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    Clinical Trial Results:
    An Open-label, Randomised, Active-controlled, Parallel Group, Multicentre Phase 3 Study to Investigate the Long-term Safety, Tolerability and Efficacy of PA21 compared with Sevelamer Carbonate in Dialysis Patients with Hyperphosphataemia. Extension Study for Protocol PA-CL-05A.

    Summary
    EudraCT number
    		 2010-022012-40
    Trial protocol
    		 GB   CZ   LV   LT   SE   AT   DE   BE  
    Global end of trial date
    25 Oct 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    09 Dec 2016
    First version publication date
    09 Dec 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PA-CL-05B
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01464190
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Vifor (International) Inc.
    Sponsor organisation address
    Rechenstrasse 37, St. Gallen, Switzerland, CH-9001
    Public contact
    MedInfo, Vifor (Internationa) Inc., medinfo@viforpharma.com
    Scientific contact
    MedInfo, Vifor (Internationa) Inc., medinfo@viforpharma.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
    03 May 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Oct 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the trial are to assess the long-term safety and tolerability of PA21, compare the long-term serum phosphorus control of PA21 versus sevelamer and compare the safety and tolerability of PA21 versus sevelamer.
    Protection of trial subjects
    The study was conducted in accordance with the principles of the Declaration of Helsinki and in compliance with the International Conference on Harmonisation (ICH) E6 Guideline for Good Clinical Practice (GCP), the Committee for Proprietary Medicinal Products Guideline (CPMP/ICH/135/95), and the EU Clinical Trial Directive (Directive 2001/20/EC) and/or the Code of Federal Regulations (CFR) for informed consent and protection of patient rights (21 CFR, Parts 50 and 56). Before each subject was admitted to the study, a signed and dated informed consent was obtained from the subject (or his/her legally authorised representative). A copy of the document was provided to the subject. No investigations specifically required for the studies were conducted until valid consent was obtained. Subjects were informed that their participation in the study was entirely voluntary and would have no effect on clinical care otherwise available, and that they could withdraw consent to participate at any time without penalty or loss of further medical treatment. Subjects were told that competent authorities and authorised persons could examine their records but that personal information would be treated as strictly confidential and would not be publicly available. A Data and Safety Monitoring Board (DSMB) was formed to assess the progress, safety data and, if needed, critical efficacy endpoints of the study. The DSMB was composed of clinicians with expertise in relevant clinical specialties and at least 1 biostatistician knowledgeable about statistical methods for clinical trials and sequential analysis of trial data.
    Background therapy
    		 -
    Evidence for comparator
    		 Sevelamer carbonate was chosen as the active comparator as its active ingredient (sevelamer) is considered a standard treatment for hyperphosphataemia in patients undergoing dialysis. The sevelamer doses were based on its approved and commonly used doses.
    Actual start date of recruitment
    20 Sep 2011
    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
    Germany: 10
    Country: Number of subjects enrolled
    Austria: 11
    Country: Number of subjects enrolled
    Belgium: 2
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    Czech Republic: 39
    Country: Number of subjects enrolled
    Latvia: 9
    Country: Number of subjects enrolled
    Lithuania: 5
    Country: Number of subjects enrolled
    Poland: 31
    Country: Number of subjects enrolled
    United States: 287
    Country: Number of subjects enrolled
    Romania: 22
    Country: Number of subjects enrolled
    Croatia: 24
    Country: Number of subjects enrolled
    Russian Federation: 109
    Country: Number of subjects enrolled
    Serbia: 55
    Country: Number of subjects enrolled
    Ukraine: 47
    Country: Number of subjects enrolled
    South Africa: 3
    Worldwide total number of subjects
    659
    EEA total number of subjects
    158
    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)
    486
    From 65 to 84 years
    168
    85 years and over
    5

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted in 143 of the centres that conducted the PA-CL-05A study and these centres enrolled 659 subjects.

    Pre-assignment
    Screening details
    		 Subjects who had completed treatment in PA-CL-05A (Stage 1 or Stage 2, except subjects randomised to the PA21 low dose (LD) group of Stage 2) were eligible for the 28-week extension study. All eligible subjects continued to receive either PA21 or sevelamer according to their randomisation into PA-CL-05A and started at the dose being administered.

