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    Clinical Trial Results:
    A Randomized Controlled, Single-Blind, Proof-of-Concept-Study to Investigate the Protective Effects of Early Treatment With C.E.R.A. in Patients With Chronic Kidney Disease on Renal Disease Progression

    Summary
    EudraCT number
    		 2009-015114-22
    Trial protocol
    		 DE  
    Global end of trial date
    30 Mar 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    ML22916
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01194154
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Roche Pharma AG
    Sponsor organisation address
    Emil-Barell-Str. 1, D-79639, Grenzach-Wyhlen, Germany, 79639
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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
    11 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate if treatment with Mircera or Continuous Erythropoietin Receptor Activator (C.E.R.A.) has a protective effect on the kidney of CKD stage III participants.
    Protection of trial subjects
    The study was designed, conducted, and evaluated according to the study protocol and in compliance with the International Conference of Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) E6 and the Declaration of Helsinki, as well as with local legal requirements.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Aug 2010
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 241
    Worldwide total number of subjects
    241
    EEA total number of subjects
    241
    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)
    114
    From 65 to 84 years
    123
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total 241 participants were randomized, 2 participants in the Mircera group and 4 participants in the placebo group did not receive medication.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Mircera
    Arm description
    		 Methoxy polyethylene glycol-epoetin beta 30 microgram (mcg) subcutaneous injection once monthly up to 24 months with sequential dose adjustments to 50 mcg or 75 mcg depending on change of hemoglobin values of more than 1.0 gram (g)/ deciliter (dL).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Mircera
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Methoxy polyethylene glycol-epoetin beta 30 microgram (mcg) subcutaneous injection once monthly up to 24 months.

    Arm title
    		 Placebo
    Arm description
    		 Placebo matching to methoxy polyethylene glycol-epoetin beta subcutaneous injection once monthly up to 24 months.
    Arm type
    		 Placebo

    Investigational medicinal product name
    NA
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo matching to methoxy polyethylene glycol-epoetin beta, administered as subcutaneous injection.

    Number of subjects in period 1
    		Mircera Placebo
    Started
    117
    124
    Completed
    68
    91
    Not completed
    49
    33
         Adverse event, serious fatal
    3
    2
         Hemoglobin decrease
    -
    1
         Consent withdrawn by subject
    5
    6
         Blood pressure increase
    5
    3
         Adverse event, non-fatal
    9
    5
         Hemoglobin increase
    12
    3
         Treatment with prohibited medication
    4
    5
         Skipping of CERA treatment at two visits
    3
    -
         Unspecified
    4
    -
         Lost to follow-up
    2
    3
         Did not receive study medication
    2
    4
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Mircera
    Reporting group description
    		 Methoxy polyethylene glycol-epoetin beta 30 microgram (mcg) subcutaneous injection once monthly up to 24 months with sequential dose adjustments to 50 mcg or 75 mcg depending on change of hemoglobin values of more than 1.0 gram (g)/ deciliter (dL).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matching to methoxy polyethylene glycol-epoetin beta subcutaneous injection once monthly up to 24 months.

    Reporting group values
    		 Mircera Placebo Total
    Number of subjects
    		 117 124 241
    Age categorical
    Units: Subjects
    Age continuous
    N (number of participants analyzed) = 235
    Units: years
        arithmetic mean (standard deviation)
    		 63.37 ( 12.26 ) 62.97 ( 14.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 44 44 88
        Male
    		 71 76 147
        Missing
    		 2 4 6

    End points

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    End points reporting groups
    Reporting group title
    Mircera
    Reporting group description
    		 Methoxy polyethylene glycol-epoetin beta 30 microgram (mcg) subcutaneous injection once monthly up to 24 months with sequential dose adjustments to 50 mcg or 75 mcg depending on change of hemoglobin values of more than 1.0 gram (g)/ deciliter (dL).

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matching to methoxy polyethylene glycol-epoetin beta subcutaneous injection once monthly up to 24 months.

