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    Clinical Trial Results:
    A Phase 2, Double-Blind, Randomized, Placebo Controlled, Dose Ranging, Parallel Group Study to Evaluate the Effect of GS-6615 on Ventricular Arrhythmia in Subjects with Implantable Cardioverter-Defibrillator (ICD) or Cardiac Resynchronization Therapy-Defibrillator (CRT-D)

    Summary
    EudraCT number
    		 2013-004430-15
    Trial protocol
    		 HU   PL   DK   CZ   NL  
    Global end of trial date
    14 Oct 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    18 May 2019
    First version publication date
    29 Oct 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Adding text to “Limitations and Caveats” section

    Trial information

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    Trial identification
    Sponsor protocol code
    GS-US-356-0101
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02104583
    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 , ClinicalTrialDisclosures@gilead.com
    Scientific contact
    Clinical Trials Mailbox, Gilead Sciences , 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
    14 Oct 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Sep 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Oct 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 eleclazine (GS-6615) compared to placebo on the overall occurrence of appropriate Implantable Cardioverter-Defibrillator (ICD) interventions (antitachycardia pacing [ATP] or shock) in participants with ICD or Cardiac Resynchronization Therapy-Defibrillator (CRT-D) during the first 24 weeks of treatment.
    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 Sep 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
    United States: 117
    Country: Number of subjects enrolled
    Israel: 38
    Country: Number of subjects enrolled
    Canada: 12
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Poland: 57
    Country: Number of subjects enrolled
    Czech Republic: 8
    Country: Number of subjects enrolled
    Denmark: 10
    Country: Number of subjects enrolled
    Germany: 24
    Country: Number of subjects enrolled
    Hungary: 35
    Worldwide total number of subjects
    313
    EEA total number of subjects
    146
    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)
    139
    From 65 to 84 years
    174
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in North America, Europe and Asia. The first participant was screened on 12 September 2014. The last study visit occurred on 14 October 2016.

    Pre-assignment
    Screening details
    		 389 participants were screened.

    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
    		 Cohort 1 Eleclazine 3 mg
    Arm description
    		 Single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eleclazine 3 mg
    Investigational medicinal product code
    Other name
    GS-6615
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eleclazine 3 mg orally daily for up to approximately 18 months

    Arm title
    		 Cohort 1 Placebo
    Arm description
    		 Single loading dose of placebo to match eleclazine followed by placebo to match eleclazine once daily for up to approximately 18 months
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match eleclazine for up to approximately 18 months

    Arm title
    		 Cohort 2 Eleclazine 3 mg
    Arm description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Participants received single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eleclazine 3 mg
    Investigational medicinal product code
    Other name
    GS-6615
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eleclazine 3 mg orally once daily for up to approximately 18 months

    Arm title
    		 Cohort 2 Eleclazine 6 mg
    Arm description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Participants received single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months
    Arm type
    		 Experimental

    Investigational medicinal product name
    Eleclazine 6 mg
    Investigational medicinal product code
    Other name
    GS-6615
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Eleclazine 6 mg (2 x 3 mg eleclazine tablets) orally daily for up to approximately 18 months

    Arm title
    		 Cohort 2 Placebo
    Arm description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Single loading dose of placebo to match eleclazine followed by placebo to match eleclazine once daily for up to approximately 18 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match eleclazine for up to approximately 18 months

    Number of subjects in period 1 [1]
    		Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo
    Started
    48
    46
    70
    73
    75
    Completed
    30
    35
    54
    57
    63
    Not completed
    18
    11
    16
    16
    12
         Subject required prohibited medication
    -
    1
    1
    -
    1
         Withdrew Consent
    3
    2
    -
    2
    1
         Adverse Event
    3
    3
    6
    6
    1
         Death
    2
    1
    3
    3
    5
         Investigator's Discretion
    1
    -
    -
    -
    -
         New ICD or CRT-D implanted
    2
    -
    1
    -
    -
         Subject required cardiac ablation
    6
    4
    4
    5
    4
         Protocol Violation
    -
    -
    1
    -
    -
         Lost to follow-up
    1
    -
    -
    -
    -
    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: One participant who was enrolled but never treated was not included in the subject disposition table.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1 Eleclazine 3 mg
    Reporting group description
    		 Single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months

    Reporting group title
    Cohort 1 Placebo
    Reporting group description
    		 Single loading dose of placebo to match eleclazine followed by placebo to match eleclazine once daily for up to approximately 18 months

    Reporting group title
    Cohort 2 Eleclazine 3 mg
    Reporting group description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Participants received single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months.

