (Q1-Q3))
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    225.0 (225.0 to 225.0)
    178.0 (178.0 to 9999)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Tricuspid Annular Plane Systolic Excursion (TAPSE)

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    End point title
    		 Change from Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Tricuspid Annular Plane Systolic Excursion (TAPSE)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    37
    35
    35
    32
    Units: centimeter
        arithmetic mean (standard error)
    0.0 ( 0.04 )
    -0.1 ( 0.06 )
    0.0 ( 0.04 )
    0.0 ( 0.04 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Myocardial Strain

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    End point title
    		 Change from Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Myocardial Strain
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    29
    28
    26
    24
    Units: percentage
        arithmetic mean (standard error)
    1 ( 0.7 )
    2 ( 0.6 )
    -1 ( 0.7 )
    1 ( 0.9 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Tricuspid Annular Peak Sys Myocard Velocity (TAS)

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    End point title
    		 Change from Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Tricuspid Annular Peak Sys Myocard Velocity (TAS)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    37
    37
    35
    32
    Units: cm/sec
        arithmetic mean (standard error)
    1 ( 0.4 )
    0 ( 0.3 )
    0 ( 0.2 )
    0 ( 0.4 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Tei Index (RVTI)

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    End point title
    		 Change from Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Tei Index (RVTI)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    37
    34
    32
    29
    Units: units on a scale
        arithmetic mean (standard error)
    0.08 ( 0.037 )
    0.05 ( 0.052 )
    0.01 ( 0.021 )
    -0.02 ( 0.038 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Fractional Area Change (RVFAC)

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    End point title
    		 Change from Baseline in Echocardiographic Measures of Right Ventricular Function at Week 24: Right Ventricular Fractional Area Change (RVFAC)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline; Week 24
    End point values
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Number of subjects analysed
    37
    36
    33
    33
    Units: percentage
        arithmetic mean (standard error)
    -0.3 ( 1.16 )
    0.0 ( 1.23 )
    -1.1 ( 1.25 )
    -0.6 ( 1.12 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 97 weeks plus 30 days
    Adverse event reporting additional description
    Safety Analysis Set: all randomized participants who received ≥ 1 dose of study drug. For Period 2 crossover participants and the Active Period, the Safety Analysis Set comprised participants who received ≥ 1 dose of selonsertib.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19
    Reporting groups
    Reporting group title
    Selonsertib 2 mg
    Reporting group description
    		 Selonsertib 2 mg for 24 weeks during the treatment phase (Period 1) and during the long-term treatment phase (Period 2). Adverse events (AEs) in this reporting group include AEs that occurred in 10 participants who were rerandomized from the Placebo Period 1 group to receive selonsertib 2 mg during the long-term treatment phase.

    Reporting group title
    Selonsertib 6 mg
    Reporting group description
    		 Selonsertib 6 mg for 24 weeks during the treatment phase (Period 1) and during the long-term treatment phase (Period 2). Adverse events (AEs) in this reporting group include AEs that occurred in 12 participants who were rerandomized from the Placebo Period 1 group to receive selonsertib 6 mg during the long-term treatment phase.

    Reporting group title
    Selonsertib 18 mg
    Reporting group description
    		 Selonsertib 18 mg for 24 weeks during the treatment phase (Period 1) and during the long-term treatment phase (Period 2). Adverse events (AEs) in this reporting group include AEs that occurred in 10 participants who were rerandomized from the Placebo Period 1 group to receive selonsertib 18 mg during the long-term treatment phase.

    Reporting group title
    Placebo
    Reporting group description
    		 Adverse events reported in this group only include AEs that occurred during Period 1.