    Primary: Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Modification of Diet in Renal Disease With 4 Variables (MDRD-4)

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    End point title
    		 Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Modification of Diet in Renal Disease With 4 Variables (MDRD-4)
    End point description
    The yearly reduction in eGFR was calculated using the MDRD-4 formula. This formula is based on age, sex, and serum creatinine and eGFR values are calculated as follows: GFR in ml/min per 1.73 m^2 = 175 x Serum Cr^-1.154 x age^-0.203 x 0.742 (if female). The yearly reduction rate (mL/min/1.73m^2 / Year) is defined as –365.25 multiplied by Beta, where Beta is the slope parameter derived for each participants separately by simple linear regression of the change from baseline in participant’s eGFR measurements (from Baseline to Visit 24) on the actual day of measurement. FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement.
    End point type
    Primary
    End point timeframe
    24 months
    End point values
    		 Mircera Placebo
    Number of subjects analysed
    115
    120
    Units: eGFR/year
        least squares mean (confidence interval 95%)
    3.04 (1.2 to 4.87)
    0.82 (-0.96 to 2.61)
    Statistical analysis title
    		 Yearly Reduction Rate of eGFR
    Statistical analysis description
    An analysis of covariance (ANCOVA) model with adjustment for baseline eGFR was used to obtain an estimate of the treatment difference.
    Comparison groups
    Mircera v Placebo
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.657
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 treatment effect
    Point estimate
    2.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.35
         upper limit
    		 4.78

    Secondary: Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)

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    End point title
    		 Yearly Reduction Rate of Estimated Glomerular Filtration Rate (eGFR) Calculated by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI)
    End point description
    The eGFR value calculated using the CKD-EPI equation. The formula used is based on age, sex, ethnicity, and serum creatinine and eGFR values are calculated as follows: GFR in milliliter(mL)/min per 1.73 m^2 = 141 x min(SerumCr/k; 1)^a x max(SerumCr/k; 1)^(-1.209) x 0.993^age x F x B, where k=0.7 for female (else=0.9); a=-0.329 for female (else=-0.411), F=1.018 for female (else=1), B=1.159 for black (else=1), min/max=minimum/maximum of listed values. The Yearly Reduction Rate (mL/min/1.73m^2 / Year) is defined as –365.25 * Beta, where Beta is the slope parameter derived for each participant separately by simple linear regression of the change from baseline in participant’s eGFR measurements (from Baseline to Visit 24) on the actual day of measurement. FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement.
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Mircera Placebo
    Number of subjects analysed
    115
    120
    Units: eGFR/year
        least squares mean (confidence interval 95%)
    3.02 (1.03 to 5)
    0.78 (-1.16 to 2.72)
    Statistical analysis title
    		 Yearly Reduction Rate of eGFR
    Statistical analysis description
    ANCOVA model with adjustment for baseline eGFR was used to obtain an estimate of the treatment difference.
    Comparison groups
    Mircera v Placebo
    Number of subjects included in analysis
    235
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.709
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 treatment effect
    Point estimate
    2.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.54
         upper limit
    		 5.01

    Secondary: Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Month 24

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    End point title
    		 Change From Baseline in Calculated Creatinine Clearance (Cockcroft-Gault Equation) at Month 24
    End point description
    Creatinine clearance was calculated according to the Cockcroft and Gault Formula. It measures rate creatinine (substance formed from metabolism of creatine) is cleared from blood by kidneys. Normal adult creatinine clearance is greater than or equal to (>=) 90 mL/min/1.73m^2. Change from baseline=CC at Week X minus CC at baseline where higher scores represented improved renal function. FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement. n=number of participants evaluable for each category.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 24
    End point values
    		 Mircera Placebo
    Number of subjects analysed
    115
    120
    Units: ml/min]
    arithmetic mean (standard deviation)
        Baseline (n=115, 120)
    53.18 ( 15.95 )
    52.48 ( 16.04 )
        Change at Month 24 (n=67, 91)
    -2.97 ( 10.52 )
    -2.08 ( 9.72 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Creatinine Concentration at Month 24

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    End point title
    		 Change From Baseline in Serum Creatinine Concentration at Month 24
    End point description
    Serum creatinine is an indicator of kidney function. Creatinine is a substance formed from the metabolism of creatine, commonly found in blood, urine, and muscle tissue. It is removed from the blood by the kidneys and excreted in urine. Normal adult blood levels of creatinine=45 to 90 micromoles per liter (mcmol/L) for females, 60 to 110 mcmol/L for males, however normal values are age-dependent. FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement. n=number of participants evaluable for each category.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 24
    End point values
    		 Mircera Placebo
    Number of subjects analysed
    115
    120
    Units: mcmol/L
    arithmetic mean (standard deviation)
        Baseline (n=115, 120)
    147.8 ( 31.71 )
    149.3 ( 35.67 )
        Change at Month 24 (n=68, 91)
    7.04 ( 27.23 )
    4.04 ( 30.99 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Month 24