    Reporting group title
    Cohort 2 Eleclazine 6 mg
    Reporting group description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Participants received single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months

    Reporting group title
    Cohort 2 Placebo
    Reporting group description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Single loading dose of placebo to match eleclazine followed by placebo to match eleclazine once daily for up to approximately 18 months.

    Reporting group values
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo Total
    Number of subjects
    		 48 46 70 73 75 312
    Age categorical
    Units: Subjects
    Age continuous
    Safety Analysis Set: participants who received at least one dose of study drug
    Units: years
        arithmetic mean (standard deviation)
    		 65 ( 10.4 ) 64 ( 9.6 ) 65 ( 10.8 ) 65 ( 8.3 ) 64 ( 9.4 ) -
    Gender categorical
    Safety Analysis Set
    Units: Subjects
        Female
    		 4 5 8 7 8 32
        Male
    		 44 41 62 66 67 280
    Race
    Safety Analysis Set
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0
        Black
    		 1 1 0 2 1 5
        Native Hawaiian or Pacific Islander
    		 0 0 0 0 0 0
        White
    		 47 45 70 70 71 303
        Not Permitted
    		 0 0 0 1 2 3
        Other
    		 0 0 0 0 1 1
    Ethnicity
    Safety Analysis Set
    Units: Subjects
        Hispanic or Latino
    		 1 0 0 1 0 2
        Not Hispanic or Latino
    		 47 45 70 71 73 306
        Not Permitted
    		 0 1 0 1 2 4
    Premature Ventricular Complex (PVC)
    Full Analysis Set: all randomized participants who received at least 1 dose of study drug. 46 participants in cohort 1 eleclazine 3 mg arm, 44 participants in cohort 1 placebo arm, 68 participants in cohort 2 eleclazine 3 mg arm, 73 participants in cohort 2 eleclazine 6 mg arm and 71 participants in cohort 2 placebo arm with available data were analyzed at baseline.
    Units: Count
        arithmetic mean (standard deviation)
    		 11002 ( 12494.1 ) 15560 ( 25009.7 ) 10646 ( 16107 ) 8194 ( 10231.4 ) 6405 ( 9073 ) -
    Non-Sustained Ventricular Tachycardia (nsVT)
    Full Analysis Set. 46 participants in cohort 1 eleclazine 3 mg arm, 44 participants in cohort 1 placebo arm, 68 participants in cohort 2 eleclazine 3 mg arm, 73 participants in cohort 2 eleclazine 6 mg arm and 71 participants in cohort 2 placebo arm with available data were analyzed at baseline.
    Units: Count
        arithmetic mean (standard deviation)
    		 21 ( 59.6 ) 49 ( 191.3 ) 66 ( 369.7 ) 24 ( 69.1 ) 5 ( 12.3 ) -
    Left Ventricular Ejection Fraction (LVEF)
    Full Analysis Set. 43 participants in cohort 1 eleclazine 3 mg arm, 45 participants in cohort 1 placebo arm, 57 participants in cohort 2 eleclazine 3 mg arm, 60 participants in cohort 2 eleclazine 3 mg arm and 66 participants in cohort 2 placebo arm with available data were analyzed at baseline.
    Units: Percentage
        arithmetic mean (standard deviation)
    		 35 ( 12.8 ) 38 ( 12.4 ) 38 ( 12.1 ) 38 ( 13.3 ) 40 ( 13.5 ) -

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1 Eleclazine 3 mg
    Reporting group description
    		 Single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months

    Reporting group title
    Cohort 1 Placebo
    Reporting group description
    		 Single loading dose of placebo to match eleclazine followed by placebo to match eleclazine once daily for up to approximately 18 months

    Reporting group title
    Cohort 2 Eleclazine 3 mg
    Reporting group description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Participants received single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months.

