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    Clinical Trial Results:
    A MULTICENTER, DOUBLE-BLIND, RANDOMIZED, PLACEBO-CONTROLLED STUDY TO EVALUATE THE SAFETY AND EFFICACY OF INTRAVENOUS CR845 IN HEMODIALYSIS PATIENTS WITH MODERATE-TO-SEVERE PRURITUS, WITH A 52-WEEK OPEN-LABEL EXTENSION

    Summary
    EudraCT number
    		 2018-001930-17
    Trial protocol
    		 HU   CZ   GB  
    Global end of trial date
    30 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Oct 2021
    First version publication date
    10 Oct 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CR845-CLIN3103
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03636269
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cara Therapeutics, Inc.
    Sponsor organisation address
    107 Elm Street, 9th Floor, Stamford, United States, 06902
    Public contact
    Regulatory Affairs, Icon clinical Research Ltd, 44 07831653684, markas.marriott@iconplc.com
    Scientific contact
    Regulatory Affairs, Icon clinical Research Ltd, 44 07831653684, markas.marriott@iconplc.com
    Sponsor organisation name
    Cara Therapeutics, Inc.
    Sponsor organisation address
    107 Elm Street, 9th Floor, Stamford, United States, 06902
    Public contact
    Cara Clinical Trials, Cara Therapeutics, Inc., 1 203-406-3700, Cara Therapeutics, Inc., 1 203-406-3700,
    Scientific contact
    Cara Clinical Trials, Cara Therapeutics, Inc., 1 203-406-3700, Cara Therapeutics, Inc., 1 203-406-3700,
    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
    30 Mar 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of IV CR845 at a dose of 0.5 mcg/kg compared to placebo in reducing the intensity of itch in hemodialysis patients with moderate-to-severe pruritus.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jul 2018
    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
    Canada: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 18
    Country: Number of subjects enrolled
    New Zealand: 3
    Country: Number of subjects enrolled
    Taiwan: 2
    Country: Number of subjects enrolled
    United States: 279
    Country: Number of subjects enrolled
    Poland: 69
    Country: Number of subjects enrolled
    United Kingdom: 20
    Country: Number of subjects enrolled
    Czechia: 3
    Country: Number of subjects enrolled
    Germany: 5
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Australia: 29
    Worldwide total number of subjects
    473
    EEA total number of subjects
    119
    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)
    300
    From 65 to 84 years
    167
    85 years and over
    6

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The Screening Visit will occur within 7 to 28 days prior to randomization to assess eligibility.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CR845
    Arm description
    		 The ITT Population consisted of 473 subjects randomized to study treatment, 237 to difelikefalin and 236 to placebo. The Double-blind Safety Population consisted of 471 randomized subjects who received at least 1 dose of double-blind study drug during the Double-blind Treatment Period; 235 of these subjects were treated with difelikefalin, and 236 were treated with placebo. Two subjects were randomized to difelikefalin but did not receive any study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    CR845
    Investigational medicinal product code
    Other name
    Difelikefalin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV Placebo administered after each dialysis session (3 times/week)

    Number of subjects in period 1
    		CR845 Placebo
    Started
    237
    236
    Completed
    206
    223
    Not completed
    31
    13
         Adverse event, serious fatal
    2
    1
         Consent withdrawn by subject
    5
    1
         Subject non-compliance
    1
    2
         Adverse event, non-fatal
    11
    6
         Eligibility (inclusion/exclusion criteria)
    2
    -
         other
    8
    3
         Lost to follow-up
    1
    -
         Lack of efficacy
    1
    -
    Period 2
    Period 2 title
    Open-label Period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 CR845
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    CR845
    Investigational medicinal product code
    Other name
    Difelikefalin
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    IV CR845 0.5 mcg/kg administered after each dialysis session (3 times/week)

