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    Clinical Trial Results:
    A double-blind, randomized, placebo-controlled, multicenter, dose escalation study to select and evaluate an oral modified release formulation of omecamtiv mecarbil in subjects with heart failure and left ventricular systolic dysfunction

    Summary
    EudraCT number
    		 2012-000327-40
    Trial protocol
    		 NL   GB   LT   CZ   HU   IT   BG   DE   BE  
    Global end of trial date
    19 Aug 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Sep 2016
    First version publication date
    04 Sep 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    20110151
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01786512
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info-Clinical Trials, Amgen (EUROPE) GmbH, MedInfoInternational@amgen.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
    19 Aug 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Aug 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were (i) to select an oral modified release (MR) formulation and dose of omecamtiv mecarbil (OM) for chronic twice daily (BID) dosing in subjects with heart failure (HF) and left ventricular systolic dysfunction and (ii) to characterize its pharmacokinetics (PK) over 20 weeks of treatment.
    Protection of trial subjects
    This study was conducted in accordance with applicable country regulations and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. Essential documents will be retained in accordance with ICH GCP. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jan 2013
    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
    Australia: 5
    Country: Number of subjects enrolled
    Belgium: 14
    Country: Number of subjects enrolled
    Bulgaria: 52
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Germany: 30
    Country: Number of subjects enrolled
    Hungary: 48
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Lithuania: 21
    Country: Number of subjects enrolled
    Netherlands: 18
    Country: Number of subjects enrolled
    United Kingdom: 37
    Country: Number of subjects enrolled
    United States: 146
    Country: Number of subjects enrolled
    Canada: 53
    Country: Number of subjects enrolled
    Poland: 92
    Worldwide total number of subjects
    544
    EEA total number of subjects
    340
    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)
    280
    From 65 to 84 years
    264
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Participants were enrolled from 26 February 2013 to 05 March 2015 at 86 centers in 13 countries in Europe, Australia, and North America. Subjects with a history of chronic heart failure being treated with stable, optimal pharmacological therapy for ≥ 4 weeks were eligible to participate.

    Pre-assignment
    Screening details
    		 The study consisted of a dose-escalation phase to select 1 of 3 OM oral formulations in 2 dose-escalation cohorts, followed by an expansion phase to evaluate 20 weeks of administration of the selected formulation at 2 target dose levels, compared with placebo. Randomization was stratified by presence or absence of atrial fibrillation/flutter.

    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
    		 Escalation Phase Cohort 1: Placebo
    Arm description
    		 Participants received placebo tablets twice a day (BID) for 7 days.
    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 orally twice a day

    Arm title
    		 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1
    Arm description
    		 Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omecamtiv Mecarbil Matrix F1
    Investigational medicinal product code
    AMG 423
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day

    Arm title
    		 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
    Arm description
    		 Participants received 25 mg omecamtiv mecarbil (OM) Matrix F2 (M-F2) tablets twice a day for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omecamtiv Mecarbil Matrix F2
    Investigational medicinal product code
    AMF 423
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day

    Arm title
    		 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
    Arm description
    		 Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omecamtiv Mecarbil Swellable Core Technology F2
    Investigational medicinal product code
    AMG 423
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day

    Arm title
    		 Escalation Phase Cohort 2: Placebo
    Arm description
    		 Participants received placebo tablets twice a day for 7 days.
    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 orally twice a day

    Arm title
    		 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1
    Arm description
    		 Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omecamtiv Mecarbil Matrix F1
    Investigational medicinal product code
    AMG 423
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day

    Arm title
    		 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2
    Arm description
    		 Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omecamtiv Mecarbil Matrix F2
    Investigational medicinal product code
    AMF 423
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day

    Arm title
    		 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Arm description
    		 Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omecamtiv Mecarbil Swellable Core Technology F2
    Investigational medicinal product code
    AMG 423
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day

    Arm title
    		 Expansion Phase: Placebo
    Arm description
    		 Participants received placebo tablets twice a day for 20 weeks.
    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 orally twice a day