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 PA21
    Arm description
    		 PA21 chewable tablets containing 2.5 g of PA21. Dose range from 5.0 g/day (2 tablets/day) to 15.0 g/day (6 tablets/day).
    Arm type
    		 Experimental

    Investigational medicinal product name
    PA21
    Investigational medicinal product code
    Other name
    Mixture of polynuclear iron(III)-oxyhydroxide, sucrose and starches; Stabilised polynuclear iron oxyhydroxide
    Pharmaceutical forms
    Chewable tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The maximum dose was 15.0 g/day (6 tablets/day) and the minimum dose was 5.0 g/day (2 tablets/day). Dose adjustments for efficacy or tolerability reasons were permitted. Dose adjustments of 2.5 g/day (one 2.5 g tablet/day) were allowed.

    Arm title
    		 Sevelamer carbonate
    Arm description
    		 Sevelamer carbonate, Renvela® tablets containing 800 mg of sevelamer carbonate.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Sevelamer carbonate
    Investigational medicinal product code
    Other name
    Poly(allylamine-co-N,N’-diallyl-1,3-diamino-2- hydroxypropane) carbonate salt
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The maximum dose of sevelamer was 14.4 g/day (18 tablets/day) and the minimum dose was 2.4 g/day (3 tablets/day). Dose adjustments for efficacy or tolerability reasons were permitted. Dose adjustments of 2.4 g/day (three 800 mg tablets/day (1 tablet/meal)) were allowed.

    Number of subjects in period 1
    		PA21 Sevelamer carbonate
    Started
    391
    268
    Completed
    322
    227
    Not completed
    69
    41
         Adverse event, serious fatal
    6
    5
         Consent withdrawn by subject
    9
    8
         Physician decision
    6
    3
         Renal Transplant
    11
    7
         Adverse event, non-fatal
    17
    4
         Transferred to another facility
    1
    1
         Predefined criteria within protocol
    14
    7
         Sponsor decision
    -
    3
         Protocol deviation
    5
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PA21
    Reporting group description
    		 PA21 chewable tablets containing 2.5 g of PA21. Dose range from 5.0 g/day (2 tablets/day) to 15.0 g/day (6 tablets/day).

    Reporting group title
    Sevelamer carbonate
    Reporting group description
    		 Sevelamer carbonate, Renvela® tablets containing 800 mg of sevelamer carbonate.

    Reporting group values
    		 PA21 Sevelamer carbonate Total
    Number of subjects
    		 391 268 659
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 296 190 486
        From 65-84 years
    		 93 75 168
        85 years and over
    		 2 3 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 55.2 ± 13.2 55.6 ± 14.6 -
    Gender categorical
    Units: Subjects
        Female
    		 171 103 274
        Male
    		 220 165 385

    End points

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    End points reporting groups
    Reporting group title
    PA21
    Reporting group description
    		 PA21 chewable tablets containing 2.5 g of PA21. Dose range from 5.0 g/day (2 tablets/day) to 15.0 g/day (6 tablets/day).

    Reporting group title
    Sevelamer carbonate
    Reporting group description
    		 Sevelamer carbonate, Renvela® tablets containing 800 mg of sevelamer carbonate.

    Subject analysis set title
    Full analysis set for PA-CL-05B (FAS5B)
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    FAS5B included subjects who received at least 1 dose of PA-CL-05B study medication and had at least 1 evaluable efficacy assessment during PA-CL-05B.

