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    Clinical Trial Results:
    A Multi-center, Open-label, Extension Study to Evaluate the Long-term Efficacy and Safety of Oral Tolvaptan Tablet Regimens in Subjects with Autosomal Dominant Polycystic Kidney Disease (ADPKD)

    Summary
    EudraCT number
    2010-018401-10
    Trial protocol
    DE   FR   GB   BE   IT   NL  
    Global end of trial date
    29 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Mar 2017
    First version publication date
    17 Mar 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    156-08-271
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01214421
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otsuka Pharmaceutical Development & Commercialization, Inc.
    Sponsor organisation address
    2440 Research Boulevard, Rockville, United States, MD 20850
    Public contact
    Otsuka Transparency Department, Otsuka Pharmaceutical Development & Commercialization, Inc., DT-inquiry@otsuka.jp
    Scientific contact
    Otsuka Transparency Department, Otsuka Pharmaceutical Development & Commercialization, Inc., DT-inquiry@otsuka.jp
    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
    29 Feb 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this ongoing open-label trial was to demonstrate whether tolvaptan modifies ADPKD progression as measured by changes in endpoints of total kidney volume (TKV) and renal function (eGFR CKD-EPI) measured from baseline in TEMPO 3:4 to Month 24 in TEMPO 4:4. Disease modification was evidenced further by the non-inferiority of endpoint progression slope during this trial for those receiving early-treatment with tolvaptan, as compared to those with delayed-treatment, ie, whose initial treatment was with placebo in Trial 2006-002768-24.
    Protection of trial subjects
    This trial is being conducted under the investigational new drug exemption of the US FDA, 21 CFR Part 312. It is being performed in compliance with Good Clinical Practice, the sponsor’s standard operating procedures, and ethical principles for the protection of human research subjects that have their origins in the Declaration of Helsinki. Consistent with ethical principles for the protection of human research subjects, no study procedures were performed on study candidates until written consent had been obtained from them. The informed consent form, protocol, and amendments for this study were submitted to and approved by the institutional review board (IRB) or ethics committee (EC) at each respective study center.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 May 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 35
    Country: Number of subjects enrolled
    Australia: 43
    Country: Number of subjects enrolled
    Belgium: 55
    Country: Number of subjects enrolled
    Canada: 40
    Country: Number of subjects enrolled
    France: 66
    Country: Number of subjects enrolled
    Germany: 124
    Country: Number of subjects enrolled
    Italy: 45
    Country: Number of subjects enrolled
    Netherlands: 69
    Country: Number of subjects enrolled
    Poland: 71
    Country: Number of subjects enrolled
    Romania: 19
    Country: Number of subjects enrolled
    Russian Federation: 13
    Country: Number of subjects enrolled
    United Kingdom: 57
    Country: Number of subjects enrolled
    United States: 446
    Worldwide total number of subjects
    1083
    EEA total number of subjects
    506
    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)
    1083
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in 1083 participants at 106 trial sites in 13 countries.

    Pre-assignment
    Screening details
    All subjects who completed a tolvaptan autosomal dominant polycystic kidney disease (ADPKD) or renal impairment trial were eligible to be screened for this study. The prespecified analyses were only for those that rolled over (transition time 13-829 days) from TEMPO 3:4 to month 24 in TEMPO 4:4.

    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 trial; blinding procedures were not applicable.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Trial 2006-002768-24 Prior Tolvaptan
    Arm description
    Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability were given orally twice daily until last participant originating from trial 2006-002768-24 who was eligible for efficacy analysis completed the Month 24 visit.
    Arm type
    Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    OPC-41061
    Other name
    OPC-156
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daily split-dose of tolvaptan titrated to the maximally tolerated dose. Starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability.

    Arm title
    Trial 2006-002768-24 Prior Placebo
    Arm description
    Participants received placebo in previous trial 2006-002768-24 were enrolled in this study.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo in previous trial 2006-002768-24 were enrolled in this study.

    Arm title
    Other Trials Prior Tolvaptan
    Arm description
    Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability were given orally twice daily until last participant originating from other trials who was eligible for efficacy analysis completed the Month 24 visit.
    Arm type
    Experimental

    Investigational medicinal product name
    Tolvaptan
    Investigational medicinal product code
    OPC-41061
    Other name
    OPC-156
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Daily split-dose of tolvaptan titrated to the maximally tolerated dose. Starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability.