    Arm title
    		 Expansion Phase: Omecamtiv Mecarbil 25 mg
    Arm description
    		 Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omecamtiv Mecarbil Matrix F1
    Investigational medicinal product code
    AMG 423
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day

    Arm title
    		 Expansion Phase: PK-based Titration
    Arm description
    		 All participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day. At week 8 the dose escalated to 50 mg twice a day if the week 2 predose plasma concentration of OM was less than the predefined cutoff of 200 ng/mL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Omecamtiv Mecarbil Matrix F1
    Investigational medicinal product code
    AMG 423
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administered orally twice a day

    Number of subjects in period 1
    		Escalation Phase Cohort 1: Placebo Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Escalation Phase Cohort 2: Placebo Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Started
    11
    11
    14
    13
    10
    11
    12
    14
    149
    150
    149
    Received Study Treatment
    11
    10
    14
    13
    10
    11
    11
    14
    149
    150
    146
    Completed
    11
    10
    14
    13
    10
    11
    11
    14
    145
    145
    137
    Not completed
    0
    1
    0
    0
    0
    0
    1
    0
    4
    5
    12
         Consent withdrawn by subject
    -
    1
    -
    -
    -
    -
    1
    -
    -
    3
    7
         Death
    -
    -
    -
    -
    -
    -
    -
    -
    4
    1
    3
         Lost to follow-up
    -
    -
    -
    -
    -
    -
    -
    -
    -
    1
    -
         Decision by sponsor
    -
    -
    -
    -
    -
    -
    -
    -
    -
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Escalation Phase Cohort 1: Placebo
    Reporting group description
    		 Participants received placebo tablets twice a day (BID) for 7 days.

    Reporting group title
    Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil (OM) Matrix F2 (M-F2) tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Placebo
    Reporting group description
    		 Participants received placebo tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1
    Reporting group description
    		 Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2
    Reporting group description
    		 Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Reporting group description
    		 Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.

    Reporting group title
    Expansion Phase: Placebo
    Reporting group description
    		 Participants received placebo tablets twice a day for 20 weeks.

    Reporting group title
    Expansion Phase: Omecamtiv Mecarbil 25 mg
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks.

    Reporting group title
    Expansion Phase: PK-based Titration
    Reporting group description
    		 All participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day. At week 8 the dose escalated to 50 mg twice a day if the week 2 predose plasma concentration of OM was less than the predefined cutoff of 200 ng/mL.

    Reporting group values
    		 Escalation Phase Cohort 1: Placebo Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Escalation Phase Cohort 2: Placebo Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration Total
    Number of subjects
    		 11 11 14 13 10 11 12 14 149 150 149 544
    Age Categorical
    Units: Subjects
        18 - 64 years
    		 3 4 7 5 5 6 5 6 82 81 76 280
        65 - 74 years
    		 8 4 4 6 5 4 4 5 46 52 50 188
        75 - 84 years
    		 0 3 3 2 0 1 3 3 21 17 23 76
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 66.5 ± 4.6 67.7 ± 11.4 65.3 ± 8.8 66.7 ± 8.7 62.1 ± 9.3 65.1 ± 7 63.8 ± 11.6 64.3 ± 11.5 63.7 ± 9.7 62.8 ± 10.2 62.7 ± 11.7 -
    Gender Categorical
    Units: Subjects
        Female
    		 2 2 3 1 3 3 4 2 30 23 24 97
        Male
    		 9 9 11 12 7 8 8 12 119 127 125 447
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0 0 0 2 1 0 3
        Black (or African American)
    		 3 1 0 0 0 3 1 2 11 5 8 34
        Mixed Race
    		 0 0 0 1 0 0 0 0 0 0 0 1
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0 0 0 1 0 1
        White
    		 7 10 14 12 10 8 11 12 136 142 140 502
        Other
    		 1 0 0 0 0 0 0 0 0 1 1 3
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 0 1 0 1 1 0 1 0 2 7 4 17
        Not Hispanic/Latino
    		 11 10 14 12 9 11 11 14 147 143 145 527
    Stratification Factor - Atrial Fibrillation/Flutter at Randomization
    Units: Subjects
        Yes
    		 0 0 3 2 0 1 2 3 32 32 32 107
        No
    		 11 11 11 11 10 10 10 11 117 118 117 437

    End points

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    End points reporting groups
    Reporting group title
    Escalation Phase Cohort 1: Placebo
    Reporting group description
    		 Participants received placebo tablets twice a day (BID) for 7 days.