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    End point title
    		 Change From Baseline in Urinary Albumin Creatinine Ratio (UACR) at Month 24
    End point description
    UACR is defined as the ratio: milligram of albumin per gram of creatinine. The presence of albumin in the urine (macroalbuminuria) is a marker of kidney disease. Albumin and creatinine concentrations were obtained from spot urine samples. FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement. Number of Participants Analyzed (N) = number of participants evaluable and available with valid data for this outcome measure. n=number of participants evaluable for each category.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 24
    End point values
    		 Mircera Placebo
    Number of subjects analysed
    110
    107
    Units: mg/g
    arithmetic mean (standard deviation)
        Baseline (n=110, 107)
    261.1 ( 564 )
    237.3 ( 699.6 )
        Change at Month 24 (n=43, 53)
    173.8 ( 573.3 )
    70.59 ( 546.8 )
    No statistical analyses for this end point

    Secondary: Change From Baseline in Serum Cystatin C Concentration at Month 24

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    End point title
    		 Change From Baseline in Serum Cystatin C Concentration at Month 24
    End point description
    Cystatin C is a protein which is mainly used as a biomarker of kidney function. If kidney function and GFR decline, the blood levels of cystatin C rise. FAS included all randomized participants who received at least one dose of the study medication and provided any successive eGFR measurement. n=number of participants evaluable for each category.
    End point type
    Secondary
    End point timeframe
    Baseline, Month 24
    End point values
    		 Mircera Placebo
    Number of subjects analysed
    115
    120
    Units: mg/L
    arithmetic mean (standard deviation)
        Baseline (n=115, 120)
    1.79 ( 0.39 )
    1.76 ( 0.46 )
        Change at Month 24 (n=67, 91)
    0.1 ( 0.29 )
    0.02 ( 0.33 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)

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    End point title
    		 Percentage of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs)
    End point description
    An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability or incapacity; and congenital anomaly. Percentage of participants with AEs included participants affected with both SAEs and non-SAEs. The Safety Analysis Set (SAF) included all participants who received at least one dose of the study medication. Analysis for SAF was performed according to the study medication actually received (’as treated’ population).
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 Mircera Placebo
    Number of subjects analysed
    115 [1]
    120 [2]
    Units: percentage of participants
    number (not applicable)
        SAEs
    35.6
    41
        AEs
    84.7
    86.3
    Notes
    [1] - N=117 (as treated population) were evaluable for this outcome measure.
    [2] - N=118 (as treated population) participants evaluable for this outcome measure.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    24 months
    Adverse event reporting additional description
    The Safety Analysis Set (SAF) included all participants who received at least one dose of study medication. Analysis for SAF was performed according to the study medication actually received (as treated population).
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matching to Methoxy polyethylene glycol-epoetin beta subcutaneous injection once monthly up to 24 months.

    Reporting group title
    Mircera
    Reporting group description
    		 Methoxy polyethylene glycol-epoetin beta 30 microgram (mcg) subcutaneous injection once monthly up to 24 months with sequential dose adjustments to 50 mcg or 75 mcg depending on change of hemoglobin values of more than 1.0 gram (g)/ deciliter (dL).