    Arm title
    Other Trials Prior Placebo
    Arm description
    Participants received placebo in other previous trials were enrolled in this study.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received placebo in other previous trials were enrolled in this study.

    Number of subjects in period 1
    Trial 2006-002768-24 Prior Tolvaptan Trial 2006-002768-24 Prior Placebo Other Trials Prior Tolvaptan Other Trials Prior Placebo
    Started
    557
    314
    181
    31
    Completed
    507
    256
    143
    22
    Not completed
    50
    58
    38
    9
         Physician decision
    2
    -
    4
    -
         Withdrawal Criteria Met
    3
    -
    2
    1
         Adverse event, non-fatal
    16
    35
    14
    3
         Consent withdrawn by subject
    21
    18
    11
    2
         Sponsor discontinued study
    1
    2
    -
    -
         Lost to follow-up
    7
    3
    7
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trial 2006-002768-24 Prior Tolvaptan
    Reporting group description
    Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability were given orally twice daily until last participant originating from trial 2006-002768-24 who was eligible for efficacy analysis completed the Month 24 visit.

    Reporting group title
    Trial 2006-002768-24 Prior Placebo
    Reporting group description
    Participants received placebo in previous trial 2006-002768-24 were enrolled in this study.

    Reporting group title
    Other Trials Prior Tolvaptan
    Reporting group description
    Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability were given orally twice daily until last participant originating from other trials who was eligible for efficacy analysis completed the Month 24 visit.

    Reporting group title
    Other Trials Prior Placebo
    Reporting group description
    Participants received placebo in other previous trials were enrolled in this study.

    Reporting group values
    Trial 2006-002768-24 Prior Tolvaptan Trial 2006-002768-24 Prior Placebo Other Trials Prior Tolvaptan Other Trials Prior Placebo Total
    Number of subjects
    557 314 181 31 1083
    Age categorical
    Units: Subjects
        In utero
    0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    0 0 0 0 0
        Newborns (0-27 days)
    0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    0 0 0 0 0
        Children (2-11 years)
    0 0 0 0 0
        Adolescents (12-17 years)
    0 0 0 0 0
        Adults (18-64 years)
    557 314 181 31 1083
        From 65-84 years
    0 0 0 0 0
        85 years and over
    0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.2 ± 6.9 42.5 ± 7.2 40 ± 10.1 35.6 ± 8.7 -
    Gender categorical
    Units: Subjects
        Female
    254 156 91 15 516
        Male
    303 158 90 16 567

    End points

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    End points reporting groups
    Reporting group title
    Trial 2006-002768-24 Prior Tolvaptan
    Reporting group description
    Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability were given orally twice daily until last participant originating from trial 2006-002768-24 who was eligible for efficacy analysis completed the Month 24 visit.

    Reporting group title
    Trial 2006-002768-24 Prior Placebo
    Reporting group description
    Participants received placebo in previous trial 2006-002768-24 were enrolled in this study.

    Reporting group title
    Other Trials Prior Tolvaptan
    Reporting group description
    Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability were given orally twice daily until last participant originating from other trials who was eligible for efficacy analysis completed the Month 24 visit.

    Reporting group title
    Other Trials Prior Placebo
    Reporting group description
    Participants received placebo in other previous trials were enrolled in this study.

    Subject analysis set title
    Early treated
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants were randomized to tolvaptan and placebo in trial 2006-002768-24.

    Subject analysis set title
    Delayed treated
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    Participants were enrolled and treated to tolvaptan and placebo in trial 2010-018401-10.

    Primary: Percent Change in Total Kidney Volume (TKV)

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    End point title
    Percent Change in Total Kidney Volume (TKV)
    End point description
    For participants continuing from protocol 2006-002768-24: change from trial 2006-002768-24 baseline TKV at month 24 of trial 2010-018401-10 comparing early-treated (those previously treated with tolvaptan) to delayed-treated (those previously treated with placebo).
    End point type
    Primary
    End point timeframe
    5+ years
    End point values
    Early treated Delayed treated
    Number of subjects analysed
    505
    267
    Units: percent change from baseline
        arithmetic mean (standard deviation)
    28.66 ± 26.14
    30.58 ± 27.21
    Statistical analysis title
    Treatment comparisons
    Statistical analysis description
    Derived from a MMRM analysis of the percent change from baseline in total kidney volume with fixed factors of treatment, visit, treatment visit interaction, hypertensive status, renal volume status and creatinine clearance status at baseline, region, baseline value, and baseline visit interaction as covariates, and with an unstructured variance covariance matrix.
    Comparison groups
    Delayed treated v Early treated
    Number of subjects included in analysis
    772
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.358
    Method
    Mixed models analysis
    Parameter type
    Ratio of geometric means (final values)
    Point estimate
    0.99
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.96
         upper limit
    1.02