    Reporting group title
    Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil (OM) Matrix F1 (M-F1) tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil (OM) Matrix F2 (M-F2) tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Placebo
    Reporting group description
    		 Participants received placebo tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1
    Reporting group description
    		 Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2
    Reporting group description
    		 Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Reporting group description
    		 Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.

    Reporting group title
    Expansion Phase: Placebo
    Reporting group description
    		 Participants received placebo tablets twice a day for 20 weeks.

    Reporting group title
    Expansion Phase: Omecamtiv Mecarbil 25 mg
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks.

    Reporting group title
    Expansion Phase: PK-based Titration
    Reporting group description
    		 All participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day. At week 8 the dose escalated to 50 mg twice a day if the week 2 predose plasma concentration of OM was less than the predefined cutoff of 200 ng/mL.

    Primary: Dose Escalation Phase: Maximum Observed Plasma Concentration for Omecamtiv Mecarbil Following the Last Dose (Day 7)

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    End point title
    		 Dose Escalation Phase: Maximum Observed Plasma Concentration for Omecamtiv Mecarbil Following the Last Dose (Day 7) [1] [2]
    End point description
    End point type
    Primary
    End point timeframe
    Day 7
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was performed.
    [2] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Number of subjects analysed
    10
    14
    13
    10
    11
    14
    Units: ng/mL
        arithmetic mean (standard deviation)
    193 ± 58.8
    201 ± 94.4
    171 ± 53.8
    492 ± 115
    502 ± 138
    601 ± 204
    No statistical analyses for this end point

    Primary: Dose Escalation Phase: Time to Maximum Observed Plasma Concentration for Omecamtiv Mecarbil Following the Last Dose (Day 7)

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    End point title
    		 Dose Escalation Phase: Time to Maximum Observed Plasma Concentration for Omecamtiv Mecarbil Following the Last Dose (Day 7) [3] [4]
    End point description
    End point type
    Primary
    End point timeframe
    Day 7
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was performed.
    [4] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Number of subjects analysed
    10
    14
    13
    10
    11
    14
    Units: hours
        arithmetic mean (standard deviation)
    3.9 ± 4.4
    2 ± 1.2
    4.2 ± 1.9
    2.6 ± 2.4
    2.2 ± 1.8
    4.6 ± 2.3
    No statistical analyses for this end point

    Primary: Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dose on Day 7

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    End point title
    		 Dose Escalation Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dose on Day 7 [5] [6]
    End point description
    End point type
    Primary
    End point timeframe
    Day 7, predose
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was performed.
    [6] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Number of subjects analysed
    10
    14
    13
    10
    11
    14
    Units: ng/mL
        arithmetic mean (standard deviation)
    157 ± 63.7
    137 ± 56.8
    134 ± 54.7
    376 ± 170
    395 ± 108
    476 ± 234
    No statistical analyses for this end point

    Primary: Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil

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    End point title
    		 Dose Escalation Phase: Area Under the Plasma Concentration-time Curve for a Dosing Interval of 12 Hours Post Dose (AUC12) for Omecamtiv Mecarbil [7] [8]
    End point description
    End point type
    Primary
    End point timeframe
    Day 7
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was performed.
    [8] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Number of subjects analysed
    10
    14
    13
    10
    11
    14
    Units: ng*hr/mL
        arithmetic mean (standard deviation)
    2030 ± 658
    2000 ± 1020
    1740 ± 586
    5070 ± 1060
    5010 ± 1160
    6550 ± 2340
    No statistical analyses for this end point

