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    Clinical Trial Results:
    MULTICENTRE, OPEN LABEL, RANDOMIZED, TWO-ARM, PARALLEL-GROUP STUDY TO ASSESS EFFICACY AND SAFETY OF ENVARSUS® COMPARED WITH TACROLIMUS USED AS PER CURRENT CLINICAL PRACTICE IN THE INITIAL MAINTENANCE SETTING IN DE NOVO KIDNEY TRANSPLANT PATIENTS.

    Summary
    EudraCT number
    2014-004314-29
    Trial protocol
    BE   AT   ES   DE   PL   IT  
    Global end of trial date
    24 Jan 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    02 Feb 2018
    First version publication date
    02 Feb 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CCD-06235AA1-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02432833
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    N/A: N/A
    Sponsors
    Sponsor organisation name
    Chiesi Farmaceutici S.p.A.
    Sponsor organisation address
    Via Palermo 26/A, Parma, Italy,
    Public contact
    Clinical Trial Trasparency, Clinical Trial Trasparency, clinicaltrials_info@chiesi.com
    Scientific contact
    Clinical Trial Trasparency, Clinical Trial Trasparency, clinicaltrials_info@chiesi.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
    27 Nov 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Jan 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare tacrolimus dosing of the new Envarsus®-based immunosuppressive regimen with current clinical practice over 6 months following de novo renal transplantation in a real-life setting in different European Countries.
    Protection of trial subjects
    The study proposal was submitted to the Independent Ethics Committee (IEC) in accordance with the requirements of each country, and the IEC provided opinion in writing. The study was conducted in accordance with the Declaration of Helsinki, the International Council for Harmonisation of Good Clinical Practice guidelines, and followed all other requirements of local laws. The consent document met all applicable local laws and provided the patient with information regarding the purpose, procedures, requirements and restrictions of the study, along with any known risks and potential benefits associated with the investigational product and the established provisions for maintaining the confidentiality of personal information. The Investigator obtained written consent from each subject or from the subject’s legal representative prior to any study related procedures taking place.
    Background therapy
    Envarsus® is a prolonged release formulation of tacrolimus developed utilising a MeltDose™ drug-delivery technology which increases the bioavailability of poorly water soluble compounds. The improved bioavailability of Envarsus, which allows a QD administration, determines lower inter- and intra subject variability of drug absorption with reduced peak-to-trough fluctuation and earlier achievement of a stable tacrolimus profile, as shown in healthy volunteers .
    Evidence for comparator
    Despite the proven immunosuppressive efficacy of tacrolimus, currently marketed formulations such as Prograf® and Advagraf exhibit limitations, primarily in terms of PK properties and tolerability. Prograf and Advagraf exhibit significant inter- and intra individual variability in absorption because of the interactions with both food and concomitant medications, and metabolism through the cytochrome P-450 system which is subject to functional polymorphisms. In addition, both Prograf and Advagraf exhibit a very low bioavailability due to poor water solubility and pre systemic gastrointestinal (GI) metabolism.
    Actual start date of recruitment
    16 May 2015
    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
    Norway: 5
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Spain: 102
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Austria: 18
    Country: Number of subjects enrolled
    Belgium: 20
    Country: Number of subjects enrolled
    France: 113
    Country: Number of subjects enrolled
    Germany: 51
    Country: Number of subjects enrolled
    Italy: 76
    Worldwide total number of subjects
    428
    EEA total number of subjects
    428
    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)
    310
    From 65 to 84 years
    118
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This study was conducted in 51 active sites out of 65 open sites, located in 10 European countries. Patient were recruited in the following 51 active sites: Austria (2 sites), Belgium (2 sites), France (11 sites), Germany (7 sites), Italy (10 sites), Norway (1 site), Poland (2 sites), Spain (11 sites), Sweden (2 sites) and UK (3 sites).

    Pre-assignment
    Screening details
    A screening visit (Visit 1) was performed from 0 to 28 days prior to kidney transplantation when feasible. The screening visit (Visit 1) could be combined with Visit 2 if all information was already available to the Investigators for the inclusion and exclusion criteria evaluation at the time of randomization.

    Pre-assignment period milestones
    Number of subjects started
    428
    Number of subjects completed
    403

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    other: 12
    Reason: Number of subjects
    no met inclusion criteria/exclusion criteria: 10
    Reason: Number of subjects
    Adverse event, non-fatal: 2
    Reason: Number of subjects
    Protocol deviation: 1
    Period 1
    Period 1 title
    1_treatment period (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    N.A

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    1_Envarsus®
    Arm description
    Active Treatment Arm with Envarsus tablets: randomization 1:1 ratio (Arm1: Arm2). Active substance: Tacrolimus monohydrate. Oral administration once daily. starting dose: 0.17mg/kg/day Whatever the treatment, patients will have their dose adjusted to maintain tacrolimus whole blood trough levels within the standard reference ranges of 5-15 ng/ml in the first three months after transplantation and 5-10 ng/ml afterwards.
    Arm type
    Experimental

    Investigational medicinal product name
    Envarsus®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Envarsus® Oval, white to off-white uncoated tablets will be administered orally once daily in the morning. The treatment should commence at the starting dose of 0.17 mg/kg/day. Whatever the treatment, patients will have their dose adjusted to maintain tacrolimus whole blood trough levels within the standard reference ranges of 5-15 ng/ml in the first three months after transplantation and 5-10 ng/ml afterwards.

    Arm title
    2_Prograf® /Advagraf®
    Arm description
    Reference therapy arm (Arm2) with randomization 1:1 ratio (Arm1: Arm2) (active substance: Tacrolimus monohydrate) - Prograf® capsules will be administered orally. The treatment should commence at the starting total daily dose of 0.2 mg/kg/day delivered in two equally divided doses 12 hours apart (one in the morning and one in the evening) or - Advagraf® capsules will be administered orally. The treatment should commence at the starting total daily dose of 0.2 mg/kg/day administered once daily in the morning. Whatever the treatment, patients will have their dose adjusted to maintain tacrolimus whole blood trough levels within the standard reference ranges of 5-15 ng/ml in the first three months after transplantation and 5-10 ng/ml afterwards.
    Arm type
    Active comparator

    Investigational medicinal product name
    Prograf®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Prograf are hard capsules for oral formulation provided in 0.5 mg, 1.0 mg and 5.0 mg dosage strengths,administered twice daily. The treatment should commence at the starting total daily dose of 0.2 mg/kg/day delivered in two equally divided doses 12 hours apart (one in the morning and one in the evening).

    Investigational medicinal product name
    Advagraf®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Prolonged-release capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Advagraf are prolonged-release hard capsules for oral formulation provided in 0.5 mg, 1.0 mg, 3.0 mg and 5.0 mg dosage strengths,administered once daily. The treatment should commence at the starting total daily dose of 0.2 mg/kg/day administered once daily in the morning.

    Number of subjects in period 1 [1]
    1_Envarsus® 2_Prograf® /Advagraf®
    Started
    201
    202
    Completed
    177
    173
    Not completed
    24
    29
         no met inclusion criteria/exclusion criteria
    1
    3
         Protocol deviation
    2
    2
         Lack of efficacy
    -
    3
         Adverse event, serious fatal
    2
    3
         Adverse event, non-fatal
    11
    13
         Consent withdrawn by subject
    5
    3
         other
    3
    2
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: In the study were enrolled 428 subject, yet 25 of these didn't attend the randomization visit for the reason described i the "Pre-assignment subject non-completion reasons". The baseline period was considered as the number of patients that attend the Randomization visit (day 0)

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    1_Envarsus®
    Reporting group description
    Active Treatment Arm with Envarsus tablets: randomization 1:1 ratio (Arm1: Arm2). Active substance: Tacrolimus monohydrate. Oral administration once daily. starting dose: 0.17mg/kg/day Whatever the treatment, patients will have their dose adjusted to maintain tacrolimus whole blood trough levels within the standard reference ranges of 5-15 ng/ml in the first three months after transplantation and 5-10 ng/ml afterwards.

    Reporting group title
    2_Prograf® /Advagraf®
    Reporting group description
    Reference therapy arm (Arm2) with randomization 1:1 ratio (Arm1: Arm2) (active substance: Tacrolimus monohydrate) - Prograf® capsules will be administered orally. The treatment should commence at the starting total daily dose of 0.2 mg/kg/day delivered in two equally divided doses 12 hours apart (one in the morning and one in the evening) or - Advagraf® capsules will be administered orally. The treatment should commence at the starting total daily dose of 0.2 mg/kg/day administered once daily in the morning. Whatever the treatment, patients will have their dose adjusted to maintain tacrolimus whole blood trough levels within the standard reference ranges of 5-15 ng/ml in the first three months after transplantation and 5-10 ng/ml afterwards.