    Secondary: Change in Estimated Glomerular Filtration Rate (eGFR)

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    End point title
    Change in Estimated Glomerular Filtration Rate (eGFR)
    End point description
    For participants randomized to tolvaptan and placebo in trial 2006-002768-24 and enrolled and treated in trial 2010-018401-10 as early-treated and delayed-treated groups: change from trial 2006-002768-24 baseline eGFR at month 24 of trial 2010-018401-10.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    Early treated Delayed treated
    Number of subjects analysed
    503
    264
    Units: ml/min/1.73m2
        least squares mean (standard deviation)
    -16.77 ± 13.16
    -19.92 ± 16.4
    Statistical analysis title
    Treatment comparisons
    Statistical analysis description
    Derived from a mixed model repeated measures (MMRM) analysis with fixed factors of treatment, visit, treatment visit interaction, hypertensive status, renal volume status and creatinine clearance status at baseline, region, baseline value, and baseline visit interaction as covariates, and with a heterogeneous toeplitz variance covariance matrix.
    Comparison groups
    Delayed treated v Early treated
    Number of subjects included in analysis
    767
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0003
    Method
    Mixed models analysis
    Parameter type
    LS mean difference (final values)
    Point estimate
    3.15
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.462
         upper limit
    4.836

    Secondary: Slope of TKV

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    End point title
    Slope of TKV
    End point description
    For participants randomized to tolvaptan and placebo in trial 2006-002768-24 and enrolled and treated in trial 2010-018401-10 as early treated and delayed treatment groups: annual growth of TKV (slope) measured from TEMPO 4:4 baseline up to Month 24.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    Early treated Delayed treated
    Number of subjects analysed
    509
    268
    Units: %/Yr
        number (not applicable)
    6.164
    4.96
    Statistical analysis title
    Treatment comparisons
    Statistical analysis description
    Derived from testing interaction of time and treatment using linear mixed model in which intercept and time are treated as random effects.
    Comparison groups
    Early treated v Delayed treated
    Number of subjects included in analysis
    777
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.0462
    Method
    Mixed models analysis
    Parameter type
    Ratio of geometric means (final values)
    Point estimate
    1.011
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1
         upper limit
    1.023

    Secondary: Slope of eGFR (CKD-EPI)

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    End point title
    Slope of eGFR (CKD-EPI)
    End point description
    For participants randomized to tolvaptan and placebo in trial 2006-002768-24 and enrolled and treated in trial 2010-018401-10 as early treated and delayed treatment groups: annual change in eGFR (slope) from 4:4 baseline up to Month 24.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    Early treated Delayed treated
    Number of subjects analysed
    549
    304
    Units: ml/min/1.73m2/year
        number (not applicable)
    -3.255
    -3.142
    Statistical analysis title
    Treatment comparisons
    Statistical analysis description
    Derived from testing interaction of time and treatment using linear mixed model in which intercept and time are treated as random effects.
    Comparison groups
    Early treated v Delayed treated
    Number of subjects included in analysis
    853
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.7259
    Method
    Mixed models analysis
    Parameter type
    Ratio of geometric means (final values)
    Point estimate
    -0.113
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.746
         upper limit
    0.52

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events (AEs) and serious adverse events (SAEs) were reported from the signing of the informed consent form until the end of the study regardless of whether the subjects were on or off active study medication (approximately 5 years).
    Adverse event reporting additional description
    The AEs were continued to be captured even when the study medication was discontinued for various participants. All subjects who died during the trial were in the rollover 251 tolvaptan treatment group. None of the 5 subjects with TEAEs that led to death were taking IMP at the time of death.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Trial 2006-002768-24 Prior Tolvaptan
    Reporting group description
    Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability were given orally twice daily until last participant originating from trial 2006-002768-24 who was eligible for efficacy analysis completed the Month 24 visit.

    Reporting group title
    Trial 2006-002768-24 Prior Placebo
    Reporting group description
    Participants received placebo in previous trial 2006-002768-24 were enrolled in this study.