    Primary: Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing

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    End point title
    		 Expansion Phase: Plasma Concentration of Omecamtiv Mecarbil Prior to Dosing [9] [10]
    End point description
    End point type
    Primary
    End point timeframe
    Weeks 2, 8, 12, 16 and 20
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was performed.
    [10] - 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: No formal hypothesis testing was performed.
    End point values
    		 Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Number of subjects analysed
    147
    141
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 2
    174 ± 62.2
    179 ± 68.8
        Week 8
    156 ± 69.1
    161 ± 74.4
        Week 12
    165 ± 67.9
    263 ± 116
        Week 16
    155 ± 69
    240 ± 120
        Week 20
    149 ± 71.2
    239 ± 118
    No statistical analyses for this end point

    Primary: Expansion Phase: Maximum Observed Plasma Concentration for Omecamtiv Mecarbil

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    End point title
    		 Expansion Phase: Maximum Observed Plasma Concentration for Omecamtiv Mecarbil [11] [12]
    End point description
    End point type
    Primary
    End point timeframe
    Week 2 and week 12
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypothesis testing was performed.
    [12] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Number of subjects analysed
    147
    141
    Units: ng/mL
    arithmetic mean (standard deviation)
        Week 2
    212 ± 70.4
    212 ± 81
        Week 12
    200 ± 71.1
    318 ± 129
    No statistical analyses for this end point

    Secondary: Expansion Phase: Change from Baseline in Systolic Ejection Time (SET) at Week 20

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    End point title
    		 Expansion Phase: Change from Baseline in Systolic Ejection Time (SET) at Week 20 [13]
    End point description
    Systolic ejection time was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline and week 20
    Notes
    [13] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Number of subjects analysed
    149
    150
    146
    Units: seconds
        least squares mean (standard error)
    0 ± 0.0025
    0.0112 ± 0.0024
    0.025 ± 0.0026
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: Omecamtiv Mecarbil 25 mg
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    0.0112
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0047
         upper limit
    		 0.0176
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0033
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: PK-based Titration
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    0.025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.0184
         upper limit
    		 0.0315
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.0033

    Secondary: Expansion Phase: Change from Baseline in Stroke Volume at Week 20

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    End point title
    		 Expansion Phase: Change from Baseline in Stroke Volume at Week 20 [14]
    End point description
    Stroke volume was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline and week 20
    Notes
    [14] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Number of subjects analysed
    149
    150
    146
    Units: mL
        least squares mean (standard error)
    -1.05 ± 1.18
    3.53 ± 1.16
    2.58 ± 1.19
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: Omecamtiv Mecarbil 25 mg
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    4.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.5
         upper limit
    		 7.65
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.56
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: PK-based Titration
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    3.63
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.53
         upper limit
    		 6.72
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.57

    Secondary: Expansion Phase: Change from Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20

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    End point title
    		 Expansion Phase: Change from Baseline in Left Ventricular End Systolic Diameter (LVESD) at Week 20 [15]
    End point description
    LVESD was measured using echocardiography.Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline and week 20
    Notes
    [15] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Number of subjects analysed
    149
    150
    146
    Units: cm
        least squares mean (standard error)
    -0.242 ± 0.043
    -0.322 ± 0.044
    -0.421 ± 0.045
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: Omecamtiv Mecarbil 25 mg
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -0.079
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.194
         upper limit
    		 0.035
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.058
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: PK-based Titration
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -0.179
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.295
         upper limit
    		 -0.062
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.059

    Secondary: Expansion Phase: Change from Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20

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    End point title
    		 Expansion Phase: Change from Baseline in Left Ventricular End Diastolic Diameter (LVEDD) at Week 20 [16]
    End point description
    LVEDD was measured using echocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline and week 20
    Notes
    [16] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Number of subjects analysed
    149
    150
    146
    Units: cm
        least squares mean (standard error)
    0.089 ± 0.038
    0.023 ± 0.038
    -0.04 ± 0.04
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: PK-based Titration
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -0.129
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.231
         upper limit
    		 -0.028
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.052
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: Omecamtiv Mecarbil 25 mg
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -0.067
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.166
         upper limit
    		 0.033
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.051