    Serious adverse events
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 49 (28.57%)
    17 / 49 (34.69%)
    16 / 47 (34.04%)
    7 / 37 (18.92%)
         number of deaths (all causes)
    3
    5
    2
    2
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic arteriosclerosis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Catheter site extravasation
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 49 (2.04%)
    2 / 49 (4.08%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infusion site inflammation
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 49 (0.00%)
    2 / 49 (4.08%)
    0 / 47 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Dyspnoea exertional
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoptysis
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    3 / 47 (6.38%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device breakage
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    2 / 47 (4.26%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Transplant dysfunction
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Right ventricular failure
         subjects affected / exposed
    2 / 49 (4.08%)
    4 / 49 (8.16%)
    1 / 47 (2.13%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 2
    2 / 5
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
    0 / 1
    Tachycardia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dysarthria
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    2 / 47 (4.26%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestinal obstruction
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal achalasia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatomegaly
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Bacteraemia
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    2 / 47 (4.26%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 47 (2.13%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    1 / 37 (2.70%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Selonsertib 2 mg Selonsertib 6 mg Selonsertib 18 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    43 / 49 (87.76%)
    44 / 49 (89.80%)
    44 / 47 (93.62%)
    34 / 37 (91.89%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 49 (8.16%)
    4 / 47 (8.51%)
    0 / 37 (0.00%)
         occurrences all number
    1
    6
    4
    0
    Hypotension
         subjects affected / exposed
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    3 / 47 (6.38%)
    2 / 37 (5.41%)
         occurrences all number
    2
    0
    4
    2
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    2 / 49 (4.08%)
    3 / 49 (6.12%)
    3 / 47 (6.38%)
    2 / 37 (5.41%)
         occurrences all number
    2
    5
    4
    2
    Fatigue
         subjects affected / exposed
    6 / 49 (12.24%)
    7 / 49 (14.29%)
    11 / 47 (23.40%)
    4 / 37 (10.81%)
         occurrences all number
    6
    9
    13
    4
    Oedema peripheral
         subjects affected / exposed
    1 / 49 (2.04%)
    8 / 49 (16.33%)
    5 / 47 (10.64%)
    2 / 37 (5.41%)
         occurrences all number
    1
    9
    5
    2
    Pyrexia
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 49 (4.08%)
    0 / 47 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    3
    3
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 49 (6.12%)
    14 / 49 (28.57%)
    8 / 47 (17.02%)
    6 / 37 (16.22%)
         occurrences all number
    3
    18
    11
    6
    Dyspnoea
         subjects affected / exposed
    7 / 49 (14.29%)
    12 / 49 (24.49%)
    7 / 47 (14.89%)
    4 / 37 (10.81%)
         occurrences all number
    8
    15
    8
    4
    Epistaxis
         subjects affected / exposed
    0 / 49 (0.00%)
    5 / 49 (10.20%)
    3 / 47 (6.38%)
    1 / 37 (2.70%)
         occurrences all number
    0
    6
    3
    2
    Nasal congestion
         subjects affected / exposed
    5 / 49 (10.20%)
    3 / 49 (6.12%)
    4 / 47 (8.51%)
    0 / 37 (0.00%)
         occurrences all number
    5
    3
    4
    0
    Oropharyngeal pain
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 49 (4.08%)
    3 / 47 (6.38%)
    1 / 37 (2.70%)
         occurrences all number
    3
    2
    3
    1
    Psychiatric disorders
    Abnormal dreams
         subjects affected / exposed
    2 / 49 (4.08%)
    2 / 49 (4.08%)
    5 / 47 (10.64%)
    1 / 37 (2.70%)
         occurrences all number
    2
    2
    5
    1
    Anxiety
         subjects affected / exposed
    0 / 49 (0.00%)
    3 / 49 (6.12%)
    1 / 47 (2.13%)
    1 / 37 (2.70%)
         occurrences all number
    0
    3
    1
    1
    Insomnia
         subjects affected / exposed
    3 / 49 (6.12%)
    3 / 49 (6.12%)
    3 / 47 (6.38%)
    3 / 37 (8.11%)
         occurrences all number
    3
    3
    4
    3
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    5 / 49 (10.20%)