    Reporting group title
    Other Trials Prior Tolvaptan
    Reporting group description
    Participants received a daily split-dose of tolvaptan titrated to the maximally tolerated dose, starting daily tolvaptan dose of 45mg/15mg titrated to 60mg/30mg, then 90mg/30mg based on tolerability were given orally twice daily until last participant originating from other trials who was eligible for efficacy analysis completed the Month 24 visit.

    Reporting group title
    Other Trials Prior Placebo
    Reporting group description
    Participants received placebo in other previous trials were enrolled in this study.

    Serious adverse events
    Trial 2006-002768-24 Prior Tolvaptan Trial 2006-002768-24 Prior Placebo Other Trials Prior Tolvaptan Other Trials Prior Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    143 / 557 (25.67%)
    79 / 314 (25.16%)
    34 / 181 (18.78%)
    5 / 31 (16.13%)
         number of deaths (all causes)
    5
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Aneurysm
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aortic Dissection
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Arterial Stenosis
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Arterial Occlusive Disease
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Venous Disease
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subclavian Vein Thrombosis
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal Cell Carcinoma
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Cancer
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix Cancer Metastatic
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholesterin Granuloma Of Middle Ear
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometrial Cancer
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal Stromal Tumour
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraductal Proliferative Breast Lesion
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malignant Melanoma
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma Cell Myeloma
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Testis Cancer
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Uterine Leiomyoma
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Allergy To Arthropod Sting
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atopy
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug Hypersensitivity
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Ectopic Pregnancy
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gestational Hypertension
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Peripheral Swelling
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Systemic Inflammatory Response Syndrome
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major Depression
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Breast Discomfort
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breast Haematoma
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endometriosis
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Menorrhagia
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metrorrhagia
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postmenopausal Haemorrhage
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental Overdose
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Contusion
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Expired Product Administered
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur Fracture
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot Fracture
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gun Shot Wound
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Incisional Hernia
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Joint Dislocation
         subjects affected / exposed
    2 / 557 (0.36%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament Rupture
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ligament Sprain
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb Injury
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meniscus Injury
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Haematoma
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Shunt Occlusion
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tendon Rupture
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Alanine Aminotransferase Increased
         subjects affected / exposed
    2 / 557 (0.36%)
    3 / 314 (0.96%)
    5 / 181 (2.76%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    3 / 181 (1.66%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Alkaline Phosphatase Increased
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Bilirubin Increased
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Creatine Phosphokinase Increased
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Creatinine Increased
         subjects affected / exposed
    6 / 557 (1.08%)
    6 / 314 (1.91%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood Lactate Dehydrogenase Increased
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gamma-Glutamyltransferase Increased
         subjects affected / exposed
    0 / 557 (0.00%)
    3 / 314 (0.96%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Glomerular Filtration Rate Decreased
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin Decreased
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Enzyme Increased
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver Function Test Abnormal
         subjects affected / exposed
    1 / 557 (0.18%)
    2 / 314 (0.64%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Smear Cervix Abnormal
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases Increased
         subjects affected / exposed
    3 / 557 (0.54%)
    2 / 314 (0.64%)
    2 / 181 (1.10%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasopressin Challenge Test Abnormal
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    White Blood Cell Count Increased
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Accelerated Idioventricular Rhythm
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Coronary Syndrome
