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    Clinical Trial Results:
    A Multicenter Single-arm Extension Study to Describe the Long-term Efficacy and Safety of AMG 416 in the Treatment of Secondary Hyperparathyroidism in Subjects With Chronic Kidney Disease on Hemodialysis

    Summary
    EudraCT number
    		 2012-002808-41
    Trial protocol
    		 HU   BE   CZ   GB   SE   ES   IT   AT   PL   NL  
    Global end of trial date
    15 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    16 Jul 2016
    First version publication date
    16 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20120231
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01785875
    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
    15 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study is designed to describe the long-term safety and efficacy of etelcalcetide (AMG 416) for the treatment of secondary hyperparathyroidism (SHPT) in adults with chronic kidney disease (CKD) on hemodialysis.
    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. 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
    31 Jul 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 14
    Country: Number of subjects enrolled
    United States: 524
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 34
    Country: Number of subjects enrolled
    Czech Republic: 29
    Country: Number of subjects enrolled
    France: 15
    Country: Number of subjects enrolled
    Germany: 13
    Country: Number of subjects enrolled
    Hungary: 43
    Country: Number of subjects enrolled
    Israel: 13
    Country: Number of subjects enrolled
    Italy: 17
    Country: Number of subjects enrolled
    Netherlands: 7
    Country: Number of subjects enrolled
    Poland: 42
    Country: Number of subjects enrolled
    Russian Federation: 54
    Country: Number of subjects enrolled
    Spain: 49
    Country: Number of subjects enrolled
    Sweden: 4
    Country: Number of subjects enrolled
    United Kingdom: 5
    Worldwide total number of subjects
    891
    EEA total number of subjects
    265
    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)
    595
    From 65 to 84 years
    282
    85 years and over
    14

    Subject disposition

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    Recruitment
    Recruitment details
    		 This single-arm study was conducted at 205 centers in the US, Canada, Europe, Israel, Russian Federation, and Australia. Participants were enrolled from 31 July 2013 to 9 June 2014.

    Pre-assignment
    Screening details
    		 This extension study enrolled participants from 1 of 3 parent studies: 20120229 (2012-002805-23), 20120230 (2012-002806-31), or 20120359. In Studies 20120229 and 20120230, patients received either placebo or etelcalcetide 3 times a week (TIW) for up to 26 weeks; In Study 20120359, patients received 5 mg etelcalcetide TIW for 4 weeks.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study in which all subjects received etelcalcetide. Participants who completed etelcalcetide and the 30-day safety follow-up period were classified as completing the study; Participants who completed etelcalcetide and rolled over into extension study 20130213 (EudraCT Number: 2013-004136-30) were classified as discontinuing the study because of protocol-specified criteria.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 20120229 / 20120230 Placebo
    Arm description
    		 Participants who received placebo in parent study 20120229 or 20120230 received etelcalcetide at a starting dose of 5 mg three times a week (TIW) for up to 52 weeks in the extension study. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etelcalcetide
    Investigational medicinal product code
    AMG 416
    Other name
    Pharmaceutical forms
    Solution for infusion, Powder for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by bolus injection into the venous line of the dialysis circuit at the end of hemodialysis treatment, and prior to or during rinse-back with each hemodialysis session (ie, 3 times per week).

    Arm title
    		 20120229 / 20120230 Etelcalcetide
    Arm description
    		 Participants who received etelcalcetide in parent study 20120229 or 20120230 received etelcalcetide at a starting dose of 5 mg TIW for up to 52 weeks in the extension study. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etelcalcetide
    Investigational medicinal product code
    AMG 416
    Other name
    Pharmaceutical forms
    Powder for solution for infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by bolus injection into the venous line of the dialysis circuit at the end of hemodialysis treatment, and prior to or during rinse-back with each hemodialysis session (ie, 3 times per week).

    Arm title
    		 20120359 Etelcalcetide
    Arm description
    		 Participants who received etelcalcetide in parent study 20120359 received etelcalcetide at a starting dose of 5 mg TIW for up to 52 weeks in the extension study. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Etelcalcetide
    Investigational medicinal product code
    AMG 416
    Other name
    Pharmaceutical forms
    Powder for solution for infusion, Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administered by bolus injection into the venous line of the dialysis circuit at the end of hemodialysis treatment, and prior to or during rinse-back with each hemodialysis session (ie, 3 times per week).

