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    Clinical Trial Results:
    A MULTICENTER, TWO ARM, RANDOMIZED, OPEN LABEL CLINICAL STUDY INVESTIGATING RENAL FUNCTION IN AN ADVAGRAF®-BASED IMMUNOSUPPRESSIVE REGIMEN WITH OR WITHOUT SIROLIMUS IN KIDNEY TRANSPLANT SUBJECTS

    Summary
    EudraCT number
    2010-019639-37
    Trial protocol
    HU   CZ   AT   DE   ES   SK   NL   IT   BE  
    Global end of trial date
    18 Sep 2013

    Results information
    Results version number
    v1(current)
    This version publication date
    01 Apr 2016
    First version publication date
    22 May 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PMR-EC-1212
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01363752
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe Ltd.
    Sponsor organisation address
    2000 Hillswood Drive, Chertsey, Surrey, United Kingdom, KT16 0RS
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe Ltd., Astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe Ltd., Astellas.resultsdisclosure@astellas.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
    18 Sep 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Sep 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to compare the effect of 2 immunosuppressive therapy regimens on glomerular filtration rate (GFR) estimated by iohexol clearance at week 52 post kidney transplantation. Arm 1: Advagraf + MMF + steroids Arm 2: Advagraf + MMF (withdrawn at day 28) + steroids + sirolimus (introduced at day 28) in combination with reduced Advagraf dose at day 42 (week 6) to achieve lower tacrolimus target levels.
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, ICH GCP Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    Advagraf®, MMF (CellCept®) and sirolimus (Rapamune®) were defined as study drugs in this study. Advagraf® and sirolimus were considered to be Investigational Medicinal Product (IMP) and were provided by the Sponsor. MMF and iohexol although not considered to be IMP in this study were also provided by the Sponsor. Corticosteroids were also not considered to be IMP and were not provided by the Sponsor. All subjects took Advagraf, MMF and Steroids prior to transplant and randomization. Advagraf Day 0 – Day 27 Pre-operative dose 0.1 mg/ kg was given orally in one dose, at any time within 12 hours prior to reperfusion and if possible within 3 hours prior to anesthesia. The initial post-operative dose is 0.2 mg/ kg/ day given orally in one dose, preferably in the morning and should not be administered less than 4 hours after pre-operative dose or more than 12 hours after reperfusion. Advagraf® doses were adjusted on the basis of clinical evidence of efficacy and occurrence of AEs and observing the following recommended whole blood trough level ranges: Day 0 – 14: 10 – 15 ng/ ml, Day 15 – 27: 8 – 12 ng/ ml. MMF Day 0 - Day 27. A loading dose of 1g of MMF was given preoperatively. First post-operative dose of MMF was administered within 24 hours following reperfusion. The daily dose of 2g (3g/ day for Black or African-American subjects) was given orally and split into two dose (equals 1g twice daily) for the first 14 days. Thereafter the daily dose is reduced to 1g given in two doses (equals 0.5g twice daily) until Day 28 (Visit 5). Corticosteroids IV (bolus) & oral, Methylprednisolone or equivalent Day 0: 0 – 1000 mg IV bolus (pre, intra, or post-op), Prednisolone or equivalent taken orally Day 1 – 13: 20 mg/ day, Day 14 – 28: 15 mg/ day.
    Evidence for comparator
    Not applicable, this was an open label study.
    Actual start date of recruitment
    08 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 34
    Country: Number of subjects enrolled
    Netherlands: 27
    Country: Number of subjects enrolled
    Spain: 52
    Country: Number of subjects enrolled
    Austria: 48
    Country: Number of subjects enrolled
    Belgium: 15
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    France: 140
    Country: Number of subjects enrolled
    Germany: 154
    Country: Number of subjects enrolled
    Hungary: 25
    Country: Number of subjects enrolled
    Italy: 80
    Country: Number of subjects enrolled
    Australia: 2
    Country: Number of subjects enrolled
    Belarus: 46
    Country: Number of subjects enrolled
    Hong Kong: 6
    Country: Number of subjects enrolled
    Korea, Republic of: 33
    Country: Number of subjects enrolled
    Russian Federation: 37
    Country: Number of subjects enrolled
    Taiwan: 3
    Country: Number of subjects enrolled
    Turkey: 15
    Worldwide total number of subjects
    730
    EEA total number of subjects
    588
    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)
    641
    From 65 to 84 years
    89
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    This multicenter study was conducted at 58 sites in 18 European and Asia-Pacific countries.

    Pre-assignment
    Screening details
    Eligibility took place baseline/Visit 1, up to 96 hours prior to transplantation Day 0-Day 27 prior to randomization on Day 28/Visit 5. Screening assessments: pregnancy test, donor/organ data, surgical details, vital signs, height, weight, laboratory assessments, dispensing/collecting study drugs, serum creatinine/glucose and EQ-5D questionnaires.