    Reporting group values
    1_Envarsus® 2_Prograf® /Advagraf® Total
    Number of subjects
    201 202 403
    Age categorical
    adult male or female of at least 18 years
    Units: Subjects
        Adults (18-64 years)
    148 147 295
        From 65-84 years
    53 55 108
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    53.7 ± 14.2 54.9 ± 14.2 -
    Gender categorical
    Units: Subjects
        Female
    55 65 120
        Male
    146 137 283
    Race
    White, Asian, Black and other races. Results reported in table 14.1.2.1 of Clinical Study Report
    Units: Subjects
        White
    196 193 389
        Asian
    2 3 5
        Black
    1 1 2
        other
    2 5 7

    End points

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    End points reporting groups
    Reporting group title
    1_Envarsus®
    Reporting group description
    Active Treatment Arm with Envarsus tablets: randomization 1:1 ratio (Arm1: Arm2). Active substance: Tacrolimus monohydrate. Oral administration once daily. starting dose: 0.17mg/kg/day Whatever the treatment, patients will have their dose adjusted to maintain tacrolimus whole blood trough levels within the standard reference ranges of 5-15 ng/ml in the first three months after transplantation and 5-10 ng/ml afterwards.

    Reporting group title
    2_Prograf® /Advagraf®
    Reporting group description
    Reference therapy arm (Arm2) with randomization 1:1 ratio (Arm1: Arm2) (active substance: Tacrolimus monohydrate) - Prograf® capsules will be administered orally. The treatment should commence at the starting total daily dose of 0.2 mg/kg/day delivered in two equally divided doses 12 hours apart (one in the morning and one in the evening) or - Advagraf® capsules will be administered orally. The treatment should commence at the starting total daily dose of 0.2 mg/kg/day administered once daily in the morning. Whatever the treatment, patients will have their dose adjusted to maintain tacrolimus whole blood trough levels within the standard reference ranges of 5-15 ng/ml in the first three months after transplantation and 5-10 ng/ml afterwards.

    Primary: 1_Tacrolimus Total Daily Dose (TTD) from Week 3 to Month 6

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    End point title
    1_Tacrolimus Total Daily Dose (TTD) from Week 3 to Month 6
    End point description
    The primary efficacy endpoint was the tacrolimus Total Daily Dose from Week 3 (Visit 9) to Month 6 (Visit 15). Results from week 3 to month 6 have been reported. Shown are the number of patients included in the model (modified Intention-to-treat [mITT] population [N]; patients with available results [n]
    End point type
    Primary
    End point timeframe
    from Week 3 (Visit 9) to Month 6 (Visit 15).
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    191 [1]
    194 [2]
    Units: milligram(s)
        arithmetic mean (standard deviation)
    5.165 ± 2.970
    6.280 ± 3.557
    Notes
    [1] - N=200 n=191
    [2] - N=201 n=194
    Statistical analysis title
    1_Average Tacrolimus TDD from week 3 to month 6
    Statistical analysis description
    Primary efficacy analysis. The average tacrolimus TDD from Week 3 (Visit 9) to Month 6 (Visit 15) will be compared between the two groups (Envarsus vs Prograf/Advagraf) using an ANOVA model.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    other [3]
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    LS Mean difference
    Point estimate
    -1.108
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.764
         upper limit
    -0.452
    Notes
    [3] - An analysis of variance (ANOVA) model was performed with treatment group and country as fixed effects. The adjusted means in each treatment group and the adjusted mean difference between treatment groups were displayed with the corresponding 2-sided 95% CI.

    Secondary: 2_Ratio between TL and TDD

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    End point title
    2_Ratio between TL and TDD
    End point description
    Efficacy endpoint. The ratio between trough levels and total daily dose was analysed, as it is an indicator of drug bioavailability. For each subject at each time point, the TL/TDD ratio was calculated as follows: TL (time t+1) / TDD (t). Shown are the number of patients included in the model (modified Intention-to-treat [mITT] population [N]; patients with available results [n]).
    End point type
    Secondary
    End point timeframe
    The ratios were calculated at visit, by period (including Week 3 to Month 6) and overall: results from Week 3 to Month 6 were reported.
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    191 [4]
    194 [5]
    Units: ng/mL/mg
    arithmetic mean (standard deviation)
        week 3-month 6
    2.262 ± 1.375
    1.692 ± 0.854
    Notes
    [4] - N=200; n=191
    [5] - N=201;n=194
    Statistical analysis title
    1_Ratio between TL and TDD
    Statistical analysis description
    Average ratio is the average of all ratios TL (time t+1) / TDD (t) measured during the time period. For the period Week 3 to Month 6 (Study Day 21 to last assessment), the ratio was analysed using an ANOVA model.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    385
    Analysis specification
    Pre-specified
    Analysis type
    other [6]
    P-value
    < 0.001
    Method
    ANOVA
    Parameter type
    LS Mean difference
    Point estimate
    0.57
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.342
         upper limit
    0.799
    Notes
    [6] - ANOVA model have been constructed with treatment arm and country as fixed effects. The adjusted means in each treatment arm and the adjusted mean difference between treatment arms have been displayed with the corresponding two-sided 95 % CI.

    Secondary: 3_Treatment failure rate

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    End point title
    3_Treatment failure rate
    End point description
    Efficacy endpoint. Treatment failure rate, a composite endpoint, includes any patient who experienced within 6 months after randomization any of the following: death, graft failure, BPAR (biopsy-proven acute rejection) or lost to follow-up. Overall results have been reported. Shown are the number of patients included in the model (modified Intention-to-treat [mITT] population [N]; patients with available results [n]).
    End point type
    Secondary
    End point timeframe
    within 6 months after randomization.
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [7]
    201 [8]
    Units: percentage of subject (0-100%)
        overall_death
    2
    2
        overall_graft failure
    2
    2
        overall_BPAR
    6
    5
        overall_lost on Follow Up
    0
    0
        overall_treatment failure
    9
    9
    Notes
    [7] - N=200;n=200
    [8] - N=201;n=201
    Statistical analysis title
    1_Treatment Failure Rate_overall_treatment Failure
    Statistical analysis description
    A Fisher’s exact test has been used to estimate the difference between treatments for the entire study period.
    Comparison groups
    2_Prograf® /Advagraf® v 1_Envarsus®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    > 0.999 [9]
    Method
    Fisher exact
    Parameter type
    difference between proportions
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.7
         upper limit
    5.8
    Notes
    [9] - P-value was based on a 2-sided Fisher's exact test to evaluate the difference between treatment groups. The 95 % CI for the difference in proportions between the two treatment arms based on the Newcombe-Wilson method
    Statistical analysis title
    2_Treatment Failure Rate_overall_death
    Statistical analysis description
    A Fisher’s exact test has been used to estimate the difference between treatments for the entire study period.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    > 0.999 [10]
    Method
    Fisher exact
    Parameter type
    LS Mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    3.3
    Notes
    [10] - P-value was based on a 2-sided Fisher's exact test to evaluate the difference between treatment groups. The 95 % CI for the difference in proportions between the two treatment arms based on the Newcombe-Wilson method
    Statistical analysis title
    3_Treatment Failure Rate_overall_graft failure
    Statistical analysis description
    A Fisher’s exact test has been used to estimate the difference between treatments for the entire study period.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    > 0.999 [11]
    Method
    Fisher exact
    Parameter type
    LS Mean difference
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.2
         upper limit
    3.3
    Notes
    [11] - P-value was based on a 2-sided Fisher's exact test to evaluate the difference between treatment groups. The 95 % CI for the difference in proportions between the two treatment arms based on the Newcombe-Wilson method
    Statistical analysis title
    4_Treatment Failure Rate_overall_BPAR
    Statistical analysis description
    A Fisher’s exact test has been used to estimate the difference between treatments for the entire study period.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.688 [12]
    Method
    Fisher exact
    Parameter type
    LS Mean difference
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    5.8
    Notes
    [12] - P-value was based on a 2-sided Fisher's exact test to evaluate the difference between treatment groups. The 95 % CI for the difference in proportions between the two treatment arms based on the Newcombe-Wilson method