    Number of subjects in period 1
    		20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide
    Started
    384
    384
    123
    Received Etelcalcetide
    383
    384
    123
    Completed
    90
    95
    16
    Not completed
    294
    289
    107
         Consent withdrawn by subject
    41
    34
    36
         Death
    27
    16
    7
         Sponsor Decision
    -
    2
    -
         Protocol Specified Criteria
    207
    214
    55
         Lost to follow-up
    19
    22
    6
         Missing
    -
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study
    Reporting group description
    		 -

    Reporting group values
    		 Overall Study Total
    Number of subjects
    		 891 891
    Age, Customized
    Units: participants
        < 65 years
    		 577 577
        ≥ 65 years
    		 314 314
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.3 ( 14.4 ) -
    Gender, Male/Female
    Units: participants
        Female
    		 341 341
        Male
    		 550 550
    Race/Ethnicity, Customized
    Units: Subjects
        American Indian or Alaska Native
    		 1 1
        Asian
    		 29 29
        Black (or African American)
    		 270 270
        Native Hawaiian or Other Pacific Islander
    		 12 12
        White
    		 567 567
        Other
    		 12 12
    Ethnicity
    Units: Subjects
        Hispanic/Latino
    		 122 122
        Not Hispanic/Latino
    		 769 769
    Parathyroid Hormone (PTH) Level
    Units: Subjects
        < 600 pg/mL
    		 405 405
        600 - ≤ 1000 pg/mL
    		 221 221
        > 1000 pg/mL
    		 228 228
        Missing
    		 37 37
    PTH Concentration
    Data available for 854 participants
    Units: pg/mL
        arithmetic mean (standard deviation)
    		 769.5 ( 574.4 ) -
    Corrected Calcium
    Data available for 889 participants
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 9.67 ( 0.68 ) -
    Phosphorus
    Data available for 887 participants
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 5.63 ( 1.75 ) -
    Corrected Calcium Phosphorus Product (cCa x P)
    Data available for 887 participants
    Units: mg²/dL²
        arithmetic mean (standard deviation)
    		 54.36 ( 17.17 ) -

    End points

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    End points reporting groups
    Reporting group title
    20120229 / 20120230 Placebo
    Reporting group description
    		 Participants who received placebo in parent study 20120229 or 20120230 received etelcalcetide at a starting dose of 5 mg three times a week (TIW) for up to 52 weeks in the extension study. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.

    Reporting group title
    20120229 / 20120230 Etelcalcetide
    Reporting group description
    		 Participants who received etelcalcetide in parent study 20120229 or 20120230 received etelcalcetide at a starting dose of 5 mg TIW for up to 52 weeks in the extension study. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.

    Reporting group title
    20120359 Etelcalcetide
    Reporting group description
    		 Participants who received etelcalcetide in parent study 20120359 received etelcalcetide at a starting dose of 5 mg TIW for up to 52 weeks in the extension study. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.

    Subject analysis set title
    Total
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received etelcalcetide at a starting dose of 5 mg three times a week (TIW) for up to 52 weeks. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.

    Primary: Number of Participants with Adverse Events (AEs)

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    End point title
    		 Number of Participants with Adverse Events (AEs) [1]
    End point description
    Treatment-related adverse events are those the investigator indicated as having a reasonable possibility of having been caused by etelcalcetide. A serious adverse event is defined as an adverse event that meets at least 1 of the following serious criteria: • fatal • life threatening • requires in-patient hospitalization or prolongation of existing hospitalization • results in persistent or significant disability/incapacity • congenital anomaly/birth defect • other medically important serious event. Results are reported for all participants who received at least 1 dose of etelcalcetide.
    End point type
    Primary
    End point timeframe
    From first dose until 30 days after last dose; the treatment period was 52 weeks.
    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 hypotheses were tested in this study.
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    383
    384
    123
    890
    Units: participants
    number (not applicable)
        Any adverse event
    354
    337
    108
    799
        Serious adverse events
    161
    142
    53
    356
        Treatment-related adverse events
    215
    141
    36
    392
        Treatment-related serious adverse events
    6
    5
    2
    13
        AEs leading to discontinuation of etelcalcetide
    22
    11
    8
    41
        Fatal adverse events
    27
    16
    8
    51
    No statistical analyses for this end point

    Primary: Number of Participants with Shift in Laboratory Values from Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4

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    End point title
    		 Number of Participants with Shift in Laboratory Values from Baseline Grade 0 or 1 to Post-baseline Grade 3 or 4 [2]
    End point description
    Laboratory toxicity grading was based on Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, where Grade 0 represents values in the normal range and grade 4 represents values with life-threatening consequences and urgent intervention indicated. Results are reported for all participants who received at least 1 dose of etelcalcetide.
    End point type
    Primary
    End point timeframe
    52 weeks
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypotheses were tested in this study.
    End point values
    		 Total
    Number of subjects analysed
    890
    Units: participants
    number (not applicable)
        Alanine aminotransferase increase
    1
        Albumin decrease
    9
        Alkaline phosphatase increase
    2
        Aspartate aminotransferase increase
    3
        Bilirubin increase
    1
        Calcium (corrected) decrease
    51
        Calcium (corrected) increase
    8
        Phosphorus decrease
    77
        Potassium decrease
    9
        Potassium increase
    69
        Hemoglobin decrease
    4
        Hemoglobin increase
    1
    No statistical analyses for this end point