    Number of subjects in period 2 [1]
    		CR845
    Started
    399
    Completed
    5
    Not completed
    394
         Adverse event, serious fatal
    13
         Consent withdrawn by subject
    11
         Administrative
    36
         Adverse event, non-fatal
    8
         Eligibility (inclusion/exclusion criteria)
    2
         other
    9
         Stop-unrelated to safety or lack of drug effect
    313
         Lack of efficacy
    2
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: A total of 399 subjects out of 473 randomized in the Double-blind Treatment Phase continued to the Open-label Phase, of whom 210 were previously randomized to the placebo group and 189 were previously randomized to the difelikefalin, respectively.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CR845
    Reporting group description
    		 The ITT Population consisted of 473 subjects randomized to study treatment, 237 to difelikefalin and 236 to placebo. The Double-blind Safety Population consisted of 471 randomized subjects who received at least 1 dose of double-blind study drug during the Double-blind Treatment Period; 235 of these subjects were treated with difelikefalin, and 236 were treated with placebo. Two subjects were randomized to difelikefalin but did not receive any study drug.

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 CR845 Placebo Total
    Number of subjects
    		 237 236 473
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.7 ( 13.11 ) 59.6 ( 13.07 ) -
    Gender categorical
    Units: Subjects
        Female
    		 100 97 197
        Male
    		 137 139 276

    End points

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    End points reporting groups
    Reporting group title
    CR845
    Reporting group description
    		 The ITT Population consisted of 473 subjects randomized to study treatment, 237 to difelikefalin and 236 to placebo. The Double-blind Safety Population consisted of 471 randomized subjects who received at least 1 dose of double-blind study drug during the Double-blind Treatment Period; 235 of these subjects were treated with difelikefalin, and 236 were treated with placebo. Two subjects were randomized to difelikefalin but did not receive any study drug.

    Reporting group title
    Placebo
    Reporting group description
    		 -
    Reporting group title
    CR845
    Reporting group description
    		 -

    Primary: Reduction of itch intensity as assessed by the proportion of patients achieving an improvement from baseline ≥3 points with respect to the weekly mean of the daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) score at Week 12

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    End point title
    		 Reduction of itch intensity as assessed by the proportion of patients achieving an improvement from baseline ≥3 points with respect to the weekly mean of the daily 24-hour Worst Itching Intensity Numerical Rating Scale (NRS) score at Week 12
    End point description
    End point type
    Primary
    End point timeframe
    Week 12
    End point values
    		 CR845 Placebo
    Number of subjects analysed
    237
    236
    Units: Percentage
        least squares mean (confidence interval 54%)
    54.0 (43.9 to 63.9)
    42.2 (32.5 to 52.5)
    Statistical analysis title
    		 LS means estimate of percent with improvement
    Statistical analysis description
    Estimated percentage, odds ratio and P value used a logistic regression model with terms for treatment group, baseline NRS score, region, use of anti-itch medication during the week prior to randomization, and the presence of specific medical conditions. Missing values were imputed using MI under MAR missing data assumption for interim subjects and post-interim subjects separately.
    Comparison groups
    CR845 v Placebo
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 CHW = Cui, Hung, Wang
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.08
         upper limit
    		 2.41

    Secondary: Reduction of itch intensity as assessed by the proportion of patients achieving an improvement from baseline ≥4 points with respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS score at Week 12

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    End point title
    		 Reduction of itch intensity as assessed by the proportion of patients achieving an improvement from baseline ≥4 points with respect to the weekly mean of the daily 24-hour Worst Itching Intensity NRS score at Week 12
    End point description
    End point type
    Secondary
    End point timeframe
    Week 12
    End point values
    		 CR845 Placebo
    Number of subjects analysed
    237 [1]
    236
    Units: Percentage
        least squares mean (confidence interval 41.2%)
    41.2 (33.0 to 55.0)
    28.4 (21.3 to 36.7)
    Notes
    [1] - 2 Subjects were randomized to CR845 but did not receive CR845
    Statistical analysis title
    		 LS means estimate of percent with improvement
    Comparison groups
    CR845 v Placebo
    Number of subjects included in analysis
    473
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.01
    Method
    		 Cui, Hung, Wang
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.77
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.14
         upper limit
    		 2.74