    Secondary: 4_Time to treatment failure

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    End point title
    4_Time to treatment failure
    End point description
    Efficacy endpoint. Time to treatment failure is determined by the first episode of death, graft failure, BPAR or lost to follow-up, whichever occurs first. Time to treatment failure (days) will be calculated as difference between the date of event and the date of randomization + 1. Patients who prematurely withdraw from the study for any other reason (without experiencing one of the four events) will be right-censored for this analysis at the time of discontinuation. Patients who complete the study without experiencing any of the four events will be right censored at last dose. Shown are the number of patients included in the model (modified Intention-to-treat [mITT] population [N]; patients with available results [n])
    End point type
    Secondary
    End point timeframe
    from the randomization day +1.
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [13]
    201 [14]
    Units: percentage of subjects (0-100%)
        subjects event
    9
    9
        subjects censored
    91
    91
    Notes
    [13] - N=200;n=200
    [14] - N=201;n=201
    Statistical analysis title
    1_Time to treatment failure
    Statistical analysis description
    the ratio was calculated as Envaruss/ Prograf/advagraf.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.965
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.01
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.23

    Secondary: 5_Proportion of patients with delayed graft function

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    End point title
    5_Proportion of patients with delayed graft function
    End point description
    Efficacy endpoint. Proportion of patients with delayed graft function (defined as dialysis in the first week) will be presented by treatment group. Difference between treatments will be evaluated using a Fisher exact test at the 0.05 significant level. The 95% CI for the treatments difference will be also computed. Number of subjects with delayed graft function was below presented. Shown are the number of patients included in the model (modified Intention-to-treat [mITT] population [N]; patients with available results [n])
    End point type
    Secondary
    End point timeframe
    overall the study.
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [15]
    201 [16]
    Units: number of subjects
    23
    22
    Notes
    [15] - N=200;n=200
    [16] - N=201;n=201
    Statistical analysis title
    1_delayed graft function
    Statistical analysis description
    A Fisher’s exact test has been used to estimate the difference between treatments.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.876 [17]
    Method
    Fisher exact
    Parameter type
    difference between proportions
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.7
         upper limit
    6.9
    Notes
    [17] - P-value was based on a 2-sided Fisher's exact test to evaluate the difference between treatment groups. The 95 % CI for the difference in proportions between the two treatment arms based on the Newcombe-Wilson method.

    Secondary: 6_Proportion of patients with local diagnosis of acute rejection requiring treatment

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    End point title
    6_Proportion of patients with local diagnosis of acute rejection requiring treatment
    End point description
    Efficacy endpoint. Proportion of patients with local diagnosis of acute rejection requiring treatment will be presented by treatment group. Difference between treatments will be evaluated using a Fisher’s exact test at the 0.05 significant level. The 95% CI for the treatments difference will be also computed. Number of patients with local diagnosis of acute rejection requiring treatment was below presented. Shown are the number of patients included in the model (modified Intention-to-treat [mITT] population [N]; patients with available results [n])
    End point type
    Secondary
    End point timeframe
    overall the study
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [18]
    201 [19]
    Units: number of subjects
    7
    6
    Notes
    [18] - N=200;n=200
    [19] - N=201;n=201
    Statistical analysis title
    1_Local diagnosis Acute Rejection requiring treat.
    Statistical analysis description
    A Fisher’s exact test has been used to estimate the difference between treatments.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.787 [20]
    Method
    Fisher exact
    Parameter type
    difference between proportions
    Point estimate
    0.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.3
         upper limit
    4.4
    Notes
    [20] - P-value was based on a 2-sided Fisher's exact test to evaluate the difference between treatment groups. The 95 % CI for the difference in proportions between the two treatment arms based on the Newcombe-Wilson method.

    Secondary: 7_Post-transplant diabetes mellitus (PTDM)

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    End point title
    7_Post-transplant diabetes mellitus (PTDM)
    End point description
    Safety endpoint. Diabetes was assessed through measurement of fasting plasma glucose (FPG), HbA1C and the need for hypoglycaemic agents (oral or insulin). Post-transplant diabetes mellitus was defined by the need for any antidiabetic agent (oral or insulin) and/or HbA1c >6.5% at Months 3 and 6 in a subject with no prior medical history of diabetes before transplantation. Shown are the number of patients included in the model (safety population [N]; patients with available results [n]) N°of subject analysed (n) at month 3 and month 6 are the number of subject with no prior medical history of diabetes before transplantation having laboratory value at a particular visit.
    End point type
    Secondary
    End point timeframe
    Months 3 and 6
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [21]
    201 [22]
    Units: number of subjects
        month 3
    23
    32
        month 6
    23
    25
    Notes
    [21] - N=200 N°of subj with no prior medical history of diabetes : n month 3: 115 n month 6:129
    [22] - N=200 N°of subj with no prior medical history of diabetes : n month 3: 126 n month 6:125
    Statistical analysis title
    1_PTDM_month 3
    Statistical analysis description
    A Fisher’s exact test will be used to estimate the difference between treatments. n° of subjects included in this statistical analysis (n) is: n Envarsus=115 out of 200 n Prograf/Advagraf=126 out of 201 total number = 241 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.214 [23]
    Method
    Fisher exact
    Parameter type
    Percentage difference
    Point estimate
    -7.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -17.3
         upper limit
    3.4
    Notes
    [23] - P-value was based on a 2-sided Fisher's exact test
    Statistical analysis title
    2_PTDM_month 6
    Statistical analysis description
    A Fisher’s exact test will be used to estimate the difference between treatments. n° of subjects included in this statistical analysis (n) is: n Envarsus=129 out of 200 n Prograf/Advagraf=125 out of 201 total number = 254 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.749 [24]
    Method
    Fisher exact
    Parameter type
    Percentage difference
    Point estimate
    -2.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -11.8
         upper limit
    7.5
    Notes
    [24] - P-value was based on a 2-sided Fisher's exact test.

    Secondary: 8_post-transplant hyperglycaemia (PTH)

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    End point title
    8_post-transplant hyperglycaemia (PTH)
    End point description
    Safety endpoint. Diabetes was assessed through measurement of fasting plasma glucose (FPG), HbA1C and the need for hypoglycaemic agents (oral or insulin). PTH would be defined by a FPG ≥126 mg/dL, and/or for subjects with no prior medical history of diabetes, an afternoon capillary glucose level of ≥200 mg/dL with or without insulin requirement or need for an oral hypoglycaemic agent Shown are the number of patients included in the model (safety population [N]; patients with available results [n]) N°of subject analysed at month 3 and month 6 are the number of subject with no prior medical history of diabetes before transplantation having laboratory value at a particular visit.
    End point type
    Secondary
    End point timeframe
    Months 3 and 6
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [25]
    201 [26]
    Units: number of subjects
        month 3
    14
    31
        month 6
    14
    25
    Notes
    [25] - N=200 N°of subj with no prior medical history of diabetes : n month 3: 155 n month 6:152
    [26] - N=201 N°of subj with no prior medical history of diabetes : n month 3: 157 n month 6:150
    Statistical analysis title
    1_PTH_month 3
    Statistical analysis description
    A Fisher’s exact test will be used to estimate the difference between treatments n° of subjects included in this statistical analysis (n) is: n Envarsus=155 out of 200 n Prograf/Advagraf=157 out of 201 total number = 312 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.009 [27]
    Method
    Fisher exact
    Parameter type
    Percentage difference
    Point estimate
    -10.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -18.5
         upper limit
    -2.9
    Notes
    [27] - P-value was based on a 2-sided Fisher's exact test
    Statistical analysis title
    2_PTH_month 6
    Statistical analysis description
    A Fisher’s exact test will be used to estimate the difference between treatments. n° of subjects included in this statistical analysis (n) is: n Envarsus=152 out of 200 n Prograf/Advagraf=150 out of 201 total number = 302 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.06 [28]
    Method
    Fisher exact
    Parameter type
    Percentage difference
    Point estimate
    -7.5
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -15.2
         upper limit
    0.2
    Notes
    [28] - P-value was based on a 2-sided Fisher's exact

    Secondary: 9_Glycated hemoglobin (HbA1c)