    Primary: Number of Participants who Developed Anti-etelcalcetide Antibodies

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    End point title
    		 Number of Participants who Developed Anti-etelcalcetide Antibodies [3]
    End point description
    A validated dual flow-cell biosensor immunoassay was used to detect antibodies capable of binding etelcalcetide. The number of participants with a negative or no result at baseline and positive binding antibodies at any time post-baseline is reported. Results include participants who received at least 1 dose of etelcalcetide and with a post-baseline antibody result.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24, Week 36, Week 53, the 30-day follow-up visit
    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 hypotheses were tested in this study.
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    369
    384
    123
    876
    Units: participants
        number (not applicable)
    10
    15
    2
    27
    No statistical analyses for this end point

    Primary: Change from Baseline in Blood Pressure

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    End point title
    		 Change from Baseline in Blood Pressure [4]
    End point description
    Blood pressure (BP) values were taken post-hemodialysis assessments. Results are reported for participants who received at least 1 dose of etelcalcetide and with available data at each time point (indicated by n).
    End point type
    Primary
    End point timeframe
    Baseline and Weeks 24 and 48
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal hypotheses were tested in this study.
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    383
    384
    123
    890
    Units: mmHg
    arithmetic mean (standard error)
        Systolic BP Week 24 (n = 329, 342, 104, 775)
    4 ( 1.5 )
    4.5 ( 1.4 )
    -5.5 ( 2.8 )
    2.9 ( 1 )
        Systolic BP Week 48 (n = 305, 317, 74, 696)
    3.5 ( 1.6 )
    6.5 ( 1.5 )
    -6.8 ( 3 )
    3.8 ( 1 )
        Diastolic BP Week 24 (n = 329, 343, 104, 776)
    2.2 ( 0.8 )
    1.2 ( 0.9 )
    -5.1 ( 1.5 )
    0.8 ( 0.6 )
        Diastolic BP Week 48 (n = 305, 317, 74, 696)
    1.1 ( 0.9 )
    0.8 ( 0.9 )
    -2.6 ( 1.7 )
    0.6 ( 0.6 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With > 30% Reduction From Baseline in PTH During the Efficacy Assessment Phase

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    End point title
    		 Percentage of Participants With > 30% Reduction From Baseline in PTH During the Efficacy Assessment Phase
    End point description
    The efficacy assessment phase (EAP) is defined as the last 6 weeks before ending treatment, which was only for participants who completed a minimum of 8 weeks of treatment with etelcalcetide. If multiple assessments were available during the EAP, values were averaged. Participants with pre-dialysis PTH assessment at baseline and during the EAP who completed a minimum of 8 weeks of treatment with etelcalcetide are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (defined as the last 6 weeks prior to ending treatment for participants who completed a minimum of 8 weeks of treatment)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    341
    332
    106
    779
    Units: percentage of participants
        number (confidence interval 95%)
    81.2 (76.7 to 85.2)
    54.5 (49 to 60)
    65.1 (55.2 to 74.1)
    67.7 (64.2 to 70.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With > 30% Reduction From Baseline in PTH During the EAP12

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    End point title
    		 Percentage of Participants With > 30% Reduction From Baseline in PTH During the EAP12
    End point description
    The efficacy assessment phase at 12 months (EAP12) was defined as the period from week 46 to 53 (inclusive). If multiple assessments were available during the EAP12, values were averaged. Participants with pre-dialysis PTH assessment at baseline and during EAP12 were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase at month 12 (weeks 46-53)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    302
    300
    74
    676
    Units: percentage of participants
        number (confidence interval 95%)
    82.5 (77.7 to 86.6)
    53.3 (47.5 to 59.1)
    63.5 (51.5 to 74.4)
    67.5 (63.8 to 71)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With PTH ≤ 300 pg/mL During the EAP

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    End point title
    		 Percentage of Participants With PTH ≤ 300 pg/mL During the EAP
    End point description
    Participants with predialysis PTH assessment during the EAP who completed a minimum of 8 weeks of treatment with etelcalcetide were included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (defined as the last 6 weeks prior to ending treatment for participants who completed a minimum of 8 weeks of treatment)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    352
    355
    108
    815
    Units: percentage of participants
        number (confidence interval 95%)
    55.7 (50.3 to 60.9)
    59.7 (54.4 to 64.9)
    54.6 (44.8 to 64.2)
    57.3 (53.8 to 60.7)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With PTH ≤ 300 pg/mL During the EAP12