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute Myocardial Infarction
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Angina Pectoris
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial Fibrillation
         subjects affected / exposed
    2 / 557 (0.36%)
    2 / 314 (0.64%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac Arrest
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Coronary Artery Disease
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Infarction
         subjects affected / exposed
    3 / 557 (0.54%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial Ischaemia
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    2 / 557 (0.36%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prinzmetal Angina
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinus Arrhythmia
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Congenital Cystic Kidney Disease
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Lung Injury
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal Septum Deviation
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oropharyngeal Pain
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngeal Oedema
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    2 / 181 (1.10%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 557 (0.36%)
    1 / 314 (0.32%)
    2 / 181 (1.10%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ataxia
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid Artery Aneurysm
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Carotid Artery Dissection
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebral Atrophy
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular Accident
         subjects affected / exposed
    1 / 557 (0.18%)
    3 / 314 (0.96%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Essential Tremor
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    1 / 31 (3.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intracranial Aneurysm
         subjects affected / exposed
    3 / 557 (0.54%)
    3 / 314 (0.96%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Ischaemic Stroke
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar Radiculopathy
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Occipital Neuralgia
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Polyneuropathy
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid Haemorrhage
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Transient Ischaemic Attack
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Retinal Detachment
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal Hernia
         subjects affected / exposed
    1 / 557 (0.18%)
    2 / 314 (0.64%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain
         subjects affected / exposed
    1 / 557 (0.18%)
    2 / 314 (0.64%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Lower
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal Pain Upper
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis Erosive
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ileus Paralytic
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Inguinal Hernia
         subjects affected / exposed
    5 / 557 (0.90%)
    3 / 314 (0.96%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal Fistula
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Large Intestine Polyp
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised Intraabdominal Fluid Collection
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Acute
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis Necrotising
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Umbilical Hernia
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute Kidney Injury
         subjects affected / exposed
    2 / 557 (0.36%)
    3 / 314 (0.96%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus Ureteric
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Calculus Urinary
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Kidney Disease
         subjects affected / exposed
    5 / 557 (0.90%)
    2 / 314 (0.64%)
    2 / 181 (1.10%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 2
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephropathy
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cyst
         subjects affected / exposed
    2 / 557 (0.36%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cyst Haemorrhage
         subjects affected / exposed
    6 / 557 (1.08%)
    4 / 314 (1.27%)
    2 / 181 (1.10%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 4
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cyst Ruptured
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Failure
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Haemorrhage
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Impairment
         subjects affected / exposed
    6 / 557 (1.08%)
    3 / 314 (0.96%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Pain
         subjects affected / exposed
    1 / 557 (0.18%)
    2 / 314 (0.64%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Incontinence
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urine Flow Decreased
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile Duct Stone
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Biliary Dyskinesia
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 557 (0.00%)
    2 / 314 (0.64%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis Acute
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Drug-Induced Liver Injury
         subjects affected / exposed
    0 / 557 (0.00%)
    2 / 314 (0.64%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhagic Hepatic Cyst
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    1 / 31 (3.23%)
         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
    Hepatic Cyst
         subjects affected / exposed
    4 / 557 (0.72%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Failure
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic Pain
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular Injury