    Reporting group title
    Cohort 2 Eleclazine 6 mg
    Reporting group description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Participants received single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months

    Reporting group title
    Cohort 2 Placebo
    Reporting group description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Single loading dose of placebo to match eleclazine followed by placebo to match eleclazine once daily for up to approximately 18 months.

    Subject analysis set title
    Cohorts 1 and 2, Eleclazine 3 mg
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized participants across cohorts 1 and 2 who received single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 20 months

    Subject analysis set title
    Cohorts 1 and 2, Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All randomized participants across cohorts 1 and 2 who received single loading dose of placebo to match eleclazine followed by placebo to match eleclazine once daily for up to approximately 20 months

    Primary: Overall Occurrence (Total Number) of Appropriate Implantable Cardioverter-Defibrillator Device (ICD) Interventions (Anti-Tachycardia Pacing or Shock) Through Week 24

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    End point title
    		 Overall Occurrence (Total Number) of Appropriate Implantable Cardioverter-Defibrillator Device (ICD) Interventions (Anti-Tachycardia Pacing or Shock) Through Week 24
    End point description
    The Full Analysis Set (FAS) for ICD/CRT-D (implantable cardioverter-defibrillator device/cardiac resynchronization therapy-defibrillator) event counts (FAS-ICD) was defined as FAS restricted to the subjects who had at least 1 postbaseline ICD/CRT-D interrogation. Participants in the FAS-ICD analysis set with available data were analyzed.
    End point type
    Primary
    End point timeframe
    Up to Week 24
    End point values
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo Cohorts 1 and 2, Eleclazine 3 mg Cohorts 1 and 2, Placebo
    Number of subjects analysed
    48
    46
    69
    73
    75
    117
    121
    Units: Number
        arithmetic mean (standard deviation)
    3.3 ( 6.99 )
    1.9 ( 3.79 )
    2.6 ( 6.8 )
    1.1 ( 2.09 )
    1.5 ( 3.92 )
    2.8 ( 6.86 )
    1.7 ( 3.86 )
    Statistical analysis title
    		 Number of Appropriate ICD Interventions
    Statistical analysis description
    The primary analysis of overall occurrence of appropriate ICD interventions through Week 24 was performed using a generalized linear model assuming a negative binomial distribution and log link. This model included terms for treatment, implanted device (ICD or CRT-D) and region (US or ROW). Least squares (LS) mean estimates and the corresponding 95% CIs (confidence intervals) were expressed in terms of appropriate ICD intervention average monthly incident rate through Week 24.
    Comparison groups
    Cohorts 1 and 2, Eleclazine 3 mg v Cohorts 1 and 2, Placebo
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    Parameter type
    		 Eleclazine : Placebo Incident Rate Ratio
    Point estimate
    1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.86
         upper limit
    		 2.71
    Notes
    [1] - Intergroup comparison
    Statistical analysis title
    		 Number of Appropriate ICD Interventions
    Statistical analysis description
    The primary analysis of overall occurrence of appropriate ICD interventions through Week 24 was performed using a generalized linear model assuming a negative binomial distribution and log link. This model included terms for treatment, implanted device (ICD or CRT-D) and region (US or ROW). LS mean estimates and the corresponding 95% CIs were expressed in terms of appropriate ICD intervention average monthly incident rate through Week 24.
    Comparison groups
    Cohort 2 Placebo v Cohort 2 Eleclazine 6 mg
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    Method
    Parameter type
    		 Eleclazine : Placebo Incident Rate Ratio
    Point estimate
    0.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.97
    Notes
    [2] - Intergroup Comparison

    Secondary: Overall Occurrence (Total Number) of Appropriate Implantable Cardioverter-Defibrillator Device (ICD) Interventions (Anti-Tachycardia Pacing or Shock) Through End of Study