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    End point title
    		 Percentage of Participants With PTH ≤ 300 pg/mL During the EAP12
    End point description
    Participants with predialysis PTH assessment during the EAP12 are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Week 46 to 53
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    312
    321
    75
    708
    Units: percentage of participants
        number (confidence interval 95%)
    54.8 (49.1 to 60.4)
    61.1 (55.5 to 66.4)
    42.7 (31.3 to 54.6)
    56.4 (52.6 to 60)
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Mean PTH During the EAP

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    End point title
    		 Percent Change From Baseline in Mean PTH During the EAP
    End point description
    Participants with available data are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (defined as the last 6 weeks prior to ending treatment for participants who completed a minimum of 8 weeks of treatment)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    341
    332
    106
    779
    Units: percent change
        arithmetic mean (standard error)
    -54.55 ( 2.12 )
    3.92 ( 8.68 )
    -28.4 ( 6.96 )
    -26.07 ( 4.04 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Mean PTH During the EAP12

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    End point title
    		 Percent Change From Baseline in Mean PTH During the EAP12
    End point description
    Participants with available data are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase at month 12 (weeks 46-53)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    302
    300
    74
    676
    Units: percent change
        arithmetic mean (standard error)
    -55.41 ( 2.2 )
    4.78 ( 9.62 )
    -27.05 ( 7.57 )
    -25.59 ( 4.59 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Mean Corrected Calcium During the EAP

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    End point title
    		 Percent Change From Baseline in Mean Corrected Calcium During the EAP
    End point description
    Participants with available data are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (defined as the last 6 weeks prior to ending treatment for participants who completed a minimum of 8 weeks of treatment)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    352
    352
    103
    807
    Units: percent change
        arithmetic mean (standard error)
    -10.01 ( 0.52 )
    -6.74 ( 0.47 )
    -8.65 ( 1.04 )
    -8.41 ( 0.34 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Mean Corrected Calcium During the EAP12

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    End point title
    		 Percent Change From Baseline in Mean Corrected Calcium During the EAP12
    End point description
    Participants with available data are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase at month 12 (weeks 46-53)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    310
    319
    75
    704
    Units: percent change
        arithmetic mean (standard error)
    -9.76 ( 0.52 )
    -6.43 ( 0.45 )
    -9.73 ( 1.14 )
    -8.25 ( 0.34 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Mean Corrected Calcium Phosphorus Product During the EAP

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    End point title
    		 Percent Change From Baseline in Mean Corrected Calcium Phosphorus Product During the EAP
    End point description
    Participants with available data are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (defined as the last 6 weeks prior to ending treatment for participants who completed a minimum of 8 weeks of treatment)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    342
    345
    99
    786
    Units: percent change
        arithmetic mean (standard error)
    -15.26 ( 1.58 )
    -10.41 ( 1.61 )
    -6.58 ( 4.28 )
    -12.04 ( 1.13 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Mean Corrected Calcium Phosphorus Product During the EAP12

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    End point title
    		 Percent Change From Baseline in Mean Corrected Calcium Phosphorus Product During the EAP12
    End point description
    Participants with available data are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase at month 12 (weeks 46-53)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    309
    317
    75
    701
    Units: percent change
        arithmetic mean (standard error)
    -15.3 ( 1.53 )
    -9.78 ( 1.62 )
    -7.29 ( 4.82 )
    -11.95 ( 1.13 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Mean Phosphorus During the EAP

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    End point title
    		 Percent Change From Baseline in Mean Phosphorus During the EAP
    End point description
    Participants with available data are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (defined as the last 6 weeks prior to ending treatment for participants who completed a minimum of 8 weeks of treatment)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    343
    348
    105
    796
    Units: percent change
        arithmetic mean (standard error)
    -5.71 ( 1.71 )
    -3.5 ( 1.68 )
    2.82 ( 4.56 )
    -3.62 ( 1.2 )
    No statistical analyses for this end point

    Secondary: Percent Change From Baseline in Mean Phosphorus During the EAP12

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    End point title
    		 Percent Change From Baseline in Mean Phosphorus During the EAP12
    End point description
    Participants with available data are included in the analysis.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase at month 12 (weeks 46-53)
    End point values
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Number of subjects analysed
    309
    319
    75
    703
    Units: percent change
        arithmetic mean (standard error)
    -5.87 ( 1.65 )
    -3.06 ( 1.73 )
    3.53 ( 5.46 )
    -3.59 ( 1.22 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose until 30 days after last dose; the treatment period was 52 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    20120229 / 20120230 Placebo
    Reporting group description
    		 Participants who received placebo in parent study 20120229 or 20120230 received etelcalcetide at a starting dose of 5 mg three times a week (TIW) for up to 52 weeks in the extension study. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.

    Reporting group title
    20120229 / 20120230 Etelcalcetide
    Reporting group description
    		 Participants who received etelcalcetide in parent study 20120229 or 20120230 received etelcalcetide at a starting dose of 5 mg TIW for up to 52 weeks in the extension study. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.