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Portal Hypertension
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eczema
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hidradenitis
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bursitis
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chondropathy
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Flank Pain
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Foot Deformity
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral Disc Protrusion
         subjects affected / exposed
    2 / 557 (0.36%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loose Body In Joint
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain In Extremity
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Goitre
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypothyroidism
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Gout
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Abscess
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopulmonary Aspergillosis
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Catheter Site Infection
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Sinusitis
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Colitis
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Clostridium Difficile Infection
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea Infectious
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    2 / 557 (0.36%)
    1 / 314 (0.32%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Viral
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    2 / 181 (1.10%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Genital Herpes
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Kidney Infection
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar Pneumonia
         subjects affected / exposed
    2 / 557 (0.36%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mastitis
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pharyngitis Streptococcal
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Tuberculosis
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    6 / 557 (1.08%)
    1 / 314 (0.32%)
    2 / 181 (1.10%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal Cyst Infection
         subjects affected / exposed
    9 / 557 (1.62%)
    3 / 314 (0.96%)
    2 / 181 (1.10%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 3
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 557 (0.54%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper Respiratory Tract Infection
         subjects affected / exposed
    0 / 557 (0.00%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    1 / 31 (3.23%)
         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
    Ureteritis
         subjects affected / exposed
    0 / 557 (0.00%)
    0 / 314 (0.00%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary Tract Infection
         subjects affected / exposed
    4 / 557 (0.72%)
    1 / 314 (0.32%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    1 / 557 (0.18%)
    1 / 314 (0.32%)
    1 / 181 (0.55%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Viral Pericarditis
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Wound Infection
         subjects affected / exposed
    1 / 557 (0.18%)
    0 / 314 (0.00%)
    0 / 181 (0.00%)
    0 / 31 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Trial 2006-002768-24 Prior Tolvaptan Trial 2006-002768-24 Prior Placebo Other Trials Prior Tolvaptan Other Trials Prior Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    528 / 557 (94.79%)
    310 / 314 (98.73%)
    175 / 181 (96.69%)
    29 / 31 (93.55%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    160 / 557 (28.73%)
    82 / 314 (26.11%)
    42 / 181 (23.20%)
    2 / 31 (6.45%)
         occurrences all number
    195
    108
    45
    2
    Investigations
    Aspartate Aminotransferase Increased
         subjects affected / exposed
    19 / 557 (3.41%)
    5 / 314 (1.59%)
    7 / 181 (3.87%)
    2 / 31 (6.45%)
         occurrences all number
    25
    7
    7
    2
    Blood Creatinine Increased
         subjects affected / exposed
    96 / 557 (17.24%)
    39 / 314 (12.42%)
    20 / 181 (11.05%)
    2 / 31 (6.45%)
         occurrences all number
    113
    49
    25
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    42 / 557 (7.54%)
    23 / 314 (7.32%)
    10 / 181 (5.52%)
    0 / 31 (0.00%)
         occurrences all number
    51
    25
    10
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    35 / 557 (6.28%)
    20 / 314 (6.37%)
    13 / 181 (7.18%)
    0 / 31 (0.00%)
         occurrences all number
    39
    25
    13
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    30 / 557 (5.39%)
    36 / 314 (11.46%)
    13 / 181 (7.18%)
    1 / 31 (3.23%)
         occurrences all number
    35
    48
    15
    1
    Headache
         subjects affected / exposed
    75 / 557 (13.46%)
    56 / 314 (17.83%)
    20 / 181 (11.05%)
    2 / 31 (6.45%)
         occurrences all number
    152
    90
    23
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    53 / 557 (9.52%)
    54 / 314 (17.20%)
    32 / 181 (17.68%)
    2 / 31 (6.45%)
         occurrences all number
    66
    71
    41
    4
    Oedema Peripheral
         subjects affected / exposed
    51 / 557 (9.16%)
    32 / 314 (10.19%)
    9 / 181 (4.97%)
    1 / 31 (3.23%)
         occurrences all number
    67
    41
    11
    1
    Thirst
         subjects affected / exposed
    261 / 557 (46.86%)
    161 / 314 (51.27%)
    80 / 181 (44.20%)
    13 / 31 (41.94%)
         occurrences all number
    291
    196
    99
    21
    Gastrointestinal disorders
    Abdominal Pain
         subjects affected / exposed
    37 / 557 (6.64%)
    15 / 314 (4.78%)
    13 / 181 (7.18%)
    0 / 31 (0.00%)
         occurrences all number
    43
    17
    14
    0
    Abdominal Pain Upper
         subjects affected / exposed
    23 / 557 (4.13%)
    16 / 314 (5.10%)
    4 / 181 (2.21%)
    0 / 31 (0.00%)
         occurrences all number
    30
    20
    4
    0
    Constipation
         subjects affected / exposed
