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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
    		 2012-002805-23
    Trial protocol
    		 HU   BE   CZ   GB   IT   DE   ES   AT  
    Global end of trial date
    12 Jun 2014

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

    Trial information

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    Trial identification
    Sponsor protocol code
    20120229 (KAI-4169-006)
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01785849
    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 Jun 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Jun 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy and safety of AMG 416 in the treatment of secondary hyperparathyroidism (SHPT) in subjects with chronic kidney disease (CKD) on hemodialysis. Primary: 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
    Poland: 23
    Country: Number of subjects enrolled
    Spain: 34
    Country: Number of subjects enrolled
    United Kingdom: 10
    Country: Number of subjects enrolled
    Austria: 10
    Country: Number of subjects enrolled
    Belgium: 23
    Country: Number of subjects enrolled
    Czech Republic: 18
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Hungary: 27
    Country: Number of subjects enrolled
    Italy: 19
    Country: Number of subjects enrolled
    Canada: 11
    Country: Number of subjects enrolled
    United States: 250
    Country: Number of subjects enrolled
    Australia: 15
    Country: Number of subjects enrolled
    Israel: 6
    Country: Number of subjects enrolled
    Russian Federation: 38
    Worldwide total number of subjects
    508
    EEA total number of subjects
    188
    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)
    332
    From 65 to 84 years
    166
    85 years and over
    10

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted at 111 centers in the US, Canada, Europe, Israel, Russian Federation, and Australia. The first subject was enrolled on 12 March 2013 and the last subject enrolled on 08 November 2013.

    Pre-assignment
    Screening details
    		 Before randomization, subjects entered a screening period of up to 8 weeks to determine eligibility. Eligible subjects were randomized in a ratio of 1:1 to AMG 416 or placebo. Randomization was stratified by mean 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
    Routes of administration
    Intravenous 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
    Routes of administration
    Intravenous 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 minimum dose was 2.5 mg and the maximum dose was 15 mg.

    Number of subjects in period 1
    		Placebo AMG 416
    Started
    254
    254
    Received Treatment
    254
    251
    Completed
    193
    220
    Not completed
    61
    34
         Consent withdrawn by subject
    15
    12
         Protocol specified criteria
    29
    1
         Death
    7
    9
         Lost to follow-up
    10
    11
         Sponsor decision
    -
    1

    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
    		 254 254 508
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 57.1 ± 14.5 58.4 ± 14.6 -
    Gender categorical
    Units: Subjects
        Female
    		 114 103 217
        Male
    		 140 151 291
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0
        Asian
    		 3 5 8
        Black (or African American)
    		 69 72 141
        Native Hawaiian or Other Pacific Islander
    		 2 0 2
        White
    		 175 173 348
        Other
    		 4 4 8
        Missing
    		 1 0 1
    Mean screening serum intact parathyroid hormone (iPTH)
    Units: Subjects
        < 600 pg/mL
    		 84 87 171
        >= 600 to <= 1000 pg/mL
    		 114 115 229
        > 1000 pg/mL
    		 56 52 108
    Recent cinacalcet use within 8 weeks prior to randomization
    Units: Subjects
        Yes
    		 34 33 67
        No
    		 220 221 441
    Region
    Units: Subjects
        North America
    		 129 132 261
        Non-North America
    		 125 122 247
    Parathyroid Hormone (PTH)
    Units: pg/mL
        arithmetic mean (standard deviation)
    		 819.7 ± 386 848.7 ± 520.4 -
    Corrected Calcium
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 9.61 ± 0.6 9.65 ± 0.66 -
    Phosphorus
    Data available for 250 subjects in each treatment group.
    Units: mg/dL
        arithmetic mean (standard deviation)
    		 5.78 ± 1.6 5.95 ± 1.59 -
    corrected calcium phosphorus product (cCa x P)
    Data available for 249 and 250 subjects in each treatment group respectively.
    Units: mg²/dL²
        arithmetic mean (standard deviation)
    		 55.54 ± 15.81 57.37 ± 15.51 -

    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
    254 [1]
    254 [2]
    Units: percentage of subjects
        number (not applicable)
    8.3
    74
    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
    AMG 416 v Placebo
    Number of subjects included in analysis
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    32.46
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 18.71
         upper limit
    		 56.31

    Secondary: Percentage of Subjects With Predialysis Parathyroid Hormone ≤ 300 pg/mL During the Efficacy Assessment Phase

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    End point title
    		 Percentage of Subjects With Predialysis Parathyroid Hormone ≤ 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
    254
    254
    Units: percentage of subjects
        number (not applicable)
    5.1
    49.6
    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
    508
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    22.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 11.47
         upper limit
    		 42.48

    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
    219 [3]
    229 [4]
    Units: percent change
        arithmetic mean (standard error)
    13 ± 2.81
    -55.11 ± 1.94
    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
    AMG 416 v Placebo
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference
    Point estimate
    -71.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -77.77
         upper limit
    		 -64.46
    Variability estimate
    Standard error of the mean
    Dispersion value
    3.39

    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
    219 [5]
    229 [6]
    Units: percent change
        arithmetic mean (standard error)
    1.18 ± 0.29
    -7.29 ± 0.53
    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 includes treatment, stratification factors, visit, and treatment by visit interaction as covariates.
    Comparison groups
    Placebo v AMG 416
    Number of subjects included in analysis
    448
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference
    Point estimate
    -8.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.52
         upper limit
    		 -7.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.58

    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
    213 [7]
    227 [8]
    Units: percent change
        arithmetic mean (standard error)
    -0.19 ± 1.44
    -14.34 ± 2.06
    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
    440
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference
    Point estimate
    -14.99
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.73
         upper limit
    		 -10.25
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.41

    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
    214 [9]
    227 [10]
    Units: percent change
        arithmetic mean (standard error)
    -1.31 ± 1.42
    -7.71 ± 2.16
    Notes
    [9] - Full analysis set subjects with observed data
    [10] - 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
    441
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.003
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference
    Point estimate
    -7.45
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.31
         upper limit
    		 -2.59
    Variability estimate
    Standard error of the mean
    Dispersion value
    2.47

    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
    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.