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    End point title
    9_Glycated hemoglobin (HbA1c)
    End point description
    Safety endpoint. Glycated hemoglobin (HbA1c).chnages from baseline of HbA1c (%) at day 90 and day 180 have been reported. Shown are the number of patients included in the model (safety population [N]; patients with available results [n])
    End point type
    Secondary
    End point timeframe
    Months 3 and 6
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [29]
    201 [30]
    Units: percent
    arithmetic mean (standard deviation)
        change from baseline_day 90
    0.42 ± 0.84
    0.54 ± 0.95
        change from baseline_day 180
    0.36 ± 0.82
    0.58 ± 0.84
    Notes
    [29] - N=200 n day 90= 102 n day 180= 109
    [30] - N=201 n day 90= 109 n day 180= 112
    Statistical analysis title
    1_HbA1c_day 90
    Statistical analysis description
    HbA1c at Visit 12 (Month 3) has been analysed using an ANCOVA model.The ANCOVA model utilised at each selected post-baseline visit includes treatment and country as fixed effects, and baseline HbA1C value as covariate. n° of subjects included in this statistical analysis (n) is: n Envarsus=102 out of 200 n Prograf/Advagraf=109 out of 201 total number = 211 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.287
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -0.125
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.356
         upper limit
    0.106
    Statistical analysis title
    2_Hb1Ac_day 180
    Statistical analysis description
    HbA1c at Visit 15 (Month 6) has been analysed using an ANCOVA model.The ANCOVA model utilised at each selected post-baseline visit includes treatment and country as fixed effects, and baseline HbA1C value as covariate n° of subjects included in this statistical analysis (n) is: n Envarsus=109 out of 200 n Prograf/Advagraf=112 out of 201 total number = 221 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.025
    Method
    ANCOVA
    Parameter type
    LS Mean difference
    Point estimate
    -0.243
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.455
         upper limit
    -0.031

    Secondary: 10_Tacrolimus Total Daily Dose

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    End point title
    10_Tacrolimus Total Daily Dose
    End point description
    Efficacy endpoint. Shown are the number of patients included in the model (modified Intention-to-treat [mITT] population [N]; patients with available results [n])
    End point type
    Secondary
    End point timeframe
    overall study
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [31]
    201 [32]
    Units: milligram(s)
    arithmetic mean (standard deviation)
        overall
    5.845 ± 3.077
    6.962 ± 3.649
        week 1
    10.959 ± 3.075
    11.722 ± 3.164
        week 2
    8.751 ± 4.009
    9.544 ± 4.545
        week 3
    8.065 ± 4.200
    9.200 ± 4.858
        week 4
    7.411 ± 4.015
    8.567 ± 4.638
        month 1 to month 3
    5.799 ± 3.273
    7.001 ± 3.803
        month 3 to month 6
    4.451 ± 2.871
    5.440 ± 3.232
    Notes
    [31] - N=200 n overall=200 n w1=200 n w2=194 n w3=193 n w4=191 n month 1 to 3=189 n month 3 to 6=184
    [32] - N=201 n overall=201 n w1=201 n w2=197 n w3=195 n w4=193 n month 1 to 3=189 n month 3 to 6=181
    Statistical analysis title
    1_TDD_overall
    Statistical analysis description
    For overall TDD (from first dose date to last dose date), the average TDD have been analysed using an ANOVA model.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.001 [33]
    Method
    ANOVA
    Parameter type
    LS Mean difference
    Point estimate
    -1.109
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.77
         upper limit
    -0.488
    Notes
    [33] - The ANOVA model includes treatment and country as fixed effects.
    Statistical analysis title
    2_TDD_week1
    Statistical analysis description
    average TDD by period have been analysed using a mixed model for repeated measures (MMRM). The MMRM model includes treatment, period, treatment by period interaction and country as fixed effects. An Unstructured covariance structure was used.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.013
    Method
    MMRM
    Parameter type
    LS Mean difference
    Point estimate
    -0.754
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.347
         upper limit
    -0.161
    Statistical analysis title
    3_TDD_week2
    Statistical analysis description
    average TDD by period have been analysed using a mixed model for repeated measures (MMRM) n° of subjects included in this statistical analysis (n) is: n Envarsus=194 out of 200 n Prograf/Advagraf=197 out of 201 total number = 391 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.064
    Method
    MMRM
    Parameter type
    LS Mean
    Point estimate
    -0.788
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.623
         upper limit
    0.047
    Statistical analysis title
    4_TDD_week3
    Statistical analysis description
    average TDD by period have been analysed using a mixed model for repeated measures (MMRM). The MMRM model includes treatment, period, treatment by period interaction and country as fixed effects. An Unstructured covariance structure was used. n° of subjects included in this statistical analysis (n) is: n Envarsus=193 out of 200 n Prograf/Advagraf=195 out of 201 total number = 388 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.018
    Method
    MMRM
    Parameter type
    LS Mean difference
    Point estimate
    -1.081
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.976
         upper limit
    -0.186
    Statistical analysis title
    5_TDD_week4
    Statistical analysis description
    average TDD by period have been analysed using a mixed model for repeated measures (MMRM). The MMRM model includes treatment, period, treatment by period interaction and country as fixed effects. An Unstructured covariance structure was used. n° of subjects included in this statistical analysis (n) is: n Envarsus=191 out of 200 n Prograf/Advagraf=193 out of 201 total number = 384 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.008
    Method
    MMRM
    Parameter type
    LS Mean difference
    Point estimate
    -1.177
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.049
         upper limit
    -0.306
    Statistical analysis title
    6_TDD_month 1 to month 3
    Statistical analysis description
    average TDD by period have been analysed using a mixed model for repeated measures (MMRM). The MMRM model includes treatment, period, treatment by period interaction and country as fixed effects. An Unstructured covariance structure was used. n° of subjects included in this statistical analysis (n) is: n Envarsus=189 out of 200 n Prograf/Advagraf=189 out of 201 total number = 378 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.001
    Method
    MMRM
    Parameter type
    LS Mean difference
    Point estimate
    -1.197
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.91
         upper limit
    -0.485
    Statistical analysis title
    7_TDD_month 3 to month 6
    Statistical analysis description
    average TDD by period have been analysed using a mixed model for repeated measures (MMRM). The MMRM model includes treatment, period, treatment by period interaction and country as fixed effects. An Unstructured covariance structure was used. n° of subjects included in this statistical analysis (n) is: n Envarsus=184 out of 200 n Prograf/Advagraf=181 out of 201 total number = 365 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.002
    Method
    MMRM
    Parameter type
    LS Mean difference
    Point estimate
    -0.984
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.603
         upper limit
    -0.364

    Secondary: 11_Time to Treatment Discontinuation

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    End point title
    11_Time to Treatment Discontinuation
    End point description
    Efficacy endpoint. Time to treatment discontinuation (days) will be calculated as difference between the date of treatment discontinuation for any reason and the date of randomization + 1. Patients who complete the study will be right-censored at last dose. Number of subjects censored and event was reported below. Shown are the number of patients included in the model (modified Intention-to-treat [mITT] population [N]; patients with available results [n])
    End point type
    Secondary
    End point timeframe
    from the randomization day +1
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [34]
    201 [35]
    Units: number of subjects
        subjects censored
    177
    173
        subjects event
    23
    28
    Notes
    [34] - N=200;n=200
    [35] - N=201;n=201
    Statistical analysis title
    1_Time to treatment discontinuation
    Statistical analysis description
    analysis perfomred on censored subjects.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.461
    Method
    Logrank
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.83
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.67
         upper limit
    1.02

    Secondary: 12_Opportunistic Infection

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    End point title
    12_Opportunistic Infection
    End point description
    Safety endpoint. Number of subjects with any opportunistic infection, were presented by treatment group (Envarsus, Prograf/Advagraf) and summarised below. Shown are the number of patients included in the model (safety population [N]; patients with available results [n]) Any infection that was deemed to have occurred due to the immunosuppression was regarded as an opportunistic infection. In particular, the infections due to the following agents were all considered as opportunistic: - herpes simplex virus (HSV), - varicella zoster virus (VZV), - Epstein-Barr virus (EBV), -Cytomegalovirus (CMV), - PcP (Pneumocystitis jiroveci pneumonia) - Mycobacterium tuberculosis -Toxoplasma gondii - Nocardia species - Listeria monocytogenes infections - fungi.
    End point type
    Secondary
    End point timeframe
    Overall the study
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [36]
    201 [37]
    Units: number of subject
        subjects
    38
    40
    Notes
    [36] - N=200;n=200
    [37] - N=201;n=201
    Statistical analysis title
    1_opportunistc infection
    Statistical analysis description
    A Fisher’s exact test will be used to estimate the difference between treatments.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.9 [38]
    Method
    Fisher exact
    Parameter type
    Percentage difference
    Point estimate
    -0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.7
         upper limit
    6.9
    Notes
    [38] - P-value was based on a 2-sided Fisher’s exact test to evaluate the difference between treatment groups in the incidence of events. The 95% CI for the difference in proportions between the two treatment groups was based on the Newcombe-Wilson method.