    Secondary: Expansion Phase: Change from Baseline in Heart Rate at Week 20

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    End point title
    		 Expansion Phase: Change from Baseline in Heart Rate at Week 20 [17]
    End point description
    Heart rate was measured using electrocardiography. Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline and week 20
    Notes
    [17] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Number of subjects analysed
    149
    150
    146
    Units: beats/minute
        least squares mean (standard error)
    0.57 ± 0.79
    -0.77 ± 0.79
    -2.4 ± 0.81
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: Omecamtiv Mecarbil 25 mg
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -1.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.47
         upper limit
    		 0.79
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.09
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: PK-based Titration
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -2.97
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.12
         upper limit
    		 -0.81
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.09

    Secondary: Expansion Phase: Change from Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20

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    End point title
    		 Expansion Phase: Change from Baseline in N-terminal Prohormone B-type Natriuretic Peptide (NT-proBNP) at Week 20 [18]
    End point description
    Least squares means are from a repeated measures model including treatment group, stratification factor, scheduled visit, interaction of treatment with scheduled visit and the baseline value as covariates.
    End point type
    Secondary
    End point timeframe
    Baseline and week 20
    Notes
    [18] - 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: Dose-escalation phase and expansion phase endpoints are reported separately.
    End point values
    		 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Number of subjects analysed
    149
    150
    146
    Units: pg/mL
        least squares mean (standard error)
    502 ± 257
    -319 ± 257
    -468 ± 262
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: PK-based Titration
    Number of subjects included in analysis
    295
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -970
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1672
         upper limit
    		 -268
    Variability estimate
    Standard error of the mean
    Dispersion value
    357
    Statistical analysis title
    		 Treatment Difference
    Comparison groups
    Expansion Phase: Placebo v Expansion Phase: Omecamtiv Mecarbil 25 mg
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 Treatment difference
    Point estimate
    -822
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1516
         upper limit
    		 -127
    Variability estimate
    Standard error of the mean
    Dispersion value
    353

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug until 4 weeks after last dose - treatment duration was 7 days in the dose escalation phase and 20 weeks in the expansion phase.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Escalation Phase Cohort 1: Placebo
    Reporting group description
    		 Participants received placebo tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil Matrix F1 (M-F1) tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil Matrix F2 (M-F2) tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil swellable core technology F2 (SCT-F2) tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Placebo
    Reporting group description
    		 Participants received placebo tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1
    Reporting group description
    		 Participants received 50 mg omecamtiv mecarbil M-F1 tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2
    Reporting group description
    		 Participants received 50 mg omecamtiv mecarbil M-F2 tablets twice a day for 7 days.

    Reporting group title
    Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2
    Reporting group description
    		 Participants received 50 mg omecamtiv mecarbil SCT-F2 tablets twice a day for 7 days.

    Reporting group title
    Expansion Phase: Placebo
    Reporting group description
    		 Participants received placebo tablets twice a day for 20 weeks.

    Reporting group title
    Expansion Phase: Omecamtiv Mecarbil 25 mg
    Reporting group description
    		 Participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day for 20 weeks.

    Reporting group title
    Expansion Phase: PK-based Titration
    Reporting group description
    		 All participants received 25 mg omecamtiv mecarbil M-F1 tablets twice a day. At week 8 the dose escalated to 50 mg twice a day if the week 2 predose plasma concentration of OM was less than the predefined cutoff of 200 ng/mL.