    23 / 557 (4.13%)
    25 / 314 (7.96%)
    8 / 181 (4.42%)
    1 / 31 (3.23%)
         occurrences all number
    25
    27
    10
    1
    Diarrhoea
         subjects affected / exposed
    60 / 557 (10.77%)
    30 / 314 (9.55%)
    13 / 181 (7.18%)
    2 / 31 (6.45%)
         occurrences all number
    78
    38
    14
    2
    Dry Mouth
         subjects affected / exposed
    45 / 557 (8.08%)
    44 / 314 (14.01%)
    25 / 181 (13.81%)
    4 / 31 (12.90%)
         occurrences all number
    54
    59
    30
    5
    Dyspepsia
         subjects affected / exposed
    29 / 557 (5.21%)
    15 / 314 (4.78%)
    8 / 181 (4.42%)
    0 / 31 (0.00%)
         occurrences all number
    29
    17
    8
    0
    Gastrooesophageal Reflux Disease
         subjects affected / exposed
    24 / 557 (4.31%)
    11 / 314 (3.50%)
    10 / 181 (5.52%)
    2 / 31 (6.45%)
         occurrences all number
    26
    12
    10
    2
    Nausea
         subjects affected / exposed
    42 / 557 (7.54%)
    32 / 314 (10.19%)
    22 / 181 (12.15%)
    2 / 31 (6.45%)
         occurrences all number
    60
    39
    28
    3
    Vomiting
         subjects affected / exposed
    32 / 557 (5.75%)
    15 / 314 (4.78%)
    9 / 181 (4.97%)
    2 / 31 (6.45%)
         occurrences all number
    42
    15
    14
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    47 / 557 (8.44%)
    36 / 314 (11.46%)
    13 / 181 (7.18%)
    4 / 31 (12.90%)
         occurrences all number
    68
    49
    23
    6
    Nocturia
         subjects affected / exposed
    145 / 557 (26.03%)
    111 / 314 (35.35%)
    94 / 181 (51.93%)
    17 / 31 (54.84%)
         occurrences all number
    156
    137
    113
    21
    Pollakiuria
         subjects affected / exposed
    30 / 557 (5.39%)
    24 / 314 (7.64%)
    20 / 181 (11.05%)
    4 / 31 (12.90%)
         occurrences all number
    32
    29
    26
    4
    Polyuria
         subjects affected / exposed
    231 / 557 (41.47%)
    175 / 314 (55.73%)
    111 / 181 (61.33%)
    22 / 31 (70.97%)
         occurrences all number
    264
    215
    128
    30
    Renal Cyst Ruptured
         subjects affected / exposed
    3 / 557 (0.54%)
    2 / 314 (0.64%)
    2 / 181 (1.10%)
    3 / 31 (9.68%)
         occurrences all number
    3
    2
    2
    3
    Renal Pain
         subjects affected / exposed
    147 / 557 (26.39%)
    90 / 314 (28.66%)
    43 / 181 (23.76%)
    7 / 31 (22.58%)
         occurrences all number
    260
    179
    78
    12
    Skin and subcutaneous tissue disorders
    Dry Skin
         subjects affected / exposed
    7 / 557 (1.26%)
    12 / 314 (3.82%)
    7 / 181 (3.87%)
    3 / 31 (9.68%)
         occurrences all number
    7
    12
    7
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    57 / 557 (10.23%)
    16 / 314 (5.10%)
    13 / 181 (7.18%)
    1 / 31 (3.23%)
         occurrences all number
    84
    23
    14
    1
    Back Pain
         subjects affected / exposed
    60 / 557 (10.77%)
    40 / 314 (12.74%)
    15 / 181 (8.29%)
    0 / 31 (0.00%)
         occurrences all number
    77
    59
    18
    0
    Muscle Spasms
         subjects affected / exposed
    28 / 557 (5.03%)
    18 / 314 (5.73%)
    5 / 181 (2.76%)
    1 / 31 (3.23%)
         occurrences all number
    35
    20
    5
    1
    Pain In Extremity
         subjects affected / exposed
    38 / 557 (6.82%)
    11 / 314 (3.50%)
    7 / 181 (3.87%)
    2 / 31 (6.45%)
         occurrences all number
    42
    11
    7
    4
    Metabolism and nutrition disorders
    Decreased Appetite
         subjects affected / exposed
    5 / 557 (0.90%)
    13 / 314 (4.14%)
    12 / 181 (6.63%)
    1 / 31 (3.23%)
         occurrences all number
    5
    13
    12
    1
    Gout
         subjects affected / exposed
    35 / 557 (6.28%)
    9 / 314 (2.87%)
    6 / 181 (3.31%)
    0 / 31 (0.00%)
         occurrences all number
    54
    12
    7
    0
    Hyperuricaemia
         subjects affected / exposed
    37 / 557 (6.64%)
    15 / 314 (4.78%)
    2 / 181 (1.10%)
    2 / 31 (6.45%)
         occurrences all number
    43
    18
    2
    2
    Polydipsia
         subjects affected / exposed
    62 / 557 (11.13%)
    51 / 314 (16.24%)
    38 / 181 (20.99%)
    6 / 31 (19.35%)
         occurrences all number
    66
    57
    39
    6
    Vitamin D Deficiency
         subjects affected / exposed
    34 / 557 (6.10%)
    16 / 314 (5.10%)
    13 / 181 (7.18%)
    4 / 31 (12.90%)
         occurrences all number
    36
    16
    14
    4
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    30 / 557 (5.39%)
    17 / 314 (5.41%)
    4 / 181 (2.21%)
    1 / 31 (3.23%)
         occurrences all number
    37
    23
    4
    2
    Gastroenteritis
         subjects affected / exposed
    31 / 557 (5.57%)
    20 / 314 (6.37%)
    9 / 181 (4.97%)
    2 / 31 (6.45%)
         occurrences all number
    37
    22
    11
    2
    Gastroenteritis Viral
         subjects affected / exposed
    12 / 557 (2.15%)
    7 / 314 (2.23%)
    6 / 181 (3.31%)
    2 / 31 (6.45%)
         occurrences all number
    16
    10
    7
    2
    Influenza
         subjects affected / exposed
    42 / 557 (7.54%)
    25 / 314 (7.96%)
    18 / 181 (9.94%)
    1 / 31 (3.23%)
         occurrences all number
    48
    30
    21
    1
    Nasopharyngitis
         subjects affected / exposed
    83 / 557 (14.90%)
    55 / 314 (17.52%)
    18 / 181 (9.94%)
    4 / 31 (12.90%)
         occurrences all number
    130
    90
    28
    4
    Sinusitis
         subjects affected / exposed
    40 / 557 (7.18%)
    19 / 314 (6.05%)
    13 / 181 (7.18%)
    1 / 31 (3.23%)
         occurrences all number
    48
    27
    20
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    61 / 557 (10.95%)
    35 / 314 (11.15%)
    28 / 181 (15.47%)
    2 / 31 (6.45%)
         occurrences all number
    110
    52
    44
    3
    Urinary Tract Infection
         subjects affected / exposed
    61 / 557 (10.95%)
    33 / 314 (10.51%)
    16 / 181 (8.84%)
    4 / 31 (12.90%)
         occurrences all number
    89
    51
    27
    4