    Pre-assignment period milestones
    Number of subjects started
    853 [1]
    Number of subjects completed
    730

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Not fulfilling inclusion/exclusion criteria: 13
    Reason: Number of subjects
    Retransplantation/graft loss: 5
    Reason: Number of subjects
    No study pre-treatment taken: 3
    Reason: Number of subjects
    Adverse event: 53
    Reason: Number of subjects
    Withdrawal of consent: 14
    Reason: Number of subjects
    Protocol violation: 7
    Reason: Number of subjects
    Miscellaneous: 28
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The Pre-assignment period "started" number reflects all subjects consented/enrolled. The Pre-assignment period "completed" number reflects all subjects that transplanted and randomized. The worldwide number includes all randomized subjects. Randomization for this study did not occur until transplantation Day 28/Visit 5.
    Period 1
    Period 1 title
    Overall Period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Not applicable, this was an open label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Advagraf + MMF + Steroids
    Arm description
    Arm 1 served as the reference arm for the study; the combination of tacrolimus and MMF has a proven efficacy and safety profile.
    Arm type
    Active comparator

    Investigational medicinal product name
    Advagraf
    Investigational medicinal product code
    FK506E (MR4)
    Other name
    prolonged release tacrolimus
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Advagraf® was defined as study drug in this study, considered to be Investigational Medicinal Product (IMP) and was provided by the Sponsor. Advagraf was available as hard gelatin capsules with 0.5 mg, 1 mg, 3 mg. For patients randomized to treatment Arm 1, the Advagraf daily dose continued to be administered orally once a day in the morning Day 28 to Day 365. The dosing was adjusted on the basis of clinical evidence of efficacy and occurrence of AEs and observing the following recommended blood trough levels: Days 28 through 41: 8 to 12 ng/mL, Days 42 through 365: 6 to 10 ng/mL. In the event that the patient was unable to swallow the Advagraf capsule, administration was permitted via nasogastric tube, as for normal oral administration of intact Advagraf capsules.

    Investigational medicinal product name
    Mycophenolate Mofetil
    Investigational medicinal product code
    Other name
    MMF, Cellcept
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    MMF (CellCept®) was defined as study drug in this study, although not considered to be IMP in this study it was provided by the Sponsor. CellCept was available as hard gelatin capsules with 250 mg MMF. MMF (Arm 1) Day 28 to Day 365, for patients randomized to treatment Arm 1, the MMF daily dose of 1 g was administered in 2 doses (equals 0.5 g twice daily) until the end-of-study (EOS) visit (visit 10).

    Investigational medicinal product name
    Corticosteroids
    Investigational medicinal product code
    Other name
    Steroids
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Corticosteroids were not provided by the Sponsor and were not considered to be investigational medicinal products (IMPs). Corticosteroids were a permitted concomitant immunosuppressive treatment. Prednisolone, or equivalent, orally was to be administered post randomization as follows: Day 29 through 42: 10 mg/day, Day 43 through 60: 5 mg/day, Day 60 through 365: ≤ 5 mg/day.

    Arm title
    Advagraf + MMF + Steroids + Sirolimus
    Arm description
    Arm 2 Advagraf + MMF(withdrawn on Day 28) + Steroids + Sirolimus(introduced on Day 28) in combination with lower tacrolimus exposure at Day 42 (week 6) was compared to Arm 1.
    Arm type
    Experimental

    Investigational medicinal product name
    Advagraf
    Investigational medicinal product code
    FK506E (MR4)
    Other name
    prolonged release tacrolimus
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Advagraf® was defined as study drug in this study, considered to be Investigational Medicinal Product (IMP) and was provided by the Sponsor. Advagraf was available as hard gelatin capsules with 0.5 mg, 1 mg, 3 mg. For patients randomized to treatment Arm 2, Advagraf daily dose continued to be administered orally once a day in the morning through day 28 with dosing adjusted based on the following tacrolimus blood trough concentrations: Day 28 through 41: 8 to 12 ng/mL. Only for patients in Arm 2, the Advagraf dose was decreased by at least 25% to the following reduced target tacrolimus trough levels on day 42 (week 6): Day 42 through 365: 4 to 5 ng/mL. In the event that the patient was unable to swallow the Advagraf capsule, administration was permitted via nasogastric tube.