    Serious adverse events
    		 Escalation Phase Cohort 1: Placebo Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Escalation Phase Cohort 2: Placebo Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    30 / 149 (20.13%)
    36 / 150 (24.00%)
    32 / 146 (21.92%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    4
    1
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carcinoma in situ of skin
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to central nervous system
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastatic carcinoma of the bladder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Tonsil cancer
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Cardiac complication associated with device
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 149 (1.34%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    2 / 150 (1.33%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicide attempt
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin I increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    2 / 150 (1.33%)
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ulnar nerve injury
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    3 / 150 (2.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    2 / 150 (1.33%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 149 (1.34%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    Cardiac asthma
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    4 / 149 (2.68%)
    3 / 150 (2.00%)
    5 / 146 (3.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 4
    1 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure acute
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    3 / 150 (2.00%)
    3 / 146 (2.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    3 / 149 (2.01%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    3 / 149 (2.01%)
    3 / 150 (2.00%)
    3 / 146 (2.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 4
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory distress
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cardiomyopathy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Left ventricular dysfunction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 149 (1.34%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    2 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    2 / 150 (1.33%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myoclonus
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic congestion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 149 (1.34%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    2 / 146 (1.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    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 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    1 / 149 (0.67%)
    1 / 150 (0.67%)
    3 / 146 (2.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Prostate infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    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
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Escalation Phase Cohort 1: Placebo Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F1 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg M-F2 Escalation Phase Cohort 1: Omecamtiv Mecarbil 25 mg SCT-F2 Escalation Phase Cohort 2: Placebo Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F1 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg M-F2 Escalation Phase Cohort 2: Omecamtiv Mecarbil 50 mg SCT-F2 Expansion Phase: Placebo Expansion Phase: Omecamtiv Mecarbil 25 mg Expansion Phase: PK-based Titration
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 11 (36.36%)
    2 / 10 (20.00%)
    5 / 14 (35.71%)
    6 / 13 (46.15%)
    1 / 10 (10.00%)
    8 / 11 (72.73%)
    3 / 11 (27.27%)
    4 / 14 (28.57%)
    48 / 149 (32.21%)
    51 / 150 (34.00%)
    48 / 146 (32.88%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 149 (1.34%)
    3 / 150 (2.00%)
    1 / 146 (0.68%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    3
    3
    1
    Hypotension
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    3 / 149 (2.01%)
    1 / 150 (0.67%)
    5 / 146 (3.42%)
         occurrences all number
    0
    1
    0
    0
    0
    1
    0
    1
    4
    1
    5
    Orthostatic hypotension
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    3 / 14 (21.43%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    2 / 149 (1.34%)
    2 / 150 (1.33%)
    2 / 146 (1.37%)
         occurrences all number
    0
    1
    3
    0
    0
    0
    1
    0
    2
    3
    2
    Fatigue
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    4 / 149 (2.68%)
    14 / 150 (9.33%)
    9 / 146 (6.16%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    5
    15
    10
    Feeling hot
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    Nodule
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    7 / 149 (4.70%)
    9 / 150 (6.00%)
    13 / 146 (8.90%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    10
    9
    13
    Nasal congestion
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 149 (1.34%)
    2 / 150 (1.33%)
    2 / 146 (1.37%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    2
    2
    2
    Pulmonary oedema
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    2 / 150 (1.33%)
    1 / 146 (0.68%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    1
    2
    1
    Mental status changes
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 149 (0.00%)
    2 / 150 (1.33%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    2
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Carotid bruit
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Heart rate increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    N-terminal prohormone brain natriuretic peptide increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    Troponin I increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    1 / 150 (0.67%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    3
    1
    Weight increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    1
    0
    Injury, poisoning and procedural complications
    Skin abrasion
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    Bundle branch block left
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Cardiac failure
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    9 / 149 (6.04%)