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    End point title
    		 Overall Occurrence (Total Number) of Appropriate Implantable Cardioverter-Defibrillator Device (ICD) Interventions (Anti-Tachycardia Pacing or Shock) Through End of Study
    End point description
    Participants in the FAS-ICD analysis set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    End point values
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo
    Number of subjects analysed
    48
    46
    69
    73
    75
    Units: Number
        arithmetic mean (standard deviation)
    5.0 ( 7.92 )
    7.2 ( 20.89 )
    3.8 ( 8.82 )
    1.2 ( 2.11 )
    2.0 ( 5.55 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Premature Ventricular Complex (PVC) Count as Assessed by Continuous Electrocardiogram [cECG] Monitoring)

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    End point title
    		 Change From Baseline in Premature Ventricular Complex (PVC) Count as Assessed by Continuous Electrocardiogram [cECG] Monitoring)
    End point description
    Change in PVC from baseline was measured in units of number of episodes/48 hours. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo
    Number of subjects analysed
    48
    40
    58
    56
    63
    Units: Number
        arithmetic mean (standard deviation)
    4282 ( 17651.5 )
    -2347 ( 8498.8 )
    -594 ( 13323.0 )
    -39 ( 13575.0 )
    1541 ( 11117.7 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Nonsustained Ventricular Tachycardia (nsVT) Count as Assessed by Continuous Electrocardiogram [cECG] Monitoring)

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    End point title
    		 Change From Baseline in Nonsustained Ventricular Tachycardia (nsVT) Count as Assessed by Continuous Electrocardiogram [cECG] Monitoring)
    End point description
    Change in nsVT from baseline was measured in units of number of episodes/48 hours. Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo
    Number of subjects analysed
    41
    40
    58
    56
    63
    Units: Number
        arithmetic mean (standard deviation)
    44 ( 171.6 )
    -14 ( 52.2 )
    -67 ( 400.4 )
    46 ( 388.4 )
    2 ( 15.1 )
    No statistical analyses for this end point

    Secondary: Overall Occurrence (Total Number) of VT (Ventricular Tachycardia)/VF (Ventricular Fibrillation) (Treated or Untreated) Through Week 24 and End of Study

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    End point title
    		 Overall Occurrence (Total Number) of VT (Ventricular Tachycardia)/VF (Ventricular Fibrillation) (Treated or Untreated) Through Week 24 and End of Study
    End point description
    Participants in the Full Analysis Set-ICD with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Up to Week 24; Up to 20 months
    End point values
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo
    Number of subjects analysed
    48
    46
    69
    73
    75
    Units: Number
    arithmetic mean (standard deviation)
        Total Number of Events Through Week 24
    3.56 ( 7.554 )
    2.07 ( 3.974 )
    2.74 ( 6.825 )
    1.44 ( 2.779 )
    1.61 ( 3.952 )
        Total Number of Events Through End of Study
    5.98 ( 8.907 )
    7.83 ( 20.949 )
    4.07 ( 9.088 )
    1.56 ( 2.794 )
    2.17 ( 5.574 )
    No statistical analyses for this end point

    Secondary: Overall Occurrence (Total Number) of Electrical Storms Through Week 24 and End of Study

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    End point title
    		 Overall Occurrence (Total Number) of Electrical Storms Through Week 24 and End of Study
    End point description
    Full Analysis Set-ICD
    End point type
    Secondary
    End point timeframe
    Up to Week 24; Up to 20 Months
    End point values
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo
    Number of subjects analysed
    48
    46
    69
    73
    75
    Units: Number
    arithmetic mean (standard deviation)
        Total Number of Events Through Week 24
    0.15 ( 0.545 )
    0.15 ( 0.631 )
    0.23 ( 0.843 )
    0.03 ( 0.164 )
    0.09 ( 0.408 )
        Total Number of Events Through End of Study
    0.21 ( 0.582 )
    0.63 ( 2.037 )
    0.35 ( 1.041 )
    0.03 ( 0.164 )
    0.12 ( 0.614 )
    No statistical analyses for this end point

    Secondary: Overall Occurrence (Total Number) of Inappropriate ICD Interventions Through Week 24 and End of Study