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The period of adverse event reporting started after the signing of the ICF through the study follow-up visit or early termination visit (or 7-10 days after the last dose if no early termination visit was conducted).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Subjects in CR845 Group in Double-blind Portion
    Reporting group description
    		 -

    Reporting group title
    Subjects in Placebo Group in Double-blind Portion
    Reporting group description
    		 -

    Reporting group title
    Subjects in CR845 Open-label Portion
    Reporting group description
    		 -

    Serious adverse events
    		 Subjects in CR845 Group in Double-blind Portion Subjects in Placebo Group in Double-blind Portion Subjects in CR845 Open-label Portion
    Total subjects affected by serious adverse events
         subjects affected / exposed
    58 / 235 (24.68%)
    51 / 236 (21.61%)
    130 / 399 (32.58%)
         number of deaths (all causes)
    2
    2
    15
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lung adenocarcinoma
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenocarcinoma of colon
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric neoplasm
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 235 (0.00%)
    5 / 236 (2.12%)
    5 / 399 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    3 / 235 (1.28%)
    1 / 236 (0.42%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 235 (0.00%)
    3 / 236 (1.27%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 235 (0.00%)
    2 / 236 (0.85%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dry gangrene
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Circulatory collapse
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Temporal arteritis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Varicose vein
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral artery occlusion
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Abdominal hernia repair
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter placement
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Multiple drug therapy
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    8 / 235 (3.40%)
    1 / 236 (0.42%)
    10 / 399 (2.51%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 1
    0 / 13
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 235 (0.85%)
    0 / 236 (0.00%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthenia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    5 / 399 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Peripheral swelling
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    4 / 235 (1.70%)
    2 / 236 (0.85%)
    5 / 399 (1.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 2
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 236 (0.42%)
    5 / 399 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 235 (0.43%)
    1 / 236 (0.42%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    2 / 235 (0.85%)
    0 / 236 (0.00%)
    7 / 399 (1.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary mass
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic respiratory failure
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemothorax
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental status changes
         subjects affected / exposed
    3 / 235 (1.28%)
    0 / 236 (0.00%)
    5 / 399 (1.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device malfunction
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chest X-ray abnormal
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Paracentesis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Weight decreased
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemoglobin decreased
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bleeding time prolonged
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    0 / 235 (0.00%)
    3 / 236 (1.27%)
    5 / 399 (1.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 236 (0.42%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular access malfunction
         subjects affected / exposed
    1 / 235 (0.43%)
    2 / 236 (0.85%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    6 / 399 (1.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous graft site haemorrhage
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous graft thrombosis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fibula fracture
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Thermal burn
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular access complication
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular graft complication
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula aneurysm
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall wound
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Femoral neck fracture
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fractured ischium
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haemodialysis complication
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ligament rupture
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular access site thrombosis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hand fracture
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 235 (0.43%)
    2 / 236 (0.85%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    2 / 235 (0.85%)
    0 / 236 (0.00%)
    5 / 399 (1.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 235 (0.43%)
    1 / 236 (0.42%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 2
    Cardiac failure
         subjects affected / exposed
    2 / 235 (0.85%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Acute coronary syndrome
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrioventricular block second degree
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiogenic shock
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Palpitations
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    Acute left ventricular failure
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    1 / 235 (0.43%)
    1 / 236 (0.42%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Amnesia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Delayed ischaemic neurological deficit
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Posterior reversible encephalopathy syndrome
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vertebrobasilar insufficiency
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 235 (0.85%)
    4 / 236 (1.69%)
    6 / 399 (1.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 235 (0.43%)
