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    Clinical Trial Results:
    A Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Assess the Efficacy and Safety of AMG 416 in the Treatment of Secondary Hyperparathyroidism in Subjects With Chronic Kidney Disease on Hemodialysis

    Summary
    EudraCT number
    		 2012-002806-31
    Trial protocol
    		 BE   CZ   IT   ES   SE   HU   PL   NL   DE  
    Global end of trial date
    12 May 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Jun 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20120230 (KAI-4169-007)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01788046
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Amgen, Inc.
    Sponsor organisation address
    One Amgen Center Drive, Thousand Oaks, CA, United States, 91320
    Public contact
    IHQ Medical Info – Clinical Trials, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com
    Scientific contact
    IHQ Medical Info – Clinical Trials, Amgen (EUROPE) GmbH, MedinfoInternational@amgen.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 May 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 May 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of AMG 416 compared with placebo for reducing the serum intact parathyroid hormone level (iPTH) by > 30%.
    Protection of trial subjects
    This study was conducted in accordance with applicable country regulations and International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) regulations/guidelines. All subjects provided written informed consent before undergoing any study-related procedures, including screening procedures. The study protocol, amendments, and the informed consent form (ICF) were reviewed by the Institutional Review Boards (IRBs) and Independent Ethics Committees (IECs). No subjects were recruited into the study and no investigational product (IP) was shipped until the IRB/IEC gave written approval of the protocol and ICF and Amgen received copies of these approvals.
    Background therapy
    		 All subjects, regardless of treatment assignment, received standard of care, which could have included calcium supplements, vitamin D sterols, nutritional vitamin D, and phosphate binders, as prescribed by the individual investigator.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Mar 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 12
    Country: Number of subjects enrolled
    Poland: 35
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    Czech Republic: 16
    Country: Number of subjects enrolled
    Germany: 1
    Country: Number of subjects enrolled
    Hungary: 25
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Canada: 13
    Country: Number of subjects enrolled
    United States: 283
    Country: Number of subjects enrolled
    Australia: 17
    Country: Number of subjects enrolled
    France: 16
    Country: Number of subjects enrolled
    Israel: 9
    Country: Number of subjects enrolled
    Russian Federation: 20
    Worldwide total number of subjects
    515
    EEA total number of subjects
    173
    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)
    334
    From 65 to 84 years
    171
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 97 centers in the US, Canada, Europe, Israel, the Russian Federation, and Australia. The first subject was enrolled on 12 March 2013, and the last subject 07 October 2013.

    Pre-assignment
    Screening details
    		 Prior to randomization, subjects entered a screening period of up to 8 weeks to determine eligibility. Eligible subjects were randomized 1:1 to receive AMG 416 or placebo. Randomization was stratified by screening PTH (< 600 pg/mL, 600 to ≤ 1000 pg/mL, and > 1000 pg/mL), prior cinacalcet use and region (North America or non North America).

    Period 1
    Period 1 title
    Overall study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Subjects received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Administered intravenously (IV) three times per week.

    Arm title
    		 AMG 416
    Arm description
    		 Subjects received AMG 416 administered by intravenous bolus injection at the end of each hemodialysis session TIW for 26 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AMG 416
    Investigational medicinal product code
    AMG 416
    Other name
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    Administered intravenously three times per week. The starting dose of AMG 416 was 5 mg. The dose may have been increased at 4-week intervals by 2.5 mg or 5 mg on the basis of the predialysis PTH and corrected calcium concentrations obtained in the prior week. The maximum dose was 15 mg.

    Number of subjects in period 1
    		Placebo AMG 416
    Started
    260
    255
    Received Treatment
    259
    252
    Completed
    204
    218
    Not completed
    56
    37
         Consent withdrawn by subject
    12
    12
         Protocol specified criteria
    25
    1
         Death
    7
    5
         Lost to follow-up
    12
    19

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.

    Reporting group title
    AMG 416
    Reporting group description
    		 Subjects received AMG 416 administered by intravenous bolus injection at the end of each hemodialysis session TIW for 26 weeks.