    2 / 150 (1.33%)
    3 / 146 (2.05%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    10
    2
    3
    Palpitations
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    3 / 149 (2.01%)
    3 / 150 (2.00%)
    4 / 146 (2.74%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    3
    5
    5
    Sinus bradycardia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Sinus tachycardia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 10 (10.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    6 / 149 (4.03%)
    8 / 150 (5.33%)
    9 / 146 (6.16%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    7
    9
    10
    Headache
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    1 / 14 (7.14%)
    5 / 13 (38.46%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    5 / 149 (3.36%)
    2 / 150 (1.33%)
    9 / 146 (6.16%)
         occurrences all number
    0
    0
    1
    5
    0
    2
    0
    0
    8
    2
    15
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    1 / 150 (0.67%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    1 / 150 (0.67%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    1
    1
    1
    Abnormal faeces
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 149 (1.34%)
    2 / 150 (1.33%)
    1 / 146 (0.68%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    2
    3
    1
    Diarrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    5 / 149 (3.36%)
    5 / 150 (3.33%)
    4 / 146 (2.74%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    5
    5
    4
    Dry mouth
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    2 / 149 (1.34%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    2
    0
    0
    Flatulence
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    1 / 14 (7.14%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    5 / 149 (3.36%)
    2 / 150 (1.33%)
    8 / 146 (5.48%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    6
    2
    8
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    2 / 150 (1.33%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    2
    3
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    2 / 11 (18.18%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    0 / 150 (0.00%)
    1 / 146 (0.68%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    0
    0
    0
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    0 / 149 (0.00%)
    3 / 150 (2.00%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    3
    0
    Pain in extremity
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
    0 / 14 (0.00%)
    1 / 149 (0.67%)
    2 / 150 (1.33%)
    0 / 146 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    1
    2
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    5 / 149 (3.36%)
    8 / 150 (5.33%)
    5 / 146 (3.42%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    0
    6
    8
    5
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 10 (0.00%)
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
    0 / 14 (0.00%)
    6 / 149 (4.03%)
    3 / 150 (2.00%)
    2 / 146 (1.37%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    7
    4
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Dec 2012
    • Added sample collection for therapeutic drug monitoring assay development • Replaced stratification by region with stratification by presence or absence of atrial fibrillation/flutter • Moved intensive PK from week 4 to week 8 of expansion phase • Clarified adjudication of deaths, all hospitalizations, and selected nonfatal CV events (including possible MI or ischemia) using prespecified criteria • Clarified LVEF eligibility requirements for subjects in the dose-escalation phase and the expansion phase • Simplified the valvular heart disease exclusion • Added daily phone contacts for days without other study contact during the first 7 days after initiation of IP administration for collection of adverse events, including possible ischemic events and for reminding subjects to be compliant with IP administration • Clarified which procedures could be done at a location external to the study site, eg, the subject’s home by home healthcare provider or other authorized staff • Added a subject diary for IP administration • Added an inclusion of acceptable echocardiographic image quality of screening echocardiogram per central reader for subjects enrolled in the expansion cohort • Added identity of specific cytochrome P450 3A4 inhibitors and inducers to the exclusion criteria • Extended study follow up to 4 weeks after last dose (day 35 + 5 days for dose-escalation phase; week 16 + 5 days for expansion phase) • Added urinalysis assessments • Added information about the troponin assay used for the study • Clarified that subjects could remain at the site overnight per study protocol on days of intensive PK sampling
    30 Apr 2013
    • Revised the IP section to remove the detail of pill count per bottle and refer to the Investigational Product Instruction Manual instead • Updated text on reporting of serious adverse events after end of study • Reduced the window for pregnancy and lactation reporting from 7 days to 24 hours per Amgen’s updated processes and protocol template
    12 Aug 2013
    • Increased the size of the expansion cohort to 150 subjects per group from 100 subjects per group for a total enrollment of 450 subjects in the expansion cohort, and a maximal study enrollment of up to approximately 570 subjects • Increased the number of study centers to 125 centers from 100 centers • Added collection of digoxin samples for subjects receiving digoxin therapy • Increased the volume of the samples collected for bioanalytical assay development • Updated the status of the ongoing phase 2 study 20100754 ATOMIC-AHF
    18 Nov 2013
    • Based on data review at the dose level review meeting 2, added a dose titration step to the OM 50 mg BID group at 25 mg BID with advancement to 50 mg BID gated by the week 2 PK. • Removed month 6 vital status follow-up as the total study duration for expansion phase was 6 months • Modified pregnancy exclusion per Amgen revised standard
    07 Apr 2014
    • Clarified exclusion criteria to exclude subjects with acute MIs • Modified contraception requirements to require 2 acceptable methods of effective birth control

    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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