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    End point title
    		 Overall Occurrence (Total Number) of Inappropriate ICD Interventions Through Week 24 and End of Study
    End point description
    Full Analysis Set- ICD
    End point type
    Secondary
    End point timeframe
    Up to Week 24; Up to 20 months
    End point values
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo
    Number of subjects analysed
    48
    46
    69
    73
    75
    Units: Number
    arithmetic mean (standard deviation)
        Total Number of Events Through Week 24
    0.17 ( 0.753 )
    0.15 ( 0.515 )
    0.14 ( 0.772 )
    0.12 ( 6.22 )
    0.39 ( 2.283 )
        Total Number of Events Through End of Study
    0.31 ( 1.613 )
    0.41 ( 2.072 )
    0.16 ( 0.779 )
    0.14 ( 0.631 )
    0.43 ( 2.395 )
    No statistical analyses for this end point

    Secondary: Change in Left Ventricular Systolic and Diastolic Function as Assessed by Left Ventricular Ejection Fraction (LVEF)

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    End point title
    		 Change in Left Ventricular Systolic and Diastolic Function as Assessed by Left Ventricular Ejection Fraction (LVEF)
    End point description
    Participants in the Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12; Baseline to Week 24
    End point values
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo
    Number of subjects analysed
    48
    46
    70
    73
    58
    Units: Percentage
    arithmetic mean (standard deviation)
        At Week 12(N=41,39,50,46,58 in arms 1,2,3,4,5)
    3 ( 8.1 )
    3 ( 6.2 )
    3 ( 9.1 )
    3 ( 8.2 )
    1 ( 8.2 )
        At Week 24(N=35,39,44,43,52 in arms 1,2,3,4,5)
    1 ( 12.3 )
    2 ( 8.2 )
    3 ( 10.0 )
    1 ( 10.7 )
    0 ( 8.3 )
    No statistical analyses for this end point

    Secondary: Time From Randomization to the First Occurrence of Appropriate ICD Interventions (ATP or Shock) or Cardiovascular (CV) Death

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    End point title
    		 Time From Randomization to the First Occurrence of Appropriate ICD Interventions (ATP or Shock) or Cardiovascular (CV) Death
    End point description
    The median time to the endpoint could only be estimated for the eleclazine 3 mg and placebo groups across cohorts 1 and 2; but first Quartile (Q1) value for cohort 2, eleclazine 6 mg group was 82.0, cohort 2, eleclazine 3 mg was 60.0 and cohort 2, placebo was 56.0. Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    End point values
    		 Cohorts 1 and 2, Eleclazine 3 mg Cohorts 1 and 2, Placebo
    Number of subjects analysed
    118
    121
    Units: Days
        median (confidence interval 95%)
    243 (147.0 to 281.0)
    265 (130.0 to 496.0)
    No statistical analyses for this end point

    Secondary: Time From Randomization to the First Occurrence of Cardiovascular (CV) Hospitalization, Emergency Room (ER) visit, or CV Death

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    End point title
    		 Time From Randomization to the First Occurrence of Cardiovascular (CV) Hospitalization, Emergency Room (ER) visit, or CV Death [3]
    End point description
    The median time to the endpoint could not be estimated for any of the treatment or placebo groups, therefore Q1 values were presented for this endpoint. Full Analysis Set.
    End point type
    Secondary
    End point timeframe
    Up to 20 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Analyses for all participants from the missing baseline cohorts receiving eleclazine 3mg and placebo have been reported as participant analysis sets per treatment group across cohorts 1 and 2.
    End point values
    		 Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo Cohorts 1 and 2, Eleclazine 3 mg Cohorts 1 and 2, Placebo
    Number of subjects analysed
    70
    73
    75
    118
    121
    Units: First Quartile (Q1) of the Median Days
        number (not applicable)
    125.0
    193.0
    189.0
    144.0
    190.0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 20 months Plus 30 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Cohort 1 Eleclazine 3 mg
    Reporting group description
    		 Single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months

    Reporting group title
    Cohort 1 Placebo
    Reporting group description
    		 Single loading dose of placebo to match eleclazine followed by placebo to match eleclazine once daily for up to approximately 18 months

    Reporting group title
    Cohort 2 Eleclazine 3 mg
    Reporting group description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Participants received single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months.