    2 / 49 (4.08%)
    1 / 47 (2.13%)
    1 / 37 (2.70%)
         occurrences all number
    5
    2
    1
    1
    Weight decreased
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    3 / 47 (6.38%)
    1 / 37 (2.70%)
         occurrences all number
    3
    1
    3
    1
    Weight increased
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    3 / 47 (6.38%)
    0 / 37 (0.00%)
         occurrences all number
    1
    4
    3
    0
    White blood cell count decreased
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    1 / 37 (2.70%)
         occurrences all number
    3
    1
    0
    1
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    3
    0
    0
    0
    Palpitations
         subjects affected / exposed
    3 / 49 (6.12%)
    7 / 49 (14.29%)
    4 / 47 (8.51%)
    4 / 37 (10.81%)
         occurrences all number
    4
    10
    4
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 49 (16.33%)
    7 / 49 (14.29%)
    13 / 47 (27.66%)
    1 / 37 (2.70%)
         occurrences all number
    8
    9
    15
    1
    Headache
         subjects affected / exposed
    8 / 49 (16.33%)
    15 / 49 (30.61%)
    20 / 47 (42.55%)
    8 / 37 (21.62%)
         occurrences all number
    8
    19
    27
    8
    Presyncope
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    8 / 47 (17.02%)
    1 / 37 (2.70%)
         occurrences all number
    0
    1
    8
    1
    Syncope
         subjects affected / exposed
    1 / 49 (2.04%)
    2 / 49 (4.08%)
    2 / 47 (4.26%)
    2 / 37 (5.41%)
         occurrences all number
    1
    2
    5
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    4 / 47 (8.51%)
    1 / 37 (2.70%)
         occurrences all number
    1
    3
    4
    1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 49 (2.04%)
    1 / 49 (2.04%)
    4 / 47 (8.51%)
    1 / 37 (2.70%)
         occurrences all number
    1
    1
    5
    1
    Leukocytosis
         subjects affected / exposed
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    1 / 47 (2.13%)
    2 / 37 (5.41%)
         occurrences all number
    0
    2
    1
    3
    Thrombocytopenia
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    4
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    2 / 47 (4.26%)
    1 / 37 (2.70%)
         occurrences all number
    3
    1
    2
    1
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    4 / 47 (8.51%)
    1 / 37 (2.70%)
         occurrences all number
    0
    0
    4
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 49 (2.04%)
    5 / 49 (10.20%)
    1 / 47 (2.13%)
    1 / 37 (2.70%)
         occurrences all number
    2
    5
    1
    1
    Abdominal pain upper
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 49 (4.08%)
    3 / 47 (6.38%)
    3 / 37 (8.11%)
         occurrences all number
    5
    3
    3
    3
    Constipation
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 49 (2.04%)
    9 / 47 (19.15%)
    1 / 37 (2.70%)
         occurrences all number
    2
    1
    11
    1
    Diarrhoea
         subjects affected / exposed
    9 / 49 (18.37%)
    15 / 49 (30.61%)
    14 / 47 (29.79%)
    5 / 37 (13.51%)
         occurrences all number
    11
    17
    18
    5
    Vomiting
         subjects affected / exposed
    3 / 49 (6.12%)
    6 / 49 (12.24%)
    4 / 47 (8.51%)
    3 / 37 (8.11%)
         occurrences all number
    3
    8
    10
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    3 / 49 (6.12%)
    5 / 49 (10.20%)
    6 / 47 (12.77%)
    2 / 37 (5.41%)
         occurrences all number
    3
    6
    6
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 49 (8.16%)
    3 / 49 (6.12%)
    3 / 47 (6.38%)
    2 / 37 (5.41%)
         occurrences all number
    4
    3
    3
    2
    Back pain
         subjects affected / exposed
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    4 / 47 (8.51%)
    1 / 37 (2.70%)
         occurrences all number
    3
    1
    5
    1
    Muscle spasms
         subjects affected / exposed
    6 / 49 (12.24%)
    1 / 49 (2.04%)
    3 / 47 (6.38%)
    0 / 37 (0.00%)
         occurrences all number
    6
    1
    3
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    2
    0
    0
    2
    Myalgia
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 49 (2.04%)
    4 / 47 (8.51%)
    2 / 37 (5.41%)
         occurrences all number
    2
    1
    4
    2
    Pain in extremity
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 49 (2.04%)
    8 / 47 (17.02%)
    5 / 37 (13.51%)
         occurrences all number
    4
    2
    9
    5
    Pain in jaw
         subjects affected / exposed
    4 / 49 (8.16%)
    3 / 49 (6.12%)
    5 / 47 (10.64%)
    0 / 37 (0.00%)
         occurrences all number
    4
    3
    6
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    2 / 49 (4.08%)