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Jun 2011
    Amendment 1 (dated 02 Jun 2011) added safety laboratory tests at 3-month intervals between the 6-month scheduled visits, added guidance to investigators regarding the work up of potential Hy’s criteria cases, and revised the statistical approach to the disease modification analysis. Additional changes were made that did not have a major impact on trial conduct. Minor procedural changes included a modification of titration instructions to allow all participants to titrate to the highest dose tolerated regardless of previous trial dosing; the addition of eGFR calculation by CKD-EPI equation; extension of trial enrollment at the sponsor’s discretion; change to entry criteria to allow participants who were unable to complete prior trials due to exceptional circumstances making them eligible for enrollment beginning in January 2012, with permission of the sponsor and approval of the medical monitor (these participants had to complete enrollment by May 2012); change to entry criteria to extend the timing of screening eGFR; and combining of the entry exclusion criterion regarding marketed therapies affecting PKD cysts with the efficacy exclusion criterion of medications or illnesses likely to confound endpoint assessments.
    19 Feb 2013
    Amendment 2 (dated 19 Feb 2013) clarified that hepatitis testing at screening was optional and that participants who chose to undergo hepatitis testing might receive appropriate pre- and post-screening counseling as per local requirements and best practices. It also clarified procedures for the inclusion and ongoing care of participants with eGFR < 30 mL/min/1.73m2 (by MDRD). It also specified the SAEs that were considered related to the underlying ADPKD being studied in the trial and, therefore, might not be reported to regulatory authorities as expedited reports. Amendment 2 also added the option to include the following evaluations to the protocol-specified chemistry panel if clinically indicated and approved by the medical monitor: serum calcium, phosphorous, parathyroid hormone, vitamin D, and bicarbonate levels. It also added serum laboratory tests at 1-month (± 1 week) intervals up to Month 18 between the scheduled 6-month visits rather than at 3-month intervals and reporting of product quality complaints. It clarified that sites would receive only the TKV assessment following each MRI evaluation, and trial participation options after participants discontinued tolvaptan. The exploratory endpoints of progressing hypertension and worsening albuminuria were removed.
    11 Mar 2014
    Amendment 3 (dated 11 Mar 2014) incorporated provisions for participants who terminated from this trial early to continue on tolvaptan treatment (under this protocol) until a subsequent trial was ready to screen and enroll participants. The exact dates for trial completion varied among sites, according to the approval dates of the individual country IRB/IECs for sites, but the trial was expected to be completed by 31 Dec 2014. Safety information for the overall program was updated, specifically the possible clinical importance of elevated hepatic transaminase levels as early indicators of hepatic toxicity. Amendment 3 also provided additional information on DNA genotyping, clarified information on the need for an MRI  24 months on treatment, and established a lower titrated dose, on a case-by-case basis, with prior consultation and approval of the medical monitor. Administrative Change 1 (dated 01 May 2014) was made primarily to restore the list of Institutions Concerned with the Trial (contained in Appendix 2 of the protocol), plus 2 additional institutions, as the former was accidentally deleted from the existing, approved amendment during the development of Amendment 3. Names of sponsor personnel listed in protocol Appendix 1 were updated to clearly depict administrative changes, and minor editorial changes were also made.

    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.
    The trial did not meet its primary endpoint as both groups showed similar decreases in the rate of TKV growth due in part to unforeseen limitations in the trial design. However, early-treatment resulted in cumulative improvements in renal function.
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