    Reporting group values
    		 Placebo AMG 416 Total
    Number of subjects
    		 260 255 515
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59 ( 13.9 ) 58.4 ( 14.6 ) -
    Gender categorical
    Units: Subjects
        Female
    		 95 93 188
        Male
    		 165 162 327
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 6 13 19
        Black (or African American)
    		 80 64 144
        Native Hawaiian or Other Pacific Islander
    		 3 7 10
        White
    		 169 163 332
        Other
    		 2 6 8
        Missing
    		 0 2 2
    Mean screening serum intact parathroid hormone (iPTH)
    Units: Subjects
        < 600 pg/mL
    		 84 84 168
        >= 600 to <= 1000 pg/mL
    		 121 118 239
        > 1000 pg/mL
    		 55 53 108
    Recent cinacalcet use within 8 weeks prior to randomization
    Units: Subjects
        Yes
    		 33 29 62
        No
    		 227 226 453
    Region
    Units: Subjects
        North America
    		 150 146 296
        Non-North America
    		 110 109 219
    Parathyroid hormone
    Units: pg/mL
        arithmetic mean (standard deviation)
    		 851.7 ( 552 ) 845 ( 464.3 ) -
    Corrected calcium (cCa)
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 9.7 ( 0.69 ) 9.63 ( 0.65 ) -
    Phosphorus
    Data available for 257 and 251 subjects in each treatment group respectively
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 5.83 ( 1.45 ) 5.76 ( 1.6 ) -
    Corrected calcium phosphorus product (cCa x P)
    Data available for 257 and 251 subjects in each treatment group respectively
    Units: mg²/dL²
        arithmetic mean (standard deviation)
    		 56.37 ( 14.5 ) 55.3 ( 15.27 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.

    Reporting group title
    AMG 416
    Reporting group description
    		 Subjects received AMG 416 administered by intravenous bolus injection at the end of each hemodialysis session TIW for 26 weeks.

    Primary: Percentage of Subjects With > 30% Decrease From Baseline in Mean PTH During the Efficacy Assessment Phase

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    End point title
    		 Percentage of Subjects With > 30% Decrease From Baseline in Mean PTH During the Efficacy Assessment Phase
    End point description
    Subjects who did not have any scheduled assessments during the EAP were considered as nonresponders.
    End point type
    Primary
    End point timeframe
    Baseline and the efficacy assessment phase (EAP; defined as Weeks 20 to 27, inclusive).
    End point values
    		 Placebo AMG 416
    Number of subjects analysed
    260 [1]
    255 [2]
    Units: percentage of subjects
        number (not applicable)
    9.6
    75.3
    Notes
    [1] - Full analysis set
    [2] - Full analysis set
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    A Cochran-Mantel-Haenszel test stratified by screening PTH category (< 600, ≥ 600 to ≤ 1000, and > 1000 pg/mL), recent cinacalcet use within 8 weeks before randomization (yes and no), and region (North America and non-North America) was used to compare the primary endpoint of proportion of subjects with > 30% reduction from baseline in PTH during the EAP between AMG 416 and placebo.
    Comparison groups
    Placebo v AMG 416
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    30.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.18
         upper limit
    		 52.17

    Secondary: Percentage of Subjects Achieving Mean PTH ≤ 300 pg/mL During the Efficacy Assessment Phase

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    End point title
    		 Percentage of Subjects Achieving Mean PTH ≤ 300 pg/mL During the Efficacy Assessment Phase
    End point description
    Subjects who had no scheduled assessments during the EAP were considered to be non-responders.
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (Week 20 to Week 27)
    End point values
    		 Placebo AMG 416
    Number of subjects analysed
    260
    255
    Units: percentage of subjects
        number (not applicable)
    4.6
    53.3
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    Stratification factors based on screening PTH level, prior cinacalcet use within 8 weeks prior to randomization, and region.
    Comparison groups
    Placebo v AMG 416
    Number of subjects included in analysis
    515
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    33.92
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 16.35
         upper limit
    		 70.37

    Secondary: Percent Change From Baseline in Predialysis PTH During the Efficacy Assessment Phase

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    End point title
    		 Percent Change From Baseline in Predialysis PTH During the Efficacy Assessment Phase
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and the Efficacy Assessment Phase (Week 20 to Week 27)
    End point values
    		 Placebo AMG 416
    Number of subjects analysed
    237 [3]
    227 [4]
    Units: percenyt change
        arithmetic mean (standard error)
    13.72 ( 2.5 )
    -57.39 ( 1.91 )
    Notes
    [3] - Full analysis set subjects with observed data
    [4] - Full analysis set subjects with observed data
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    Mixed-effects model includes treatment, stratification factors, visit, and treatment by visit interaction as covariates.
    Comparison groups
    Placebo v AMG 416
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference
    Point estimate
    -71.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -77.53
         upper limit
    		 -65.14
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.15