    Reporting group title
    20120359 Etelcalcetide
    Reporting group description
    		 Participants who received etelcalcetide in parent study 20120359 received etelcalcetide at a starting dose of 5 mg TIW for up to 52 weeks in the extension study. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.

    Reporting group title
    Total
    Reporting group description
    		 Participants received etelcalcetide at a starting dose of 5 mg three times a week (TIW) for up to 52 weeks. Etelcalcetide dose could be increased at weeks 5, 9, 17, 25, 33, 41, and 49 to a maximum dose of 15 mg to achieve predialysis serum parathyroid hormone levels ≤ 300 pg/mL.

    Serious adverse events
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    161 / 383 (42.04%)
    142 / 384 (36.98%)
    53 / 123 (43.09%)
    356 / 890 (40.00%)
         number of deaths (all causes)
    27
    16
    8
    51
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma of colon
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bladder adenocarcinoma stage unspecified
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast cancer
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Clear cell renal cell carcinoma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colon cancer stage II
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lung cancer metastatic
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Metastases to spine
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm malignant
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Prostate cancer
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sarcoma
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of skin
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroid neoplasm
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial occlusive disease
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    5 / 383 (1.31%)
    4 / 384 (1.04%)
    1 / 123 (0.81%)
    10 / 890 (1.12%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 1
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    5 / 383 (1.31%)
    4 / 384 (1.04%)
    2 / 123 (1.63%)
    11 / 890 (1.24%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
    0 / 2
    0 / 11
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Jugular vein thrombosis
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    2 / 383 (0.52%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    2 / 383 (0.52%)
    4 / 384 (1.04%)
    0 / 123 (0.00%)
    6 / 890 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Shock haemorrhagic
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Steal syndrome
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arteriovenous graft
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Therapy cessation
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    2 / 383 (0.52%)
    2 / 384 (0.52%)
    1 / 123 (0.81%)
    5 / 890 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest pain
         subjects affected / exposed
    3 / 383 (0.78%)
    7 / 384 (1.82%)
    1 / 123 (0.81%)
    11 / 890 (1.24%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 8
    0 / 1
    0 / 12
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug resistance
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic cyst
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthermia malignant
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothermia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    6 / 383 (1.57%)
    5 / 384 (1.30%)
    1 / 123 (0.81%)
    12 / 890 (1.35%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 5
    0 / 2
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 383 (0.52%)
    2 / 384 (0.52%)
    3 / 123 (2.44%)
    7 / 890 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 3
    Thrombosis in device
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    2 / 123 (1.63%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypersensitivity
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seasonal allergy
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pelvic haemorrhage
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal haemorrhage
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    2 / 383 (0.52%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Aspiration
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Asthma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchospasm
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 383 (0.00%)
    3 / 384 (0.78%)
    1 / 123 (0.81%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    2 / 383 (0.52%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary cavitation
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 384 (0.52%)
    1 / 123 (0.81%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pulmonary infarction
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 383 (0.26%)
    3 / 384 (0.78%)
    0 / 123 (0.00%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    3 / 383 (0.78%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    5 / 890 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Stridor
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Throat tightness
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Confusional state
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    1 / 123 (0.81%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression suicidal
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination, visual
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    6 / 383 (1.57%)
    0 / 384 (0.00%)
    2 / 123 (1.63%)
    8 / 890 (0.90%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 0
    0 / 2
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anticoagulation drug level below therapeutic
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bilirubin conjugated increased
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood bilirubin increased
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood calcium decreased
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood pressure increased
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis C antibody positive
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    International normalised ratio increased
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula occlusion
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    7 / 383 (1.83%)
    6 / 384 (1.56%)
    0 / 123 (0.00%)
    13 / 890 (1.46%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 6
    0 / 0
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    3 / 383 (0.78%)
    4 / 384 (1.04%)
    1 / 123 (0.81%)
    8 / 890 (0.90%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 7
    0 / 1
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    4 / 383 (1.04%)
    6 / 384 (1.56%)
    0 / 123 (0.00%)
    10 / 890 (1.12%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 9
    0 / 0
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervical vertebral fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Complications of transplanted kidney
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Compression fracture
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary bypass thrombosis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dialysis related complication
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    1 / 123 (0.81%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    3 / 383 (0.78%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Graft thrombosis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemodialysis-induced symptom
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Humerus fracture
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intentional overdose
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Jaw fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower limb fracture
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple fractures
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Patella fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial reocclusion
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirenal haematoma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural complication
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative respiratory failure
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shunt stenosis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Soft tissue injury
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Splenic injury
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Stoma site pain
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular graft complication
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    2 / 123 (1.63%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular graft thrombosis