    Reporting group title
    Cohort 2 Eleclazine 6 mg
    Reporting group description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Participants received single loading dose of eleclazine 30 mg on Day 1, followed by eleclazine 3 mg daily as maintenance for up to approximately 18 months

    Reporting group title
    Cohort 2 Placebo
    Reporting group description
    		 Cohort 2 randomization started following the initial safety evaluation in Cohort 1. Single loading dose of placebo to match eleclazine followed by placebo to match eleclazine once daily for up to approximately 18 months.

    Serious adverse events
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    27 / 48 (56.25%)
    25 / 46 (54.35%)
    28 / 70 (40.00%)
    26 / 73 (35.62%)
    26 / 75 (34.67%)
         number of deaths (all causes)
    2
    2
    3
    4
    5
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Acute leukaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Endometrial cancer
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    2 / 73 (2.74%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phantom shocks
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Cellulitis
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 46 (2.17%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Pneumothorax
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device inappropriate shock delivery
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device malfunction
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Anticoagulation drug level below therapeutic
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chemical burn of skin
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute right ventricular failure
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anginal equivalent
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 46 (2.17%)
    4 / 70 (5.71%)
    1 / 73 (1.37%)
    4 / 75 (5.33%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 4
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    Cardiac failure
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    2 / 70 (2.86%)
    3 / 73 (4.11%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 8
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    Cardiac failure acute
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    2 / 75 (2.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Cardiac failure chronic
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 46 (2.17%)
    1 / 70 (1.43%)
    2 / 73 (2.74%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 2
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic left ventricular failure
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Cor pulmonale
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    2 / 70 (2.86%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular arrhythmia
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 46 (4.35%)
    5 / 70 (7.14%)
    2 / 73 (2.74%)
    5 / 75 (6.67%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 3
    0 / 5
    1 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 46 (6.52%)
    0 / 70 (0.00%)
    2 / 73 (2.74%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular flutter
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachyarrhythmia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    11 / 48 (22.92%)
    10 / 46 (21.74%)
    7 / 70 (10.00%)
    10 / 73 (13.70%)
    8 / 75 (10.67%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 15
    0 / 8
    0 / 13
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Brain injury
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Parosmia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Coeliac artery compression syndrome
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dry mouth
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydrocholecystis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Petechiae
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 48 (2.08%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    3 / 73 (4.11%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Calculus urinary
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urethral stenosis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gouty arthritis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis pseudomonal
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    3 / 75 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    2 / 73 (2.74%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    Tooth infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    2 / 73 (2.74%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gout
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 48 (2.08%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1 Eleclazine 3 mg Cohort 1 Placebo Cohort 2 Eleclazine 3 mg Cohort 2 Eleclazine 6 mg Cohort 2 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 48 (66.67%)
    26 / 46 (56.52%)
    42 / 70 (60.00%)
    34 / 73 (46.58%)
    33 / 75 (44.00%)
    Vascular disorders
    Hypotension
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 46 (4.35%)
    4 / 70 (5.71%)
    2 / 73 (2.74%)
    2 / 75 (2.67%)