    Secondary: Percent Change From Baseline in Predialysis Corrected Calcium During the Efficacy Assessment Phase

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    End point title
    		 Percent Change From Baseline in Predialysis Corrected Calcium During the Efficacy Assessment Phase
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (Week 20 to Week 27)
    End point values
    		 Placebo AMG 416
    Number of subjects analysed
    237 [5]
    227 [6]
    Units: percent change
        arithmetic mean (standard error)
    0.58 ( 0.29 )
    -6.69 ( 0.55 )
    Notes
    [5] - Full analysis set subjects with observed data
    [6] - Full analysis set subjects with observed data
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    Mixed-effects model included treatment, stratification factors, visit, and treatment by visit interaction as covariates.
    Comparison groups
    Placebo v AMG 416
    Number of subjects included in analysis
    464
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference
    Point estimate
    -7.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.38
         upper limit
    		 -6.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.6

    Secondary: Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product During the Efficacy Assessment Phase

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    End point title
    		 Percent Change From Baseline in Predialysis Corrected Calcium Phosphorus Product During the Efficacy Assessment Phase
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (Week 20 to Week 27)
    End point values
    		 Placebo AMG 416
    Number of subjects analysed
    234 [7]
    223 [8]
    Units: percent change
        arithmetic mean (standard error)
    -1.06 ( 1.42 )
    -15.84 ( 1.57 )
    Notes
    [7] - Full analysis set subjects with observed data
    [8] - Full analysis set subjects with observed data
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    Mixed-effects model included treatment, stratification factors, visit, and treatment by visit interaction as covariates.
    Comparison groups
    Placebo v AMG 416
    Number of subjects included in analysis
    457
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference
    Point estimate
    -14.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -18.65
         upper limit
    		 -10.51
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.07

    Secondary: Percent Change From Baseline in Predialysis Phosphorus During the Efficacy Assessment Phase

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    End point title
    		 Percent Change From Baseline in Predialysis Phosphorus During the Efficacy Assessment Phase
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and the efficacy assessment phase (Week 20 to Week 27)
    End point values
    		 Placebo AMG 416
    Number of subjects analysed
    234 [9]
    223 [10]
    Units: percent change
        arithmetic mean (standard error)
    -1.6 ( 1.42 )
    -9.63 ( 1.61 )
    Notes
    [9] - Full analysis set subjects with available data
    [10] - Full analysis set subjects with available data
    Statistical analysis title
    		 Primary Analysis
    Statistical analysis description
    Mixed-effects model included treatment, stratification factors, visit, and treatment by visit interaction as covariates.
    Comparison groups
    Placebo v AMG 416
    Number of subjects included in analysis
    457
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference
    Point estimate
    -8.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.15
         upper limit
    		 -3.92
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.09

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 until 30 days after the last dose; the treatment period was 26 weeks.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17
    Reporting groups
    Reporting group title
    AMG 416
    Reporting group description
    		 Subjects received AMG 416 administered by intravenous bolus injection at the end of each hemodialysis session TIW for 26 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Subjects received placebo administered by intravenous bolus injection at the end of each hemodialysis session, three times per week (TIW) for 26 weeks.