         subjects affected / exposed
    4 / 383 (1.04%)
    2 / 384 (0.52%)
    2 / 123 (1.63%)
    8 / 890 (0.90%)
         occurrences causally related to treatment / all
    0 / 9
    0 / 2
    0 / 3
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound complication
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound haemorrhage
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    3 / 383 (0.78%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    5 / 383 (1.31%)
    6 / 384 (1.56%)
    0 / 123 (0.00%)
    11 / 890 (1.24%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 7
    0 / 0
    0 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    Angina pectoris
         subjects affected / exposed
    2 / 383 (0.52%)
    3 / 384 (0.78%)
    2 / 123 (1.63%)
    7 / 890 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 3
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve disease
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve incompetence
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Arrhythmia
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    9 / 383 (2.35%)
    4 / 384 (1.04%)
    0 / 123 (0.00%)
    13 / 890 (1.46%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 4
    0 / 0
    0 / 16
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 383 (0.52%)
    2 / 384 (0.52%)
    1 / 123 (0.81%)
    5 / 890 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    6 / 383 (1.57%)
    2 / 384 (0.52%)
    4 / 123 (3.25%)
    12 / 890 (1.35%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 4
    0 / 12
         deaths causally related to treatment / all
    0 / 3
    0 / 2
    0 / 4
    0 / 9
    Cardiac disorder
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    2 / 383 (0.52%)
    3 / 384 (0.78%)
    0 / 123 (0.00%)
    5 / 890 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
    Cardiac failure acute
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Cardiac failure chronic
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    8 / 383 (2.09%)
    7 / 384 (1.82%)
    3 / 123 (2.44%)
    18 / 890 (2.02%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 7
    0 / 5
    0 / 23
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cardiac valve disease
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 383 (0.26%)
    3 / 384 (0.78%)
    0 / 123 (0.00%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 3
    Cardiogenic shock
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    3 / 383 (0.78%)
    6 / 384 (1.56%)
    0 / 123 (0.00%)
    9 / 890 (1.01%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 6
    0 / 0
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    3 / 383 (0.78%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mitral valve incompetence
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 383 (0.52%)
    4 / 384 (1.04%)
    1 / 123 (0.81%)
    7 / 890 (0.79%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 1
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Palpitations
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus node dysfunction
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Torsade de pointes
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    2 / 383 (0.52%)
    2 / 384 (0.52%)
    2 / 123 (1.63%)
    6 / 890 (0.67%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 3
    Nervous system disorders
    Altered state of consciousness
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid artery stenosis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral haemorrhage
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Cerebral infarction
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    3 / 383 (0.78%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 383 (0.00%)
    3 / 384 (0.78%)
    1 / 123 (0.81%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Loss of consciousness
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meralgia paraesthetica
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Migraine
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    3 / 383 (0.78%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    6 / 383 (1.57%)
    2 / 384 (0.52%)
    3 / 123 (2.44%)
    11 / 890 (1.24%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 2
    0 / 3
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 383 (0.78%)
    1 / 384 (0.26%)
    2 / 123 (1.63%)
    6 / 890 (0.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 3
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anaemia of chronic disease
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic anaemia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrogenic anaemia
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    2 / 383 (0.52%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diplopia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lens dislocation
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Optic neuropathy
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal adhesions
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    3 / 383 (0.78%)
    3 / 384 (0.78%)
    1 / 123 (0.81%)
    7 / 890 (0.79%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
    0 / 1
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain lower
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Anorectal varices haemorrhage
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dental caries
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic gastroparesis
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 383 (0.52%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticular perforation
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulum intestinal
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocutaneous fistula
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric antral vascular ectasia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastric haemorrhage
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis erosive
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis haemorrhagic
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    2 / 123 (1.63%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 2
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 383 (0.52%)
    4 / 384 (1.04%)
    4 / 123 (3.25%)
    10 / 890 (1.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 6
    0 / 4
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal necrosis
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal vascular malformation
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Inguinal hernia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    3 / 383 (0.78%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Megacolon
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic duct obstruction
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    2 / 383 (0.52%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 384 (0.52%)
    1 / 123 (0.81%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    3 / 383 (0.78%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    5 / 890 (0.56%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 1
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary colic
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholangitis acute
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    2 / 383 (0.52%)
    3 / 384 (0.78%)
    0 / 123 (0.00%)
    5 / 890 (0.56%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatotoxicity
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Decubitus ulcer
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 384 (0.52%)
    2 / 123 (1.63%)
    5 / 890 (0.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 4
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Henoch-Schonlein purpura
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Purpura
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 383 (0.26%)
    5 / 384 (1.30%)
    0 / 123 (0.00%)
    6 / 890 (0.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitic rash
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Azotaemia
         subjects affected / exposed
    2 / 383 (0.52%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrosclerosis
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal colic
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cyst haemorrhage
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arthritis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bone pain
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal pain
         subjects affected / exposed
    0 / 383 (0.00%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuropathic arthropathy
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acinetobacter bacteraemia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acinetobacter infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous graft site infection