         occurrences all number
    4
    2
    5
    2
    2
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 48 (6.25%)
    1 / 46 (2.17%)
    1 / 70 (1.43%)
    3 / 73 (4.11%)
    1 / 75 (1.33%)
         occurrences all number
    4
    1
    1
    3
    1
    Chest discomfort
         subjects affected / exposed
    4 / 48 (8.33%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    4
    0
    1
    0
    0
    Chest pain
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 46 (6.52%)
    3 / 70 (4.29%)
    4 / 73 (5.48%)
    2 / 75 (2.67%)
         occurrences all number
    1
    3
    3
    4
    2
    Fatigue
         subjects affected / exposed
    5 / 48 (10.42%)
    7 / 46 (15.22%)
    6 / 70 (8.57%)
    3 / 73 (4.11%)
    5 / 75 (6.67%)
         occurrences all number
    6
    7
    6
    4
    5
    Oedema peripheral
         subjects affected / exposed
    3 / 48 (6.25%)
    3 / 46 (6.52%)
    2 / 70 (2.86%)
    2 / 73 (2.74%)
    3 / 75 (4.00%)
         occurrences all number
    3
    3
    2
    2
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    5 / 48 (10.42%)
    4 / 46 (8.70%)
    7 / 70 (10.00%)
    2 / 73 (2.74%)
    5 / 75 (6.67%)
         occurrences all number
    5
    4
    7
    2
    6
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 46 (6.52%)
    1 / 70 (1.43%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences all number
    1
    3
    1
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 48 (0.00%)
    5 / 46 (10.87%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    0
    5
    1
    0
    0
    Investigations
    Blood magnesium decreased
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 48 (2.08%)
    3 / 46 (6.52%)
    0 / 70 (0.00%)
    1 / 73 (1.37%)
    1 / 75 (1.33%)
         occurrences all number
    1
    3
    0
    1
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 48 (0.00%)
    0 / 46 (0.00%)
    2 / 70 (2.86%)
    5 / 73 (6.85%)
    1 / 75 (1.33%)
         occurrences all number
    0
    0
    2
    5
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 46 (4.35%)
    4 / 70 (5.71%)
    2 / 73 (2.74%)
    3 / 75 (4.00%)
         occurrences all number
    4
    2
    4
    2
    3
    Ventricular tachycardia
         subjects affected / exposed
    8 / 48 (16.67%)
    2 / 46 (4.35%)
    8 / 70 (11.43%)
    7 / 73 (9.59%)
    9 / 75 (12.00%)
         occurrences all number
    23
    2
    10
    10
    14
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    5 / 48 (10.42%)
    4 / 46 (8.70%)
    6 / 70 (8.57%)
    8 / 73 (10.96%)
    2 / 75 (2.67%)
         occurrences all number
    5
    4
    7
    8
    2
    Headache
         subjects affected / exposed
    4 / 48 (8.33%)
    2 / 46 (4.35%)
    3 / 70 (4.29%)
    3 / 73 (4.11%)
    3 / 75 (4.00%)
         occurrences all number
    4
    2
    3
    4
    3
    Syncope
         subjects affected / exposed
    2 / 48 (4.17%)
    4 / 46 (8.70%)
    2 / 70 (2.86%)
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences all number
    2
    4
    2
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 46 (2.17%)
    2 / 70 (2.86%)
    4 / 73 (5.48%)
    2 / 75 (2.67%)
         occurrences all number
    4
    1
    2
    4
    2
    Diarrhoea
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 46 (4.35%)
    5 / 70 (7.14%)
    4 / 73 (5.48%)
    2 / 75 (2.67%)
         occurrences all number
    3
    2
    5
    4
    2
    Nausea
         subjects affected / exposed
    2 / 48 (4.17%)
    0 / 46 (0.00%)
    4 / 70 (5.71%)
    3 / 73 (4.11%)
    2 / 75 (2.67%)
         occurrences all number
    2
    0
    4
    3
    2
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 46 (0.00%)
    0 / 70 (0.00%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    3
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 48 (6.25%)
    0 / 46 (0.00%)
    1 / 70 (1.43%)
    3 / 73 (4.11%)
    0 / 75 (0.00%)
         occurrences all number
    3
    0
    1
    3
    0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    4 / 48 (8.33%)
    1 / 46 (2.17%)
    1 / 70 (1.43%)
    0 / 73 (0.00%)
    0 / 75 (0.00%)
         occurrences all number
    5
    1
    1
    0
    0
    Urinary tract infection
         subjects affected / exposed
    3 / 48 (6.25%)
    4 / 46 (8.70%)
    1 / 70 (1.43%)
    2 / 73 (2.74%)
    2 / 75 (2.67%)
         occurrences all number
    3
    6
    2
    2
    3
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    3 / 48 (6.25%)
    2 / 46 (4.35%)
    2 / 70 (2.86%)
    1 / 73 (1.37%)
    1 / 75 (1.33%)
         occurrences all number
    4
    2
    2
    1
    1
    Hyponatraemia
         subjects affected / exposed
    0 / 48 (0.00%)
    1 / 46 (2.17%)
    0 / 70 (0.00%)
    4 / 73 (5.48%)
    0 / 75 (0.00%)
         occurrences all number
    0
    1
    0
    4
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    An unplanned review of unblinded clinical trial data was performed in this study that was not prospectively specified in the protocol. There was no impact on the overall integrity or conclusions of the study.
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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