    Secondary: 13_BKV Viremia

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    End point title
    13_BKV Viremia
    End point description
    Safety endpoint. The number of subjects with BKV viremia (defined as the presence of BKV viremia detected in the in blood sample by nuclear acid testing ),were presented by treatment group (Envarsus, Prograf/Advagraf) and summarised below. For subjects in the safety analysis set over the entire treatment period.Incidents of BKV viremia was recorded as AEs. Shown are the number of patients included in the model (safety population [N]; patients with available results [n])
    End point type
    Secondary
    End point timeframe
    Overall treatment period
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [39]
    201 [40]
    Units: number of subject
        total
    32
    32
        Not clinically significant
    24
    20
        clinically significant
    8
    12
    Notes
    [39] - N=200;n=200
    [40] - N=201;n=201
    Statistical analysis title
    1_BKV Viremia
    Statistical analysis description
    A Fisher’s exact test will be used to estimate the difference between treatments.
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    > 0.999 [41]
    Method
    Fisher exact
    Parameter type
    Percentage difference
    Point estimate
    0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.1
         upper limit
    7.3
    Notes
    [41] - P-value was based on a 2-sided Fisher’s exact test to evaluate the difference between treatment groups in the incidence of events. The 95% CI for the difference in proportions between the two treatment groups was based on the Newcombe-Wilson method.

    Secondary: 14_Malignancy

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    End point title
    14_Malignancy
    End point description
    Safety endpoint. The number of subjects with any malignancy was presented by treatment group (Envarsus, Prograf/Advagraf) and summarised below. Incidents of any malignancy was recorded as AEs. Shown are the number of patients included in the model (safety population [N]; patients with available results [n])
    End point type
    Secondary
    End point timeframe
    Overall study treatment
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [42]
    201 [43]
    Units: number of subject
        subjects
    1
    3
    Notes
    [42] - N=200;n=200
    [43] - N=201;n=201
    Statistical analysis title
    1_malignancy
    Statistical analysis description
    A Fisher’s exact test will be used to estimate the difference between treatments
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.623 [44]
    Method
    Fisher exact
    Parameter type
    Percentage difference
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.8
         upper limit
    1.5
    Notes
    [44] - P-value was based on a 2-sided Fisher’s exact test to evaluate the difference between treatment groups in the incidence of events. The 95% CI for the difference in proportions between the two treatment groups was based on the Newcombe-Wilson method.

    Secondary: 15_Estimated glomerular filtration rate (eGFR)

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    End point title
    15_Estimated glomerular filtration rate (eGFR)
    End point description
    Safety endpoint. The eGFR was calculated according to the 2009 Chronic Kidney Disease Epidemiology Collaboration creatinine equation, utilising the value of serum creatinine of the day. For eGFR, baseline was defined as the Visit 10 (Study Day 28) evaluation. Change from baseline for eGFR results have been reported from day 60 to day 180. Shown are the number of patients included in the model (safety population [N]; patients with available results [n])
    End point type
    Secondary
    End point timeframe
    untill month 6
    End point values
    1_Envarsus® 2_Prograf® /Advagraf®
    Number of subjects analysed
    200 [45]
    201 [46]
    Units: ml/min per 1.73m2
    arithmetic mean (standard deviation)
        change from baseline_day 60
    1.846 ± 10.837
    0.877 ± 10.382
        change from baseline_day 90
    1.214 ± 12.564
    1.830 ± 12.038
        change from baseline_day 120
    2.566 ± 13.348
    2.797 ± 12.997
        change from baseline_day 150
    2.083 ± 14.434
    4.073 ± 13.342
        change from baseline_day 180
    3.196 ± 13.247
    4.654 ± 14.132
    Notes
    [45] - N=200 n day 60 =184 n day 90 =180 n day 120 =178 n day 150 =176 n day 180 =175
    [46] - N=201 n day 60 =185 n day 90 =180 n day 120 =178 n day 150 =175 n day 180 =171
    Statistical analysis title
    1_eGFR_day 60
    Statistical analysis description
    A mixed model for repeated measures (MMRM) will be performed.The MMRM model includes treatment, visit, treatment by visit interaction and country as fixed effects, and baseline eGFR value at Day 28 (Visit 10) as covariate. An Unstructured covariance structure was used. n° of subjects included in this statistical analysis (n) is: n Envarsus=184 out of 200 n Prograf/Advagraf=185 out of 201 total number = 369 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.285
    Method
    MMRM
    Parameter type
    LS Mean difference
    Point estimate
    1.146
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.958
         upper limit
    3.25
    Statistical analysis title
    2_eGFR_day 90
    Statistical analysis description
    A mixed model for repeated measures (MMRM) will be performed.The MMRM model includes treatment, visit, treatment by visit interaction and country as fixed effects, and baseline eGFR value at Day 28 (Visit 10) as covariate. An Unstructured covariance structure was used. n° of subjects included in this statistical analysis (n) is: n Envarsus=180 out of 200 n Prograf/Advagraf=180 out of 201 total number = 360 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.59
    Method
    MMRM
    Parameter type
    LS Mean difference
    Point estimate
    -0.649
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.013
         upper limit
    1.716
    Statistical analysis title
    3_eGFR_day 120
    Statistical analysis description
    A mixed model for repeated measures (MMRM) will be performed.The MMRM model includes treatment, visit, treatment by visit interaction and country as fixed effects, and baseline eGFR value at Day 28 (Visit 10) as covariate. An Unstructured covariance structure was used. n° of subjects included in this statistical analysis (n) is: n Envarsus=178 out of 200 n Prograf/Advagraf=178 out of 201 total number = 356 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.783
    Method
    MMRM
    Parameter type
    LS Mean difference
    Point estimate
    -0.346
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.821
         upper limit
    2.129
    Statistical analysis title
    4_eGFR_day 150
    Statistical analysis description
    A mixed model for repeated measures (MMRM) will be performed.The MMRM model includes treatment, visit, treatment by visit interaction and country as fixed effects, and baseline eGFR value at Day 28 (Visit 10) as covariate. An Unstructured covariance structure was used. n° of subjects included in this statistical analysis (n) is: n Envarsus=176 out of 200 n Prograf/Advagraf=175 out of 201 total number = 351 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.323
    Method
    MMRM
    Parameter type
    LS Mean difference
    Point estimate
    -1.383
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.13
         upper limit
    1.364
    Statistical analysis title
    5_eGFR_day 180
    Statistical analysis description
    A mixed model for repeated measures (MMRM) will be performed.The MMRM model includes treatment, visit, treatment by visit interaction and country as fixed effects, and baseline eGFR value at Day 28 (Visit 10) as covariate. An Unstructured covariance structure was used. n° of subjects included in this statistical analysis (n) is: n Envarsus=175 out of 200 n Prograf/Advagraf=171 out of 201 total number = 346 out of 401
    Comparison groups
    1_Envarsus® v 2_Prograf® /Advagraf®
    Number of subjects included in analysis
    401
    Analysis specification
    Pre-specified
    Analysis type
    other
    P-value
    = 0.426
    Method
    MMRM
    Parameter type
    LS Mean difference
    Point estimate
    -1.093
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.79
         upper limit
    1.604

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From day -28 to day 180+/-7
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    1_Envarsus®
    Reporting group description
    Active Treatment Arm with Envarsus tablets: randomization 1:1 ratio (Arm1: Arm2). Active substance: Tacrolimus monohydrate. Oral administration once daily. starting dose: 0.17mg/kg/day Whatever the treatment, patients will have their dose adjusted to maintain tacrolimus whole blood trough levels within the standard reference ranges of 5-15 ng/ml in the first three months after transplantation and 5-10 ng/ml afterwards.

    Reporting group title
    2_Prograf® /Advagraf®
    Reporting group description
    Reference therapy arm (Arm2) with randomization 1:1 ratio (Arm1: Arm2) (active substance: Tacrolimus monohydrate) - Prograf® capsules will be administered orally. The treatment should commence at the starting total daily dose of 0.2 mg/kg/day delivered in two equally divided doses 12 hours apart (one in the morning and one in the evening) or - Advagraf® capsules will be administered orally. The treatment should commence at the starting total daily dose of 0.2 mg/kg/day administered once daily in the morning. Whatever the treatment, patients will have their dose adjusted to maintain tacrolimus whole blood trough levels within the standard reference ranges of 5-15 ng/ml in the first three months after transplantation and 5-10 ng/ml afterwards.