    Serious adverse events
    		 Placebo Mircera
    Total subjects affected by serious adverse events
         subjects affected / exposed
    48 / 117 (41.03%)
    42 / 118 (35.59%)
         number of deaths (all causes)
    2
    3
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Thyroid cancer
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenocarcinoma
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Basal cell carcinoma
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lip neoplasm malignant stage unspecified
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lipoma
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Plasmacytoma
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Squamous cell carcinoma
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Peripheral arterial occlusive disease
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 117 (2.56%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertensive crisis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Aortic anastomosis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    General physical health deterioration
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Pain
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Transplant rejection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         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
    Benign prostatic hyperplasia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    4 / 118 (3.39%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive airways disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Haemoglobin decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         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
    Humerus fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniscus lesion
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Traumatic brain injury
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wrist fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Tibial torsion
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 117 (1.71%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bundle branch block left
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute coronary syndrome
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (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
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intracardiac thrombus
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 117 (1.71%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral ischaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebral haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cerebrovascular disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Facial paresis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myelopathy
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient global amnesia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Normochromic normocytic anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Vertigo
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Ectropion
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lens dislocation
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 117 (2.56%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal hernia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Faecaloma
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 117 (1.71%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic gastroparesis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticular perforation
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reflux oesophagitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Liver disorder
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bile duct stone
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 117 (1.71%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rash
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 117 (1.71%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postrenal failure
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperthyroidism
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         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
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 117 (1.71%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pain in extremity
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal pain
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Erysipelas
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchopneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Influenza
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia primary atypical
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis externa
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyperkalaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    2 / 118 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 117 (0.85%)
    0 / 118 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypokalaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lactic acidosis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    1 / 118 (0.85%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Mircera
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    99 / 117 (84.62%)
    95 / 118 (80.51%)
    Vascular disorders
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    14 / 117 (11.97%)
    11 / 118 (9.32%)
         occurrences all number
    16
    12
    General disorders and administration site conditions
    Oedema peripheral
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 117 (8.55%)
    11 / 118 (9.32%)
         occurrences all number
    12
    12
    Gastrointestinal disorders
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    13 / 117 (11.11%)
    11 / 118 (9.32%)
         occurrences all number
    15
    12
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 117 (6.84%)
    0 / 118 (0.00%)
         occurrences all number
    12
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    alternative assessment type: Systematic
         subjects affected / exposed
    10 / 117 (8.55%)
    13 / 118 (11.02%)
         occurrences all number
    10
    13
    Musculoskeletal and connective tissue disorders
    Back pain
    alternative assessment type: Systematic
         subjects affected / exposed
    8 / 117 (6.84%)
    0 / 118 (0.00%)
         occurrences all number
    9
    0
    Osteoarthritis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 117 (0.00%)
    6 / 118 (5.08%)
         occurrences all number
    0
    6
    Pain in extremity
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 117 (5.13%)
    0 / 118 (0.00%)
         occurrences all number
    6
    0
    Infections and infestations
    Bronchitis
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 117 (7.69%)
    0 / 118 (0.00%)
         occurrences all number
    9
    0
    Influenza
    alternative assessment type: Systematic
         subjects affected / exposed
    9 / 117 (7.69%)
    9 / 118 (7.63%)
         occurrences all number
    15
    10
    Nasopharyngitis
    alternative assessment type: Systematic
         subjects affected / exposed
    24 / 117 (20.51%)
    29 / 118 (24.58%)
         occurrences all number
    33
    40
    Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    7 / 117 (5.98%)
    12 / 118 (10.17%)
         occurrences all number
    14
    14

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Dec 2010
    Version 1: Protocol was amended to clarify the inclusion criteria (UACR, creatinine and total protein values needed for inclusion in the study) and exclusion criteria (an additional organ transplant, other than kidney and participants with myelofibrosis or a diagnosed hematologic disease were excluded). Acute transplant rejection and pregnancy were included as withdrawal criteria and erythropoietin-stimulating agent (ESAs) were included as prohibited concomitant medication. Visit 2 was defined to be the time point for starting possible dose adjustments of C.E.R.A.
    16 Aug 2011
    Version 2: UACR, creatinine and total protein values needed for inclusion in the study were changed. Increases and decreases in hemoglobin values of more than 1.5 g/dl now had to be present in combination with a current value of >14,0 g/dl or <10 g/dl respectively to allow for treatment discontinuation or premature withdrawal of the participant.
    04 Jun 2012
    Version 3: Due to temporarily stopped manufacturing of C.E.R.A., enrollment of new participants into the study was halted. To avoid any recruitment problems and any further extension of the duration of the study, the sample size calculation, total participant numbers as well as recruitment timelines were adapted. To avoid any recruitment problems and any further extension of the duration of the study, the sample size calculation, total participant numbers as well as recruitment timelines were adapted. The reporting time lines for possible SAE and pregnancies were specified in more detail.
    06 May 2014
    Version 4: As most of the participants had already had their EoS visit after the recruitment stop of the study, an interim analysis was no longer scheduled as originally planned. Change in eGFR over time calculated additionally by CKD-EPI equation (based on the same variables as MDRD) was included as a secondary efficacy parameter.

    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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