    2 / 236 (0.85%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 236 (0.42%)
    4 / 399 (1.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 235 (0.85%)
    0 / 236 (0.00%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    Alcoholic pancreatitis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Colitis ischaemic
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic gastroparesis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Duodenal ulcer perforation
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastric polyps
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incarcerated inguinal hernia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis chronic
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumoperitoneum
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rectal polyp
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Pneumobilia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute hepatic failure
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angioedema
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    End stage renal disease
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Nephrolithiasis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Flank pain
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arthralgia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    3 / 235 (1.28%)
    4 / 236 (1.69%)
    14 / 399 (3.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
    Cellulitis
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 236 (0.42%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 236 (0.42%)
    4 / 399 (1.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 236 (0.42%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 235 (0.85%)
    1 / 236 (0.42%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 235 (0.00%)
    2 / 236 (0.85%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    2 / 235 (0.85%)
    0 / 236 (0.00%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    3 / 235 (1.28%)
    0 / 236 (0.00%)
    22 / 399 (5.51%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Abscess limb
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site infection
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site cellulitis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Endocarditis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    3 / 399 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic cyst infection
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Incision site cellulitis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infectious mononucleosis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    4 / 399 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Skin infection
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    2 / 399 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subcutaneous abscess
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 235 (0.00%)
    1 / 236 (0.42%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal wall abscess
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Emphysematous cystitis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis Escherichia coli
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Perirectal abscess
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    0 / 399 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia escherichia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
         subjects affected / exposed
    4 / 235 (1.70%)
    3 / 236 (1.27%)
    4 / 399 (1.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    0 / 235 (0.00%)
    2 / 236 (0.85%)
    6 / 399 (1.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 235 (0.43%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Calciphylaxis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Decreased appetite
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diabetic ketosis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 235 (0.00%)
    0 / 236 (0.00%)
    1 / 399 (0.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Subjects in CR845 Group in Double-blind Portion Subjects in Placebo Group in Double-blind Portion Subjects in CR845 Open-label Portion
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 235 (23.83%)
    43 / 236 (18.22%)
    204 / 399 (51.13%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    14 / 235 (5.96%)
    11 / 236 (4.66%)
    52 / 399 (13.03%)
         occurrences all number
    15
    11
    61
    Vascular disorders
    Hypotension
         subjects affected / exposed
    9 / 235 (3.83%)
    4 / 236 (1.69%)
    25 / 399 (6.27%)
         occurrences all number
    10
    4
    40
    Hypertension
         subjects affected / exposed
    6 / 235 (2.55%)
    10 / 236 (4.24%)
    24 / 399 (6.02%)
         occurrences all number
    11
    17
    40
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 235 (5.11%)
    12 / 236 (5.08%)
    31 / 399 (7.77%)
         occurrences all number
    13
    14
    36
    Headache
         subjects affected / exposed
    10 / 235 (4.26%)
    6 / 236 (2.54%)
    20 / 399 (5.01%)
         occurrences all number
    10
    6
    21
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    18 / 235 (7.66%)
    12 / 236 (5.08%)
    45 / 399 (11.28%)
         occurrences all number
    22
    13
    55
    Vomiting
         subjects affected / exposed
    15 / 235 (6.38%)
    13 / 236 (5.51%)
    36 / 399 (9.02%)
         occurrences all number
    19
    14
    45
    Nausea
         subjects affected / exposed
    15 / 235 (6.38%)
    10 / 236 (4.24%)
    37 / 399 (9.27%)
         occurrences all number
    19
    11
    43
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    8 / 235 (3.40%)
    5 / 236 (2.12%)
    20 / 399 (5.01%)
         occurrences all number
    9
    5
    26
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 235 (1.28%)
    5 / 236 (2.12%)
    22 / 399 (5.51%)
         occurrences all number
    3
    5
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Feb 2019
    Update protocol to global amendment
    12 Jul 2019
    Modify the order of the secondary endpoints
    10 Sep 2019
    Analysis of treatment effect at specific early timepoints, Week 4 and Week 8, has been added as secondary efficacy endpoints, and an adjustment for multiplicity will be implemented to protect the overall Type 1 error. Change from baseline at Week 12 for the Skindex-10 Scale total score and the 5-D Itch Scale total score will be analyzed using an analysis of covariance (ANCOVA) model.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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