    Primary: Serum Phosphorus Change from PA-CL-05B Baseline at Key Time Points

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    End point title
    		 Serum Phosphorus Change from PA-CL-05B Baseline at Key Time Points
    End point description
    The changes from PA-CL-05B baseline in serum phosphorus levels at each PA-CL-05B visit (observed cases) and at endpoint (last observation on treatment) were also compared between the PA21 and sevelamer groups with an analysis of covariance (ANCOVA) using baseline phosphorus level, region and dialysis status as covariates. All tests were at the alpha 0.05 level with no adjustments made for the multiplicity of tests. 95% confidence intervals of the difference in the serum phosphorus levels between the PA21 and sevelamer groups were calculated. The FAS5B set was considered (N=644; PA21:384 and sevelamer:260).
    End point type
    Primary
    End point timeframe
    Extension baseline (Week 0), and Weeks 4, 8, 12, 16, 20, 24 and 28. They correspond to Weeks 24, 28, 32, 36, 40, 44, 48 and 52 of the integrated studies PA-CL-05A and PA-CL-05B.
    End point values
    		 PA21 Sevelamer carbonate
    Number of subjects analysed
    391
    268
    Units: mg/dL
    least squares mean (standard error)
        Extension Week 4 (Week 28), N=582
    -0.25 ± 0.1
    -0.27 ± 0.11
        Extension Week 8 (Week 32), N=563
    -0.21 ± 0.1
    0.04 ± 0.12
        Extension Week 12 (Week 36), N=564
    -0.1 ± 0.11
    0.09 ± 0.12
        Extension Week 16 (Week 40), N=541
    0.01 ± 0.12
    0.16 ± 0.14
        Extension Week 20 (Week 44), N=521
    -0.05 ± 0.11
    0.1 ± 0.13
        Extension Week 24 (Week 48), N=494
    0.03 ± 0.12
    0.12 ± 0.14
        Extension Week 28 (Week 52), N=497
    0.13 ± 0.12
    0.08 ± 0.14
        Endpoint, N=644
    0.01 ± 0.11
    0.14 ± 0.13
    Statistical analysis title
    		 Contrast ANCOVA - Extension Week 4 (Week 28)
    Statistical analysis description
    Comparison: PA21 v Sevelamer carbonate
    Comparison groups
    PA21 v Sevelamer carbonate
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.878
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.19
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [1] - Exploratory analysis. N for this analysis was 582. A mixed-effect model for repeated measures/missing at random (MMRM-MAR) assumption model was run for sensitivity purpose and similar results were obtained.
    Statistical analysis title
    		 Contrast ANCOVA - Extension Week 8 (Week 32)
    Comparison groups
    PA21 v Sevelamer carbonate
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    		 other [2]
    P-value
    		 = 0.026
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.46
         upper limit
    		 -0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [2] - Exploratory analysis. N for this analysis was 563. A MMRM-MAR assumption model was run for sensitivity purpose and similar results were obtained.
    Statistical analysis title
    		 Contrast ANCOVA - Extension Week 12 (Week 36)
    Comparison groups
    PA21 v Sevelamer carbonate
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.092
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.41
         upper limit
    		 0.03
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [3] - Exploratory analysis. N for this analysis was 564. A MMRM-MAR assumption model was run for sensitivity purpose and similar results were obtained.
    Statistical analysis title
    		 Contrast ANCOVA - Extension Week 16 (Week 40)
    Comparison groups
    PA21 v Sevelamer carbonate
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.231
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.4
         upper limit
    		 0.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Notes
    [4] - Exploratory analysis. N for this analysis was 541. A MMRM-MAR assumption model was run for sensitivity purpose and similar results were obtained.
    Statistical analysis title
    		 Contrast ANCOVA - Extension Week 20 (Week 44)
    Comparison groups
    PA21 v Sevelamer carbonate
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.182
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.37
         upper limit
    		 0.07
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.11
    Notes
    [5] - Exploratory analysis. N for this analysis was 521. A MMRM-MAR assumption model was run for sensitivity purpose and similar results were obtained.
    Statistical analysis title
    		 Contrast ANCOVA - Extension Week 24 (Week 48)
    Comparison groups
    PA21 v Sevelamer carbonate
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.47
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 0.16
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Notes
    [6] - Exploratory analysis. N for this analysis was 494. A MMRM-MAR assumption model was run for sensitivity purpose and similar results were obtained.
    Statistical analysis title
    		 Contrast ANCOVA - Extension Week 28 (Week 52)
    Comparison groups
    PA21 v Sevelamer carbonate
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.705
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 0.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.13
    Notes
    [7] - Exploratory analysis. N for this analysis was 497. A MMRM-MAR assumption model was run for sensitivity purpose and similar results were obtained.
    Statistical analysis title
    		 Contrast ANCOVA - Endpoint
    Comparison groups
    PA21 v Sevelamer carbonate
    Number of subjects included in analysis
    659
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.293
    Method
    		 ANCOVA
    Parameter type
    		 least squares mean
    Point estimate
    -0.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 0.11
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.12
    Notes
    [8] - Exploratory analysis. N for this analysis was 644. A MMRM-MAR assumption model was run for sensitivity purpose and similar results were obtained.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the signing of informed consent. The AE reporting period ended at the study follow-up visit, 14 days following the last intake of study medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    PA21
    Reporting group description
    		 PA21 (2.5 g tablet). Dose range of 5.0 g/day (2tablets/day) to 15.0 g/day (6 tablets/day).