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    2 / 123 (1.63%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    2 / 383 (0.52%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bacterial tracheitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Campylobacter gastroenteritis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    8 / 383 (2.09%)
    4 / 384 (1.04%)
    1 / 123 (0.81%)
    13 / 890 (1.46%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 5
    0 / 1
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic gangrene
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enteritis infectious
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    2 / 123 (1.63%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    6 / 383 (1.57%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    6 / 890 (0.67%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Genital abscess
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Graft infection
         subjects affected / exposed
    0 / 383 (0.00%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Helicobacter gastritis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected skin ulcer
         subjects affected / exposed
    3 / 383 (0.78%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    3 / 383 (0.78%)
    1 / 384 (0.26%)
    2 / 123 (1.63%)
    6 / 890 (0.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    4 / 383 (1.04%)
    3 / 384 (0.78%)
    1 / 123 (0.81%)
    8 / 890 (0.90%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
    0 / 1
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis acute
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    7 / 383 (1.83%)
    5 / 384 (1.30%)
    3 / 123 (2.44%)
    15 / 890 (1.69%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 6
    0 / 3
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal cyst infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    10 / 383 (2.61%)
    2 / 384 (0.52%)
    3 / 123 (2.44%)
    15 / 890 (1.69%)
         occurrences causally related to treatment / all
    0 / 12
    0 / 2
    0 / 4
    0 / 18
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 3
    Septic shock
         subjects affected / exposed
    3 / 383 (0.78%)
    1 / 384 (0.26%)
    2 / 123 (1.63%)
    6 / 890 (0.67%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
    Shunt infection
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    1 / 123 (0.81%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheitis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tracheobronchitis
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    1 / 123 (0.81%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 384 (0.52%)
    1 / 123 (0.81%)
    4 / 890 (0.45%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 383 (0.26%)
    2 / 384 (0.52%)
    0 / 123 (0.00%)
    3 / 890 (0.34%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound sepsis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Failure to thrive
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    Fluid overload
         subjects affected / exposed
    3 / 383 (0.78%)
    8 / 384 (2.08%)
    4 / 123 (3.25%)
    15 / 890 (1.69%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 8
    0 / 4
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    14 / 383 (3.66%)
    10 / 384 (2.60%)
    5 / 123 (4.07%)
    29 / 890 (3.26%)
         occurrences causally related to treatment / all
    0 / 14
    0 / 11
    0 / 7
    0 / 32
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    1 / 383 (0.26%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    2 / 383 (0.52%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    2 / 890 (0.22%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    5 / 383 (1.31%)
    4 / 384 (1.04%)
    1 / 123 (0.81%)
    10 / 890 (1.12%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 5
    0 / 1
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypophosphataemia
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 383 (0.26%)
    0 / 384 (0.00%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 383 (0.00%)
    1 / 384 (0.26%)
    0 / 123 (0.00%)
    1 / 890 (0.11%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 20120229 / 20120230 Placebo 20120229 / 20120230 Etelcalcetide 20120359 Etelcalcetide Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    289 / 383 (75.46%)
    249 / 384 (64.84%)
    75 / 123 (60.98%)
    613 / 890 (68.88%)
    Investigations
    Blood calcium decreased
         subjects affected / exposed
    226 / 383 (59.01%)
    129 / 384 (33.59%)
    30 / 123 (24.39%)
    385 / 890 (43.26%)
         occurrences all number
    337
    192
    44
    573
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    22 / 383 (5.74%)
    27 / 384 (7.03%)
    8 / 123 (6.50%)
    57 / 890 (6.40%)
         occurrences all number
    39
    31
    13
    83
    Fall
         subjects affected / exposed
    22 / 383 (5.74%)
    14 / 384 (3.65%)
    6 / 123 (4.88%)
    42 / 890 (4.72%)
         occurrences all number
    26
    18
    7
    51
    Procedural hypotension
         subjects affected / exposed
    17 / 383 (4.44%)
    8 / 384 (2.08%)
    8 / 123 (6.50%)
    33 / 890 (3.71%)
         occurrences all number
    27
    10
    47
    84
    Vascular disorders
    Hypertension
         subjects affected / exposed
    30 / 383 (7.83%)
    18 / 384 (4.69%)
    10 / 123 (8.13%)
    58 / 890 (6.52%)
         occurrences all number
    36
    36
    18
    90
    Hypotension
         subjects affected / exposed
    36 / 383 (9.40%)
    25 / 384 (6.51%)
    5 / 123 (4.07%)
    66 / 890 (7.42%)
         occurrences all number
    60
    41
    5
    106
    Nervous system disorders
    Headache
         subjects affected / exposed
    25 / 383 (6.53%)
    25 / 384 (6.51%)
    2 / 123 (1.63%)
    52 / 890 (5.84%)
         occurrences all number
    31
    29
    2
    62
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    22 / 383 (5.74%)
    12 / 384 (3.13%)
    3 / 123 (2.44%)
    37 / 890 (4.16%)
         occurrences all number
    23
    14
    3
    40
    Diarrhoea
         subjects affected / exposed
    41 / 383 (10.70%)
    46 / 384 (11.98%)
    8 / 123 (6.50%)
    95 / 890 (10.67%)
         occurrences all number
    53
    63
    14
    130
    Nausea
         subjects affected / exposed
    43 / 383 (11.23%)
    27 / 384 (7.03%)
    13 / 123 (10.57%)
    83 / 890 (9.33%)
         occurrences all number
    51
    37
    16
    104
    Vomiting
         subjects affected / exposed
    40 / 383 (10.44%)
    37 / 384 (9.64%)
    11 / 123 (8.94%)
    88 / 890 (9.89%)
         occurrences all number
    53
    46
    13
    112
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    21 / 383 (5.48%)
    20 / 384 (5.21%)
    13 / 123 (10.57%)
    54 / 890 (6.07%)
         occurrences all number
    23
    22
    15
    60
    Dyspnoea
         subjects affected / exposed
    24 / 383 (6.27%)
    17 / 384 (4.43%)
    5 / 123 (4.07%)
    46 / 890 (5.17%)
         occurrences all number
    43
    20
    12
    75
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    8 / 383 (2.09%)
    10 / 384 (2.60%)
    7 / 123 (5.69%)
    25 / 890 (2.81%)
         occurrences all number
    8
    12
    8
    28
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    19 / 383 (4.96%)
    18 / 384 (4.69%)
    10 / 123 (8.13%)
    47 / 890 (5.28%)
         occurrences all number
    21
    20
    10
    51
    Back pain
         subjects affected / exposed
    26 / 383 (6.79%)
    20 / 384 (5.21%)
    4 / 123 (3.25%)
    50 / 890 (5.62%)
         occurrences all number
    27
    22
    4
    53
    Muscle spasms
         subjects affected / exposed
    36 / 383 (9.40%)
    33 / 384 (8.59%)
    10 / 123 (8.13%)
    79 / 890 (8.88%)
         occurrences all number
    55
    51
    30
    136
    Pain in extremity
         subjects affected / exposed
    16 / 383 (4.18%)
    23 / 384 (5.99%)
    6 / 123 (4.88%)
    45 / 890 (5.06%)
         occurrences all number
    24
    29
    11
    64
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    20 / 383 (5.22%)
    6 / 384 (1.56%)
    2 / 123 (1.63%)
    28 / 890 (3.15%)
         occurrences all number
    21
    8
    3
    32
    Nasopharyngitis
         subjects affected / exposed
    19 / 383 (4.96%)
    21 / 384 (5.47%)
    3 / 123 (2.44%)
    43 / 890 (4.83%)
         occurrences all number
    25
    28
    3
    56
    Upper respiratory tract infection
         subjects affected / exposed
    20 / 383 (5.22%)
    14 / 384 (3.65%)
    20 / 123 (16.26%)
    54 / 890 (6.07%)
         occurrences all number
    21
    17
    24
    62