    Serious adverse events
    1_Envarsus® 2_Prograf® /Advagraf®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    99 / 200 (49.50%)
    93 / 201 (46.27%)
         number of deaths (all causes)
    4
    4
         number of deaths resulting from adverse events
    1
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arterial haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood pressure fluctuation
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intra-abdominal haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    4 / 200 (2.00%)
    4 / 201 (1.99%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic venous thrombosis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyarteritis nodosa
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Transplant rejection
         subjects affected / exposed
    9 / 200 (4.50%)
    8 / 201 (3.98%)
         occurrences causally related to treatment / all
    2 / 9
    2 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incarcerated hernia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Medical device pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    Oedema peripheral
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multimorbidity
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hallucination
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatic obstruction
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         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
    Anastomotic stenosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Animal bite
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bladder injury
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complications of transplanted kidney
         subjects affected / exposed
    12 / 200 (6.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    3 / 13
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fascial rupture
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft complication
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incision site haematoma
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perirenal haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         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 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural urine leak
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal haematoma
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal transplant failure
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxicity to various agents
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant dysfunction
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention postoperative
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular graft thrombosis
         subjects affected / exposed
    2 / 200 (1.00%)
    4 / 201 (1.99%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    10 / 200 (5.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    4 / 10
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    3 / 200 (1.50%)
    3 / 201 (1.49%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Cardiac failure
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 200 (0.50%)
    3 / 201 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Stress cardiomyopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         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 / 200 (0.00%)
    1 / 201 (0.50%)
         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
    Acute pulmonary oedema
         subjects affected / exposed
    0 / 200 (0.00%)
    4 / 201 (1.99%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Bronchitis chronic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Febrile bone marrow aplasia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukocytosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         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
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (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 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Toxic encephalopathy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (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
    3 / 200 (1.50%)
    7 / 201 (3.48%)
         occurrences causally related to treatment / all
    0 / 3
    2 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Duodenal ulcer
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Gastric ulcer
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         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
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Large intestinal haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Large intestine perforation
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophageal ulcer
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis ulcerative
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Subileus
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Anuria
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis proliferative
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 200 (0.50%)
    3 / 201 (1.49%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrectasia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    obstructive uropathy
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postrenal failure
         subjects affected / exposed
    3 / 200 (1.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal aneurysm
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery stenosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (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
         subjects affected / exposed
    3 / 200 (1.50%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 200 (0.50%)
    4 / 201 (1.99%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal necrosis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal tubular necrosis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteral disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteral necrosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric dilatation
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary fistula
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vesical fistula
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic failure
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Flank pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscle haemorrhage
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypocalcaemia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Anal abscess
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial infection
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Citrobacter infection
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis escherichia
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis klebsiella
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus gastroenteritis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    5 / 200 (2.50%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    2 / 6
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia infection
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia pyelonephritis
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    3 / 200 (1.50%)
    4 / 201 (1.99%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    2 / 200 (1.00%)
    4 / 201 (1.99%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella bacteraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Klebsiella sepsis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (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 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mycotic aneurysm
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nosocomial infection
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral candidiasis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 200 (0.00%)
    3 / 201 (1.49%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyomavirus-associated nephropathy
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural infection
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonas infection
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pseudomonal sepsis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    5 / 200 (2.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    2 / 7
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    2 / 200 (1.00%)
    5 / 201 (2.49%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant abscess
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    6 / 200 (3.00%)
    11 / 201 (5.47%)
         occurrences causally related to treatment / all
    1 / 7
    5 / 14
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    5 / 200 (2.50%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection bacterial
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection fungal
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    1_Envarsus® 2_Prograf® /Advagraf®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    187 / 200 (93.50%)
    188 / 201 (93.53%)
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Arterial disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Arteriovenous fistula
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Deep vein thrombosis
         subjects affected / exposed
    2 / 200 (1.00%)
    3 / 201 (1.49%)
         occurrences all number
    2
    3
    Haematoma
         subjects affected / exposed
    3 / 200 (1.50%)
    2 / 201 (1.00%)
         occurrences all number
    3
    2
    Hot flush
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    39 / 200 (19.50%)
    29 / 201 (14.43%)
         occurrences all number
    41
    30
    Hypertensive crisis
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    3
    Hypotension
         subjects affected / exposed
    8 / 200 (4.00%)
    6 / 201 (2.99%)
         occurrences all number
    8
    6
    Intra-abdominal haematoma
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 201 (0.00%)
         occurrences all number
    3
    0
    Jugular vein thrombosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Lymphocele
         subjects affected / exposed
    4 / 200 (2.00%)
    9 / 201 (4.48%)
         occurrences all number
    4
    9
    Lymphorrhoea
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Orthostatic hypotension
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Peripheral artery stenosis
         subjects affected / exposed
    0 / 200 (0.00%)
    4 / 201 (1.99%)
         occurrences all number
    0
    4
    Phlebitis
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Secondary hypertension
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Thrombophlebitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Thrombosis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    2
    Vascular pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    2
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Mycosis fungoides
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Prostatic adenoma
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Renal cancer
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Skin cancer
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Vulvovaginal warts
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Immune system disorders
    Drug hypersensitivity
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Hypogammaglobulinaemia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Seasonal allergy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Transplant rejection
         subjects affected / exposed
    9 / 200 (4.50%)
    4 / 201 (1.99%)
         occurrences all number
    10
    4
    General disorders and administration site conditions
    Acute phase reaction
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Administration site inflammation
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Asthenia
         subjects affected / exposed
    6 / 200 (3.00%)
    6 / 201 (2.99%)
         occurrences all number
    6
    7
    Catheter site inflammation
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Catheter site pain
         subjects affected / exposed
    1 / 200 (0.50%)
    6 / 201 (2.99%)
         occurrences all number
    1
    6
    Chest discomfort
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Chest pain
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Chills
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Decreased activity
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Device dislocation
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Face oedema
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Fatigue
         subjects affected / exposed
    6 / 200 (3.00%)
    8 / 201 (3.98%)
         occurrences all number
    6
    8
    Feeling hot
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Fibrosis
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Impaired healing
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Implant site extravasation
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    3 / 200 (1.50%)
    1 / 201 (0.50%)
         occurrences all number
    3
    1
    Localised oedema
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Malaise
         subjects affected / exposed
    3 / 200 (1.50%)
    1 / 201 (0.50%)
         occurrences all number
    4
    1
    Medical device complication
         subjects affected / exposed
    1 / 200 (0.50%)
    3 / 201 (1.49%)
         occurrences all number
    1
    3
    Medical device pain
         subjects affected / exposed
    4 / 200 (2.00%)
    1 / 201 (0.50%)
         occurrences all number
    5
    1
    Non-cardiac chest pain
         subjects affected / exposed
    5 / 200 (2.50%)
    0 / 201 (0.00%)
         occurrences all number
    5
    0
    Oedema peripheral
         subjects affected / exposed
    36 / 200 (18.00%)
    30 / 201 (14.93%)
         occurrences all number
    43
    30
    Oedema
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    3 / 200 (1.50%)
    4 / 201 (1.99%)
         occurrences all number
    3
    4
    Pyrexia
         subjects affected / exposed
    21 / 200 (10.50%)
    9 / 201 (4.48%)
         occurrences all number
    23
    11
    Xerosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 200 (0.50%)
    4 / 201 (1.99%)
         occurrences all number
    1
    4
    Anxiety disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Anxiety
         subjects affected / exposed
    13 / 200 (6.50%)
    9 / 201 (4.48%)
         occurrences all number
    13
    10
    Confusional state