    Reporting group title
    Sevelamer carbonate
    Reporting group description
    		 -

    Serious adverse events
    		 PA21 Sevelamer carbonate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    78 / 391 (19.95%)
    52 / 267 (19.48%)
         number of deaths (all causes)
    7
    7
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Colon cancer
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung squamous cell carcinoma stage unspecified
         subjects affected / exposed
    1 / 391 (0.26%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transitional cell carcinoma
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma stage IV
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Haematoma
         subjects affected / exposed
    4 / 391 (1.02%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial stenosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial thrombosis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriosclerosis
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Circulatory collapse
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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
    1 / 391 (0.26%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aneurysm ruptured
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Aortic aneurysm
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intermittent claudication
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subclavian artery stenosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         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 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Arteriovenous graft
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal operation
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         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
    Chest pain
         subjects affected / exposed
    3 / 391 (0.77%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device occlusion
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device complication
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis in device
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menorrhagia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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
    Pulmonary oedema
         subjects affected / exposed
    2 / 391 (0.51%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 267 (0.37%)
         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 / 391 (0.26%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary alveolar haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis chronic
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    International normalised ratio increased
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Troponin increased
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Vascular graft thrombosis
         subjects affected / exposed
    3 / 391 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    2 / 391 (0.51%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Accidental overdose
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Operative haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Procedural hypotension
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pubis fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft occlusion
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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 haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Arteriovenous graft site haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         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 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirenal haematoma
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal compression fracture
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    3 / 391 (0.77%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 391 (0.26%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bradycardia
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Left ventricular failure
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Myocardial ischaemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         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
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiomyopathy
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Supraventricular tachycardia
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         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
    3 / 391 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral infarction
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular disorder
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhage intracranial
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic encephalopathy
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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 / 391 (0.00%)
    1 / 267 (0.37%)
         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
    1 / 391 (0.26%)
    3 / 267 (1.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemolysis
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocoagulable state
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vestibular disorder
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Eye haemorrhage
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Peritonitis
         subjects affected / exposed
    3 / 391 (0.77%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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 / 391 (0.26%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric disorder
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mallory-Weiss syndrome
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 391 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal obstruction
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    3 / 391 (0.77%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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 / 391 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gallbladder perforation
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal cyst ruptured
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal mass
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         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
    Osteoarthritis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    6 / 391 (1.53%)
    6 / 267 (2.25%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 6
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 391 (0.77%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gangrene
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    2 / 391 (0.51%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Catheter site infection
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    1 / 391 (0.26%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia haemophilus
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdiaphragmatic abscess
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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
    1 / 391 (0.26%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis perforated
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterococcal bacteraemia
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Groin abscess
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint abscess
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonsillar abscess
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         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
    0 / 391 (0.00%)
    2 / 267 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Thrombophlebitis septic
         subjects affected / exposed
    0 / 391 (0.00%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Fluid overload
         subjects affected / exposed
    4 / 391 (1.02%)
    6 / 267 (2.25%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 391 (0.51%)
    1 / 267 (0.37%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Diabetic foot
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fluid retention
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 391 (0.26%)
    0 / 267 (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 / 391 (0.26%)
    0 / 267 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 PA21 Sevelamer carbonate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    280 / 391 (71.61%)
    197 / 267 (73.78%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    38 / 391 (9.72%)
    20 / 267 (7.49%)
         occurrences all number
    53
    29
    Hypotension
         subjects affected / exposed
    19 / 391 (4.86%)
    20 / 267 (7.49%)
         occurrences all number
    37
    36
    Nervous system disorders
    Headache
         subjects affected / exposed
    20 / 391 (5.12%)
    8 / 267 (3.00%)
         occurrences all number
    28
    19
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    14 / 391 (3.58%)
    14 / 267 (5.24%)
         occurrences all number
    15
    14
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    31 / 391 (7.93%)
    14 / 267 (5.24%)
         occurrences all number
    42
    18
    Nausea
         subjects affected / exposed
    23 / 391 (5.88%)
    11 / 267 (4.12%)
         occurrences all number
    26
    12
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    15 / 391 (3.84%)
    23 / 267 (8.61%)
         occurrences all number
    15
    24
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    26 / 391 (6.65%)
    16 / 267 (5.99%)
         occurrences all number
    39
    20
    Metabolism and nutrition disorders
    Hyperphosphataemia
         subjects affected / exposed
    47 / 391 (12.02%)
    29 / 267 (10.86%)
         occurrences all number
    73
    47
    Hypophosphataemia
         subjects affected / exposed
    22 / 391 (5.63%)
    14 / 267 (5.24%)
         occurrences all number
    26
    14
    Hyperkalaemia
         subjects affected / exposed
    15 / 391 (3.84%)
    16 / 267 (5.99%)
         occurrences all number
    29
    27