    Serious adverse events
    		 AMG 416 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    62 / 252 (24.60%)
    71 / 259 (27.41%)
         number of deaths (all causes)
    4
    8
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oesophageal adenocarcinoma
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Accelerated hypertension
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant hypertension
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Poor peripheral circulation
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombophlebitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous stenosis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Finger amputation
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site haematoma
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia obstructive
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 252 (1.19%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Surgical failure
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 252 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 252 (0.79%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiogenic pulmonary oedema
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary congestion
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety disorder
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula aneurysm
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula occlusion
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site haematoma
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site haemorrhage
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Avulsion fracture
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burns second degree
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complications of transplanted kidney
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Face injury
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft complication
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative respiratory failure
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural vomiting
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin graft failure
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft complication
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft thrombosis
         subjects affected / exposed
    2 / 252 (0.79%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    3 / 252 (1.19%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis coronary artery
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block complete
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block right
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 252 (0.79%)
    4 / 259 (1.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Brain injury
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 252 (0.40%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic stroke
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hyperglycaemic seizure
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tremor
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unresponsive to stimuli
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Uraemic encephalopathy
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric antral vascular ectasia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Blister
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic neuropathic ulcer
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ulcer
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Palpable purpura
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin ulcer
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst haemorrhage
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure chronic
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Urethral stenosis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Primary hyperaldosteronism
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    0 / 252 (0.00%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle twitching
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Systemic lupus erythematosus
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial sepsis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Burn infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile sepsis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related sepsis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 252 (0.40%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster meningoencephalitis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral discitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meningitis aseptic
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metapneumovirus infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ophthalmic herpes zoster
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    0 / 252 (0.00%)
    3 / 259 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Periodontitis
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 252 (1.59%)
    10 / 259 (3.86%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 10
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative abscess
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatic abscess
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 252 (0.79%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Sepsis syndrome
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin graft infection
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection fungal
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral myocarditis
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Abnormal loss of weight
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    2 / 252 (0.79%)
    2 / 259 (0.77%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    6 / 252 (2.38%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hypervolaemia
         subjects affected / exposed
    1 / 252 (0.40%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    0 / 252 (0.00%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    2 / 252 (0.79%)
    0 / 259 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obesity
         subjects affected / exposed
    1 / 252 (0.40%)
    1 / 259 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 AMG 416 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    200 / 252 (79.37%)
    133 / 259 (51.35%)
    Investigations
    Blood calcium decreased
         subjects affected / exposed
    168 / 252 (66.67%)
    31 / 259 (11.97%)
         occurrences all number
    299
    35
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    16 / 252 (6.35%)
    12 / 259 (4.63%)
         occurrences all number
    18
    14
    Vascular disorders
    Hypertension
         subjects affected / exposed
    18 / 252 (7.14%)
    12 / 259 (4.63%)
         occurrences all number
    24
    17
    Hypotension
         subjects affected / exposed
    14 / 252 (5.56%)
    15 / 259 (5.79%)
         occurrences all number
    21
    18
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 252 (7.94%)
    11 / 259 (4.25%)
         occurrences all number
    21
    16
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 252 (3.17%)
    13 / 259 (5.02%)
         occurrences all number
    8
    18
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    35 / 252 (13.89%)
    25 / 259 (9.65%)
         occurrences all number
    40
    42
    Nausea
         subjects affected / exposed
    23 / 252 (9.13%)
    18 / 259 (6.95%)
         occurrences all number
    28
    21
    Vomiting
         subjects affected / exposed
    19 / 252 (7.54%)
    8 / 259 (3.09%)
         occurrences all number
    19
    8
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    10 / 252 (3.97%)
    15 / 259 (5.79%)
         occurrences all number
    10
    15
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    11 / 252 (4.37%)
    15 / 259 (5.79%)
         occurrences all number
    12
    15
    Back pain
         subjects affected / exposed
    14 / 252 (5.56%)
    9 / 259 (3.47%)
         occurrences all number
    17
    10
    Muscle spasms
         subjects affected / exposed
    28 / 252 (11.11%)
    16 / 259 (6.18%)
         occurrences all number
    47
    25
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    7 / 252 (2.78%)
    3 / 259 (1.16%)
         occurrences all number
    9
    3
    Upper respiratory tract infection
         subjects affected / exposed
    13 / 252 (5.16%)
    15 / 259 (5.79%)
         occurrences all number
    13
    16
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    17 / 252 (6.75%)
    0 / 259 (0.00%)
         occurrences all number
    17
    0

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Mar 2013
    - Allowed initiation of AMG 416 administration Monday-Friday, instead of the previous restriction of Wednesday or Thursday only. - Clarified that AMG 416 should not be administered subcutaneously or via any other route other than IV, and that it should not be administered concurrently with other IV medications. -Clarified that if suspended for symptomatic hypocalcemia, dosing should only resume after checking corrected calcium concentrations, in addition to the currently stated resolution of symptomatic hypocalcemia. - Allowed adjustment of vitamin D for hypocalcemia during the study. - Provided a recommended sequence of interventions for treating hypocalcemia with reference to modification of oral calcium supplements, dialysate calcium concentration, and then vitamin D. - Provided a sample “Serious Adverse Event Form” as Appendix D - Pregnancy testing for women of childbearing potential was increased from the previous 2 times in total (before study start and at end of study), to be 4 times in total (every 12 weeks).
    04 Sep 2013
    - Removed requirement for male contraception in the entry criteria to reflect updated core risks and discomforts safety language - Included updated standard safety language on instructions for reporting serious adverse events after the 30-day follow-up visit - Included updated standard safety language on the shortened notification period for pregnancy and lactation reporting from the original 7 days to now be within 24 hours.

    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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