    1 / 49 (2.04%)
    4 / 47 (8.51%)
    2 / 37 (5.41%)
         occurrences all number
    3
    1
    5
    2
    Cellulitis
         subjects affected / exposed
    1 / 49 (2.04%)
    4 / 49 (8.16%)
    0 / 47 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    1
    4
    0
    3
    Gastroenteritis
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 49 (4.08%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    3
    3
    0
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    4 / 49 (8.16%)
    0 / 49 (0.00%)
    3 / 47 (6.38%)
    1 / 37 (2.70%)
         occurrences all number
    4
    0
    4
    1
    Influenza
         subjects affected / exposed
    4 / 49 (8.16%)
    1 / 49 (2.04%)
    0 / 47 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    4
    1
    0
    3
    Nasopharyngitis
         subjects affected / exposed
    9 / 49 (18.37%)
    6 / 49 (12.24%)
    7 / 47 (14.89%)
    9 / 37 (24.32%)
         occurrences all number
    10
    12
    10
    12
    Pneumonia
         subjects affected / exposed
    2 / 49 (4.08%)
    4 / 49 (8.16%)
    1 / 47 (2.13%)
    1 / 37 (2.70%)
         occurrences all number
    2
    4
    1
    1
    Respiratory tract infection
         subjects affected / exposed
    2 / 49 (4.08%)
    2 / 49 (4.08%)
    0 / 47 (0.00%)
    3 / 37 (8.11%)
         occurrences all number
    3
    2
    0
    3
    Sepsis
         subjects affected / exposed
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 47 (0.00%)
    2 / 37 (5.41%)
         occurrences all number
    0
    0
    0
    2
    Sinusitis
         subjects affected / exposed
    3 / 49 (6.12%)
    2 / 49 (4.08%)
    2 / 47 (4.26%)
    2 / 37 (5.41%)
         occurrences all number
    3
    3
    2
    2
    Upper respiratory tract infection
         subjects affected / exposed
    7 / 49 (14.29%)
    13 / 49 (26.53%)
    7 / 47 (14.89%)
    3 / 37 (8.11%)
         occurrences all number
    8
    17
    7
    4
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 49 (6.12%)
    4 / 49 (8.16%)
    0 / 47 (0.00%)
    0 / 37 (0.00%)
         occurrences all number
    4
    4
    0
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 49 (4.08%)
    6 / 49 (12.24%)
    4 / 47 (8.51%)
    3 / 37 (8.11%)
         occurrences all number
    2
    7
    6
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Nov 2014
    ● The ClinicalTrials.gov Identifier was provided. ● Data from two Phase 1 drug-drug interaction studies (GS-US-223-1432 and GS-US-223-1434) were included. Accordingly, updates were made to the guidance on concomitant medication use. ● Inclusion Criteria 7 was clarified to state that pulmonary function tests may be performed with or without bronchodilation. ● Exclusion Criteria 22 and 23, which prohibited the concomitant use of P-gp substrates and organic anion transporting polypeptide 1 inhibitors, were removed. ● The percentage of subjects to be randomized who were receiving stable treatment with bosentan was limited to 25%. ● The duration of treatment for Canadian subjects in the long-term treatment period was reduced from a maximum of 7 years to 2.5 years. ● The maximum limit on the number of subjects enrolled per site was added. ● The duration of time that certain PAH medications (eg, oral and inhaled prostanoids) must be held prior to efficacy assessments was reduced. ● The recommended sequence of study assessments was revised so that blood collection was performed prior to exercise (the 6-minute walk test [6MWT]). ● A list of recommended assessments to perform at unscheduled visits was added. ● Instructions for conducting the 6MWT and Borg category-ratio (CR) 10 scale were added. ● Instructions for retaining original copies of ECG and RHC tracings were added. ● The guidance for PAH medication dose hold prior to efficacy assessments was updated for oral treprostinil, from 10 to 4 hours, to reflect 3 times daily dosing.
    01 Oct 2015
    ● Updated Cover Page contact information ● Updated information for completed studies of GS-4997 ● Moved Section 3.6 Pharmacokinetic Assessments to Section 6.3.3, where it was more appropriate ● Clarified inclusion exclusion criteria 8 and 11 and added exclusion criterion 32 ● Further defined which concomitant medications were allowed or prohibited and provided timeframes for such ● Updated Cover Page contact information ● Updated information for completed studies of GS-4997 ● Moved Section 3.6 Pharmacokinetic Assessments to Section 6.3.3, where it was more appropriate ● Clarified inclusion exclusion criteria 8 and 11 and added exclusion criterion 32 ● Further defined which concomitant medications were allowed or prohibited and provided timeframes for such

    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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