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Feb 2011
    Protocol Amendment 1: Amendment 1 was implemented prior to enrolment of subjects into PA-CL-05B and introduced the following changes that impacted the conduct of the study or data analyses: • Corrected and ionised calcium were added to the laboratory parameters reported. • Flexibility of timing of physical examination assessment was added. • Flexibility of timing of ECG assessment was added. • Specifications for follow-up telephone calls to subjects were added. • “Largest meal” was defined. • A DSMB was added. • Drug storage requirements were clarified. • Requirement for daily recording of drug storage temperature was added. • Flexibility of method of body temperature measurement was added. • Dialysis and dietary data parameters were added. • AE outcome options and wording were amended for consistency with the case report form. • Follow-up requirements for SAE reporting after study completion were clarified. • The definition of SAE resolution was clarified. • The SAE form template was revised to make it specific and consistent with the protocol and case report form.
    04 Jul 2011
    Protocol Amendment 2: Amendment 2 was implemented prior to enrolment of subjects into PA-CL-05B and introduced the following changes that impacted the conduct of the study or data analyses: • Exclusion criteria 7, serum ferritin levels were amended to exclude subjects with serum ferritin >2,000 mcg/L, raised from >1,500 mcg/L. • Sample size was increased and enrolment of subjects was to be continued to ensure a sufficient number of subjects to meet regulatory requirements for long-term safety. • Statistical testing of demographic, baseline characteristics and safety data was removed. • Frequency of Kt/V calculation was changed, and parameters for Kt/V calculation were corrected. • Calcium-based antacids were added to the list of prohibited medications. • The requirement for trade names of concomitant medications to be recorded in the eCRF was added. • White blood cell differential was amended to include percentage and absolute values.
    12 Aug 2011
    Protocol Amendment 3: Amendment 3 was implemented prior to subject enrolment into PA-CL-05B and introduced the following change that impacted the conduct of the study or data analyses: • The HD parameters to be recorded at each study visit were clarified.
    31 Jan 2012
    Protocol Amendment 4: Amendment 4 was implemented after subjects had enrolled, however, the amendment did not impact the conduct of the study or data analyses as it involved only the change of a signatory and a correction of a typographical error.
    04 Sep 2012
    Protocol Amendment 5: Amendment 5 was implemented after subjects had enrolled and introduced the following changes that impacted the conduct of the study or data analyses: • Clarification of withdrawal of non-eligible subjects. • Revision of study drug storage conditions. • Clarification of prohibited oral iron preparations. • Clarification of ECG reporting instructions. • Addition of guidance on unscheduled visits. • Clarification of SAE recording of kidney transplants. • Revision to reference the latest version of the PA21 Investigator’s Brochure (Version 12), and update the AEs for the comparator medicinal product (sevelamer carbonate) to be in line with the Renvela Summary of Product Characteristics. • Inclusion of a planned interim safety analysis.

    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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