    Serious adverse events
    		 Placebo AMG 416
    Total subjects affected by serious adverse events
         subjects affected / exposed
    78 / 254 (30.71%)
    68 / 251 (27.09%)
         number of deaths (all causes)
    7
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Biliary cancer metastatic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bone giant cell tumour benign
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung neoplasm
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malignant melanoma
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         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
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure fluctuation
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Granulomatosis with polyangiitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive emergency
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery stenosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular rupture
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular stenosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous stenosis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         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
    Brain death
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Chills
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Device issue
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    2 / 254 (0.79%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 254 (1.18%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Ovarian cyst
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea exertional
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         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 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Delirium
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mental status changes
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    3 / 254 (1.18%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clavicle fracture
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Concussion
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (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
    2 / 254 (0.79%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Foot fracture
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Hip fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Limb injury
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral artery restenosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirenal haematoma
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative respiratory distress
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Scapula fracture
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft complication
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft thrombosis
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound secretion
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Sickle cell anaemia with crisis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 254 (0.39%)
    6 / 251 (2.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic valve stenosis
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    4 / 254 (1.57%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrioventricular block first degree
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradyarrhythmia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiac failure
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 254 (0.39%)
    3 / 251 (1.20%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Cardiogenic shock
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery disease
         subjects affected / exposed
    2 / 254 (0.79%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         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
    1 / 254 (0.39%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular fibrillation
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Ventricular tachycardia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    2 / 254 (0.79%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhagic cerebral infarction
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxic-ischaemic encephalopathy
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Neuropathy peripheral
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    4 / 254 (1.57%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bone marrow failure
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrogenic anaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Conjunctivitis allergic
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 254 (0.79%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal telangiectasia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematochezia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine polyp
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer haemorrhage
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tooth impacted
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Acute hepatic failure
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic hepatitis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Diabetic foot
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (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 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         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
    Arthritis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemarthrosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar spinal stenosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal pain
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous graft site infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile infection
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         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
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis bacterial
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gangrene
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 254 (0.00%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 influenza
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis acute
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    4 / 254 (1.57%)
    6 / 251 (2.39%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 254 (1.18%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Septic embolus
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 254 (0.39%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Staphylococcal sepsis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subacute endocarditis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         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 / 254 (0.79%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic ketoacidosis
         subjects affected / exposed
    1 / 254 (0.39%)
    0 / 251 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    5 / 254 (1.97%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    4 / 251 (1.59%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    2 / 254 (0.79%)
    2 / 251 (0.80%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 254 (0.00%)
    1 / 251 (0.40%)
         occurrences causally related to treatment / all
    0 / 0
    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
    		 Placebo AMG 416
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    110 / 254 (43.31%)
    194 / 251 (77.29%)
    Investigations
    Blood calcium decreased
         subjects affected / exposed
    21 / 254 (8.27%)
    153 / 251 (60.96%)
         occurrences all number
    26
    240
    Injury, poisoning and procedural complications
    Arteriovenous fistula site complication
         subjects affected / exposed
    14 / 254 (5.51%)
    11 / 251 (4.38%)
         occurrences all number
    18
    17
    Vascular disorders
    Hypertension
         subjects affected / exposed
    16 / 254 (6.30%)
    12 / 251 (4.78%)
         occurrences all number
    19
    21
    Hypotension
         subjects affected / exposed
    10 / 254 (3.94%)
    14 / 251 (5.58%)
         occurrences all number
    11
    14
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 254 (7.87%)
    18 / 251 (7.17%)
         occurrences all number
    26
    22
    Paraesthesia
         subjects affected / exposed
    3 / 254 (1.18%)
    13 / 251 (5.18%)
         occurrences all number
    5
    24
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    17 / 254 (6.69%)
    18 / 251 (7.17%)
         occurrences all number
    19
    18
    Nausea
         subjects affected / exposed
    13 / 254 (5.12%)
    31 / 251 (12.35%)
         occurrences all number
    20
    38
    Vomiting
         subjects affected / exposed
    18 / 254 (7.09%)
    25 / 251 (9.96%)
         occurrences all number
    23
    29
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    18 / 254 (7.09%)
    30 / 251 (11.95%)
         occurrences all number
    20
    36
    Pain in extremity
         subjects affected / exposed
    11 / 254 (4.33%)
    17 / 251 (6.77%)
         occurrences all number
    11
    21
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    13 / 254 (5.12%)
    11 / 251 (4.38%)
         occurrences all number
    15
    11
    Metabolism and nutrition disorders
    Hypocalcaemia
         subjects affected / exposed
    1 / 254 (0.39%)
    18 / 251 (7.17%)
         occurrences all number
    1
    19

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 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 cCa 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. - Change specification that postdialysis blood samples must be collected after the postdialysis ECG, to now be collected before the ECG sequence. - Expand the postdialysis ECG and blood sample collection window from the previous 15 to 30 minutes postdose, to now be 10 to 60 minutes postdose. - 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).
    03 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 - Removed blinding of postdialysis ECG results

    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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