    Investigational medicinal product name
    Mycophenolate Mofetil
    Investigational medicinal product code
    Other name
    MMF, Cellcept
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    MMF (CellCept®) was defined as study drug in this study, although not considered to be IMP in this study it was provided by the Sponsor. CellCept was available as hard gelatin capsules with 250 mg MMF. MMF dose was 1 g, given in 2 doses (equals 0.5 g twice daily), for patients randomized to treatment Arm 2, MMF was stopped on day 28 (visit 5) randomization day.

    Investigational medicinal product name
    Corticosteroids
    Investigational medicinal product code
    Other name
    Steroids
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Corticosteroids were not provided by the Sponsor and were not considered to be investigational medicinal products (IMPs). Corticosteroids were a permitted concomitant immunosuppressive treatment. Prednisolone, or equivalent, orally was to be administered post randomization as follows: Day 29 through 42: 10 mg/day, Day 43 through 60: 5 mg/day, Day 60 through 365: ≤ 5 mg/day.

    Investigational medicinal product name
    Sirolimus
    Investigational medicinal product code
    Other name
    Rapamune
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Sirolimus (Rapamune®) was available as 1 mg or 0.5 mg tablets. For patients randomized to treatment Arm 2, sirolimus was administered on days 28 through 365. Sirolimus initial daily doses of 1 mg were administered orally once a day in the morning. After the initial dosing subsequent sirolimus doses were taken orally once a day only in the morning and doses could be adjusted up to a maximum dose of 2 mg on the basis of clinical evidence of efficacy and occurrence of AEs and observing the following recommended whole blood trough level range: Day 28 through 365: 2 to 4 ng/mL.

    Number of subjects in period 1
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Started
    362
    368
    Completed
    324
    301
    Not completed
    38
    67
         Not fulfilling inclusion/exclusion criteria
    1
    -
         Miscellaneous
    5
    3
         Protocol violation
    1
    3
         Withdrawal of consent
    7
    4
         Adverse event
    19
    53
         Retransplantation/graft loss
    2
    2
         Lost to follow-up
    3
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Advagraf + MMF + Steroids
    Reporting group description
    Arm 1 served as the reference arm for the study; the combination of tacrolimus and MMF has a proven efficacy and safety profile.

    Reporting group title
    Advagraf + MMF + Steroids + Sirolimus
    Reporting group description
    Arm 2 Advagraf + MMF(withdrawn on Day 28) + Steroids + Sirolimus(introduced on Day 28) in combination with lower tacrolimus exposure at Day 42 (week 6) was compared to Arm 1.

    Reporting group values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus Total
    Number of subjects
    362 368 730
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Age values provided are for the Intent-to-treat (ITT) population. The ITT population consisted of patients who had been transplanted (underwent reperfusion) and randomized.
    Units: years
        arithmetic mean (standard deviation)
    49.44 ± 13.065 49.74 ± 13.11 -
    Gender categorical
    Gender values provided are for the ITT population, the ITT population consisted of patients who had been transplanted (underwent reperfusion) and randomized.
    Units: Subjects
        Female
    128 121 249
        Male
    234 247 481

    End points

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    End points reporting groups
    Reporting group title
    Advagraf + MMF + Steroids
    Reporting group description
    Arm 1 served as the reference arm for the study; the combination of tacrolimus and MMF has a proven efficacy and safety profile.

    Reporting group title
    Advagraf + MMF + Steroids + Sirolimus
    Reporting group description
    Arm 2 Advagraf + MMF(withdrawn on Day 28) + Steroids + Sirolimus(introduced on Day 28) in combination with lower tacrolimus exposure at Day 42 (week 6) was compared to Arm 1.

    Primary: Glomerular filtration rate (GFR) estimated by iohexol clearance at week 52 post kidney transplantation

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    End point title
    Glomerular filtration rate (GFR) estimated by iohexol clearance at week 52 post kidney transplantation
    End point description
    Determination of GFR by iohexol clearance was obtained for each patient by performing regression analysis of the natural logarithm (iohexol plasma concentration) on sample time points, calculating the AUC, obtaining the iohexol clearance, and estimating the GFR from iohexol using Brochner-Mortensen correction. Patients who had graft loss (death, retransplantation or dialysis ongoing at study end or discontinuation) were included with a GFR of zero (0). Study analysis population for this endpoint consisted of the Full Analysis Set (FAS) population. The FAS population included patients who had been transplanted, randomized, and had a post-randomization assessment of the primary endpoint (that is, evaluable iohexol sample measurements). Missing end of treatment variables were imputed by last observation carried forward (LOCF).
    End point type
    Primary
    End point timeframe
    End of Study (EOS), Week 52
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    287
    282
    Units: GFR by iohexol clearance mL/min/1.73 m2
        arithmetic mean (standard deviation)
    45.48 ± 18.018
    46.37 ± 20.304
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    The hypothesis being tested for the primary variable is described as follows: H0: Mean iohexol clearance ARM 1 = Mean iohexol clearance rate ARM 2 H1: Mean iohexol clearance ARM 1 ≠ Mean iohexol clearance rate ARM 2
    Comparison groups
    Advagraf + MMF + Steroids + Sirolimus v Advagraf + MMF + Steroids
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.405
    Method
    ANCOVA
    Parameter type
    Least-squares mean difference Arm2-Arm1
    Point estimate
    1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.392
         upper limit
    3.441
    Notes
    [1] - Analysis of Covariance (ANCOVA) model. The P value is from an ANCOVA model in which treatment arm, sex, race (Black or non-Black), site and donor status (deceased or nondeceased) were included as factors, estimated glomerular filtration rate (eGFR) Modification Diet in Renal Disease (4-variable) (MDRD4) at randomization and donor age are included as continuous covariates.