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Mar 2013
    - Allowed initiation of etelcalcetide administration Monday to Friday, instead of the previous restriction of Wednesday or Thursday only - Clarified that etelcalcetide should not be administered subcutaneously or through any other route other than IV, and that it should not be administered concurrently with other IV medications. - Clarified that if suspended for symptomatic hypocalcemia, dosing should only resume after checking cCa levels, in addition to the currently stated resolution of symptomatic hypocalcemia. - Allowed adjustment of vitamin D for hypocalcemia during the study. - Provided recommended interventions for treating hypocalcemia with modification of oral calcium supplements, dialysate calcium concentration, and vitamin D. - Eliminated 4 hematology, 5 PTH, and 6 albumin/ calcium/ phosphorous assays in the dose maintenance phase. - Provided a sample Serious Adverse Event Form. - Increased pregnancy testing for women of childbearing potential from 2 times in total (before study start and at end of study), to 5 times in total (every 12 weeks).
    19 Aug 2013
    - Removed requirement for male contraception „ - Added text describing the new liquid formulation of etelcalcetide - Reduced the dose titration portion to the first 9 weeks, and commensurately increased the dose maintenance phase (entire study duration was unchanged) - Excluded the use of any concomitant medications known to be associated with hypocalcemia - Added a + 1 week window for the dose titration phase and a +/- 2 week window for the dose maintenance phase - Revised and reduced the assessments to reflect the new titration versus maintenance weeks - Eliminated all electrocardiogram measurements - Added new standard text for serious adverse event reporting procedures

    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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