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    1 / 200 (0.50%)
    3 / 201 (1.49%)
         occurrences all number
    1
    3
    Dysthymic disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Emotional distress
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Hallucination
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Insomnia
         subjects affected / exposed
    21 / 200 (10.50%)
    20 / 201 (9.95%)
         occurrences all number
    21
    22
    Mental disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Nervousness
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Restlessness
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Sleep disorder
         subjects affected / exposed
    5 / 200 (2.50%)
    8 / 201 (3.98%)
         occurrences all number
    6
    8
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    1 / 200 (0.50%)
    6 / 201 (2.99%)
         occurrences all number
    1
    6
    Breast mass
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Dysmenorrhoea
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Erectile dysfunction
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Gynaecomastia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Ovarian cyst
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Pelvic haematoma
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Penile oedema
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Penile pain
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    3
    Prostatomegaly
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Rectocele
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Scrotal oedema
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Scrotal swelling
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Testicular oedema
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Testicular pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Testicular swelling
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Anaemia postoperative
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Anaesthetic complication
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Arteriovenous fistula site complication
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    3 / 200 (1.50%)
    3 / 201 (1.49%)
         occurrences all number
    3
    3
    Chronic allograft nephropathy
         subjects affected / exposed
    1 / 200 (0.50%)
    3 / 201 (1.49%)
         occurrences all number
    1
    3
    Complications of transplant surgery
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Complications of transplanted kidney
         subjects affected / exposed
    22 / 200 (11.00%)
    28 / 201 (13.93%)
         occurrences all number
    25
    28
    Contusion
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Face injury
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Fall
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences all number
    2
    1
    Foot fracture
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Graft complication
         subjects affected / exposed
    4 / 200 (2.00%)
    0 / 201 (0.00%)
         occurrences all number
    4
    0
    Incisional hernia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Laceration
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Overdose
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Perirenal haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Post procedural complication
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Post procedural haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Postoperative wound complication
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Procedural anxiety
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Procedural pain
         subjects affected / exposed
    7 / 200 (3.50%)
    6 / 201 (2.99%)
         occurrences all number
    7
    6
    Radius fracture
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Renal haematoma
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Rib fracture
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Scrotal haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Seroma
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 201 (0.00%)
         occurrences all number
    3
    0
    Shunt thrombosis
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Subcutaneous haematoma
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Toxicity to various agents
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Transplant dysfunction
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Transplantation complication
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Wound complication
         subjects affected / exposed
    9 / 200 (4.50%)
    17 / 201 (8.46%)
         occurrences all number
    10
    17
    Wound dehiscence
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Wound haematoma
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Investigations
    Acid base balance abnormal
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Blood bicarbonate decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Blood calcium decreased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Blood creatinine increased
         subjects affected / exposed
    6 / 200 (3.00%)
    5 / 201 (2.49%)
         occurrences all number
    6
    5
    Blood glucose abnormal
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Blood glucose increased
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    2 / 200 (1.00%)
    3 / 201 (1.49%)
         occurrences all number
    2
    3
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Blood potassium increased
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Blood pressure increased
         subjects affected / exposed
    0 / 200 (0.00%)
    3 / 201 (1.49%)
         occurrences all number
    0
    3
    Blood pressure systolic increased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Blood sodium decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Blood sodium increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    C-reactive protein increased
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Cardiac murmur
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Coagulation factor
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Cytomegalovirus test positive
         subjects affected / exposed
    3 / 200 (1.50%)
    4 / 201 (1.99%)
         occurrences all number
    3
    4
    Electrocardiogram abnormal
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Enterococcus test positive
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Escherichia test positive
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Fungal test positive
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Glucose tolerance test abnormal
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Glycosylated haemoglobin increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Haematocrit decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Immunosuppressant drug level increased
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Inflammatory marker increased
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Liver function test abnormal
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Low density lipoprotein increased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Oxygen saturation decreased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Polyomavirus test positive
         subjects affected / exposed
    4 / 200 (2.00%)
    1 / 201 (0.50%)
         occurrences all number
    4
    1
    Red blood cell count decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Renal function test abnormal
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Staphylococcus test positive
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Transaminases increased
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Viral test positive
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Volume blood decreased
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Weight increased
         subjects affected / exposed
    3 / 200 (1.50%)
    3 / 201 (1.49%)
         occurrences all number
    3
    3
    White blood cell count decreased
         subjects affected / exposed
    0 / 200 (0.00%)
    3 / 201 (1.49%)
         occurrences all number
    0
    3
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    3 / 200 (1.50%)
    4 / 201 (1.99%)
         occurrences all number
    3
    4
    Atrial fibrillation
         subjects affected / exposed
    2 / 200 (1.00%)
    5 / 201 (2.49%)
         occurrences all number
    2
    6
    Bradycardia
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Cardiac arrest
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Extrasystoles
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Mitral valve incompetence
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Palpitations
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Sinus tachycardia
         subjects affected / exposed
    1 / 200 (0.50%)
    6 / 201 (2.99%)
         occurrences all number
    1
    6
    Tachyarrhythmia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Tachycardia
         subjects affected / exposed
    5 / 200 (2.50%)
    3 / 201 (1.49%)
         occurrences all number
    5
    3
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Congenital, familial and genetic disorders
    Hydrocele
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Hypertrophic cardiomyopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Atelectasis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Bronchial irritation
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Cough
         subjects affected / exposed
    11 / 200 (5.50%)
    9 / 201 (4.48%)
         occurrences all number
    11
    10
    Dyspnoea
         subjects affected / exposed
    11 / 200 (5.50%)
    9 / 201 (4.48%)
         occurrences all number
    11
    9
    Hiccups
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Nasal congestion
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences all number
    2
    1
    Oropharyngeal pain
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    3
    Pleural effusion
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Pneumothorax
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Productive cough
         subjects affected / exposed
    3 / 200 (1.50%)
    2 / 201 (1.00%)
         occurrences all number
    3
    2
    Pulmonary venous thrombosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Rales
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Respiratory failure
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Sinus congestion
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Sputum increased
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Throat irritation
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Wheezing
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    67 / 200 (33.50%)
    66 / 201 (32.84%)
         occurrences all number
    68
    68
    Bone marrow failure
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Coagulopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Febrile neutropenia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Leukocytosis
         subjects affected / exposed
    15 / 200 (7.50%)
    9 / 201 (4.48%)
         occurrences all number
    17
    9
    Leukopenia
         subjects affected / exposed
    25 / 200 (12.50%)
    28 / 201 (13.93%)
         occurrences all number
    26
    30
    Lymph node pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Lymphadenopathy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Lymphopenia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Nephrogenic anaemia
         subjects affected / exposed
    6 / 200 (3.00%)
    5 / 201 (2.49%)
         occurrences all number
    7
    5
    Neutropenia
         subjects affected / exposed
    7 / 200 (3.50%)
    5 / 201 (2.49%)
         occurrences all number
    7
    5
    Neutrophilia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Pancytopenia
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 201 (0.00%)
         occurrences all number
    3
    0
    Polycythaemia
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Splenomegaly
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Thrombocytopenia
         subjects affected / exposed
    8 / 200 (4.00%)
    3 / 201 (1.49%)
         occurrences all number
    9
    3
    Thrombocytosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Brachial plexopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Carotid arteriosclerosis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Cerebral infarction
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Dizziness
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Dysaesthesia
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 201 (0.00%)
         occurrences all number
    3
    0
    Dysgeusia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Dyskinesia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Headache
         subjects affected / exposed
    18 / 200 (9.00%)
    12 / 201 (5.97%)
         occurrences all number
    19
    13
    Meralgia paraesthetica
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Monoparesis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Neuralgia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Paraesthesia
         subjects affected / exposed
    3 / 200 (1.50%)
    1 / 201 (0.50%)
         occurrences all number
    3
    1
    Presyncope
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Resting tremor
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Restless legs syndrome
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Sciatica
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Syncope
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Tremor
         subjects affected / exposed
    37 / 200 (18.50%)
    23 / 201 (11.44%)
         occurrences all number
    39
    24
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Chorioretinopathy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Conjunctival haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Corneal erosion
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Dry eye
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Retinal vascular thrombosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Uveitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Visual impairment
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Vitreous detachment
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Hypoacusis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Tinnitus
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Vertigo
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Abdominal distension
         subjects affected / exposed
    3 / 200 (1.50%)
    2 / 201 (1.00%)
         occurrences all number
    3
    2
    Abdominal hernia
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Abdominal pain upper
         subjects affected / exposed
    5 / 200 (2.50%)
    1 / 201 (0.50%)
         occurrences all number
    5
    1
    Abdominal pain
         subjects affected / exposed
    19 / 200 (9.50%)
    21 / 201 (10.45%)
         occurrences all number
    20
    21
    Abdominal wall haematoma
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Abnormal faeces
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Anal fissure
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Anorectal discomfort
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Aphthous stomatitis
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Cheilitis
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Colitis
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Constipation
         subjects affected / exposed
    24 / 200 (12.00%)
    35 / 201 (17.41%)
         occurrences all number
    25
    36
    Diarrhoea
         subjects affected / exposed
    40 / 200 (20.00%)
    36 / 201 (17.91%)
         occurrences all number
    50
    41
    Dry mouth
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Dysbacteriosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Dyspepsia
         subjects affected / exposed
    6 / 200 (3.00%)
    12 / 201 (5.97%)
         occurrences all number
    6
    12
    Dysphagia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Flatulence
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences all number
    2
    1
    Functional gastrointestinal disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Gastric dilatation
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Gastric ulcer
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Gastritis erosive
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Gastritis
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Gastrointestinal motility disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Gastrooesophageal reflux disease
         subjects affected / exposed
    3 / 200 (1.50%)
    4 / 201 (1.99%)
         occurrences all number
    3
    4
    Gingival hyperplasia
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Gingival inflammation
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Gingival swelling
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Haematemesis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Haemorrhoids
         subjects affected / exposed
    6 / 200 (3.00%)
    6 / 201 (2.99%)
         occurrences all number
    6
    6
    Ileus paralytic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Ileus
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Inguinal hernia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Intestinal obstruction
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Lip dry
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Melaena
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Nausea
         subjects affected / exposed
    21 / 200 (10.50%)
    16 / 201 (7.96%)
         occurrences all number
    22
    18
    Oral mucosa erosion
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Oral pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Pancreatitis chronic
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Reactive gastropathy
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Stomatitis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Varices oesophageal
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    13 / 200 (6.50%)
    12 / 201 (5.97%)
         occurrences all number
    14
    13
    Renal and urinary disorders
    Albuminuria
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Anuria
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences all number
    2
    1
    Azotaemia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Bladder pain
         subjects affected / exposed
    1 / 200 (0.50%)
    4 / 201 (1.99%)
         occurrences all number
    1
    4
    Bladder spasm
         subjects affected / exposed
    11 / 200 (5.50%)
    8 / 201 (3.98%)
         occurrences all number
    12
    8
    Dysuria
         subjects affected / exposed
    7 / 200 (3.50%)
    3 / 201 (1.49%)
         occurrences all number
    8
    3
    Haematuria
         subjects affected / exposed
    14 / 200 (7.00%)
    10 / 201 (4.98%)
         occurrences all number
    15
    10
    Haemorrhage urinary tract
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Hydronephrosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Hypertonic bladder
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Leukocyturia
         subjects affected / exposed
    4 / 200 (2.00%)
    2 / 201 (1.00%)
         occurrences all number
    4
    2
    Microalbuminuria
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Nephrectasia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Nephropathy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Nephrotic syndrome
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Nocturia
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Obstructive uropathy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Oliguria
         subjects affected / exposed
    1 / 200 (0.50%)
    4 / 201 (1.99%)
         occurrences all number
    1
    5
    Pollakiuria
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences all number
    2
    1
    Polyuria
         subjects affected / exposed
    3 / 200 (1.50%)
    2 / 201 (1.00%)
         occurrences all number
    3
    2
    Proteinuria
         subjects affected / exposed
    8 / 200 (4.00%)
    8 / 201 (3.98%)
         occurrences all number
    8
    8
    Pyelocaliectasis
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences all number
    2
    1
    Renal colic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Renal artery stenosis
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Renal failure acute
         subjects affected / exposed
    2 / 200 (1.00%)
    3 / 201 (1.49%)
         occurrences all number
    2
    3
    Renal failure chronic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Renal glycosuria
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Renal haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Renal impairment
         subjects affected / exposed
    5 / 200 (2.50%)
    9 / 201 (4.48%)
         occurrences all number
    6
    9
    Renal pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Renal tubular acidosis
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Renal tubular disorder
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Strangury
         subjects affected / exposed
    0 / 200 (0.00%)
    2 / 201 (1.00%)
         occurrences all number
    0
    2
    Ureteric dilatation
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Ureteric stenosis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Urethral dilatation
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Urethral haemorrhage
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Urethral obstruction
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Urethral pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Urge incontinence
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Urinary bladder polyp
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Urinary incontinence
         subjects affected / exposed
    2 / 200 (1.00%)
    3 / 201 (1.49%)
         occurrences all number
    2
    3
    Urinary retention
         subjects affected / exposed
    2 / 200 (1.00%)
    3 / 201 (1.49%)
         occurrences all number
    3
    3
    Urinary tract disorder
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Urinary tract obstruction
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Urinary tract pain
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Urinoma
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    4 / 200 (2.00%)
    1 / 201 (0.50%)
         occurrences all number
    4
    1
    Drug-induced liver injury
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Hepatic function abnormal
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Hepatitis
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Hepatocellular injury
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Hypertransaminasaemia
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Jaundice cholestatic
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Liver disorder
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 201 (0.00%)
         occurrences all number
    3
    0
    Alopecia
         subjects affected / exposed
    4 / 200 (2.00%)
    5 / 201 (2.49%)
         occurrences all number
    4
    5
    Capillaritis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Diabetic foot
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Ecchymosis
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Eczema
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Erythema
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences all number
    2
    1
    Night sweats
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Petechiae
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Pityriasis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Prurigo
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    3
    0
    Pruritus allergic
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Pruritus generalised
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Pruritus
         subjects affected / exposed
    4 / 200 (2.00%)
    0 / 201 (0.00%)
         occurrences all number
    4
    0
    Rash pruritic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    5 / 200 (2.50%)
    0 / 201 (0.00%)
         occurrences all number
    5
    0
    Scar pain
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Skin lesion
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Skin ulcer
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Urticaria
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    4 / 200 (2.00%)
    2 / 201 (1.00%)
         occurrences all number
    4
    2
    Back pain
         subjects affected / exposed
    8 / 200 (4.00%)
    6 / 201 (2.99%)
         occurrences all number
    8
    6
    Flank pain
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Groin pain
         subjects affected / exposed
    2 / 200 (1.00%)
    1 / 201 (0.50%)
         occurrences all number
    2
    1
    Intervertebral disc compression
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Joint swelling
         subjects affected / exposed
    3 / 200 (1.50%)
    1 / 201 (0.50%)
         occurrences all number
    3
    1
    Muscle atrophy
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Muscle spasms
         subjects affected / exposed
    7 / 200 (3.50%)
    3 / 201 (1.49%)
         occurrences all number
    7
    3
    Muscular weakness
         subjects affected / exposed
    2 / 200 (1.00%)
    0 / 201 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Musculoskeletal pain
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    3
    2
    Myalgia
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Myopathy
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Neck mass
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    1 / 200 (0.50%)
    2 / 201 (1.00%)
         occurrences all number
    1
    2
    Osteopenia
         subjects affected / exposed
    3 / 200 (1.50%)
    1 / 201 (0.50%)
         occurrences all number
    3
    1
    Osteoporosis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    2 / 200 (1.00%)
    5 / 201 (2.49%)
         occurrences all number
    2
    5
    Spinal pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Tendon pain
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Tendonitis
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Endocrine disorders
    Hyperparathyroidism secondary
         subjects affected / exposed
    2 / 200 (1.00%)
    2 / 201 (1.00%)
         occurrences all number
    2
    2
    Hyperparathyroidism
         subjects affected / exposed
    3 / 200 (1.50%)
    0 / 201 (0.00%)
         occurrences all number
    3
    0
    Hypoparathyroidism
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Hypothyroidism
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Acidosis hyperchloraemic
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Acidosis
         subjects affected / exposed
    6 / 200 (3.00%)
    3 / 201 (1.49%)
         occurrences all number
    8
    3
    Alkalosis
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Calcium deficiency
         subjects affected / exposed
    0 / 200 (0.00%)
    1 / 201 (0.50%)
         occurrences all number
    0
    1
    Cell death
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Decreased appetite
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Dehydration
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1
    1
    Diabetes mellitus
         subjects affected / exposed
    12 / 200 (6.00%)
    20 / 201 (9.95%)
         occurrences all number
    12
    20
    Dyslipidaemia
         subjects affected / exposed
    6 / 200 (3.00%)
    11 / 201 (5.47%)
         occurrences all number
    6
    11
    Electrolyte depletion
         subjects affected / exposed
    1 / 200 (0.50%)
    0 / 201 (0.00%)
         occurrences all number
    1
    0
    Electrolyte imbalance
         subjects affected / exposed
    4 / 200 (2.00%)
    7 / 201 (3.48%)
         occurrences all number
    5
    8
    Fluid overload
         subjects affected / exposed
    4 / 200 (2.00%)
    4 / 201 (1.99%)
         occurrences all number
    4
    4
    Fluid retention
         subjects affected / exposed
    12 / 200 (6.00%)
    7 / 201 (3.48%)
         occurrences all number
    12
    9
    Folate deficiency
         subjects affected / exposed
    0 / 200 (0.00%)
    4 / 201 (1.99%)
         occurrences all number
    0
    4
    Glucose tolerance impaired
         subjects affected / exposed
    0 / 200 (0.00%)
    3 / 201 (1.49%)
         occurrences all number
    0
    3
    Gout
         subjects affected / exposed
    1 / 200 (0.50%)
    1 / 201 (0.50%)
         occurrences all number
    1