    Secondary: Renal function at week 52 after transplantation assessed by GFR with the MDRD4

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    End point title
    Renal function at week 52 after transplantation assessed by GFR with the MDRD4
    End point description
    The study analysis population for this endpoint consisted of the FAS population. Patients who had graft loss (death, re-transplantation or dialysis ongoing at study end or discontinuation) were included with a GFR of 0.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    287
    282
    Units: mL/min/1.73 m2
        arithmetic mean (standard deviation)
    54.54 ± 20.388
    55.42 ± 23.368
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Advagraf + MMF + Steroids v Advagraf + MMF + Steroids + Sirolimus
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.72
    Method
    ANCOVA
    Parameter type
    Least-squares mean difference Arm2-Arm1
    Point estimate
    0.49
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.213
         upper limit
    3.202
    Notes
    [2] - Analysis of Covariance (ANCOVA) model. The P value is from an ANCOVA model in which treatment arm, sex, race (Black or non-Black), site and donor status (deceased or nondeceased) were included as factors, eGFR MDRD4 at randomization and donor age are included as continuous covariates.

    Secondary: Renal function at week 52 after transplantation assessed by calculated creatinine clearance using the Cockcroft-Gault formula

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    End point title
    Renal function at week 52 after transplantation assessed by calculated creatinine clearance using the Cockcroft-Gault formula
    End point description
    The study analysis population for this endpoint consisted of the FAS population. Patients who had graft loss (death, re-transplantation or dialysis ongoing at study end or discontinuation) were included with a GFR of 0.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    287
    282
    Units: mL/min
        arithmetic mean (standard deviation)
    65.03 ± 26.761
    66.12 ± 27.868
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Advagraf + MMF + Steroids v Advagraf + MMF + Steroids + Sirolimus
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.736
    Method
    ANCOVA
    Parameter type
    Least-squares mean difference Arm2-Arm1
    Point estimate
    0.53
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.541
         upper limit
    3.594
    Notes
    [3] - Analysis of Covariance (ANCOVA) model. The P value is from an ANCOVA model in which treatment arm, sex, race (Black or non-Black), site and donor status (deceased or nondeceased) were included as factors, eGFR MDRD4 at randomization and donor age are included as continuous covariates.

    Secondary: Renal function at week 52 after transplantation assessed by creatinine clearance with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula

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    End point title
    Renal function at week 52 after transplantation assessed by creatinine clearance with the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula
    End point description
    The study analysis population for this endpoint consisted of the FAS population. Patients who had graft loss (death, re-transplantation or dialysis ongoing at study end or discontinuation) were included with a GFR of 0.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    287
    282
    Units: mL/min/1.73m²
        arithmetic mean (standard deviation)
    56 ± 21.935
    56.6 ± 24.242
    Statistical analysis title
    Statistical analysis 1
    Comparison groups
    Advagraf + MMF + Steroids v Advagraf + MMF + Steroids + Sirolimus
    Number of subjects included in analysis
    569
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.823
    Method
    ANCOVA
    Parameter type
    Least-squares mean difference Arm2-Arm1
    Point estimate
    0.31
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.44
         upper limit
    3.066
    Notes
    [4] - Analysis of Covariance (ANCOVA) model. The P value is from an ANCOVA model in which treatment arm, sex, race (Black or non-Black), site and donor status (deceased or nondeceased) were included as factors, eGFR MDRD4 at randomization and donor age are included as continuous covariates.

    Secondary: Efficacy failure

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    End point title
    Efficacy failure
    End point description
    Efficacy failure defined as a composite endpoint consisting of any of the following: Graft Loss (retransplantation, nephrectomy, death or dialysis ongoing at the study end or at time of discontinuation from the study, unless superseded by follow-up information) or patient withdrawal. The study analysis population for this endpoint consisted of the ITT set. Patients with no events were censored at the date of last follow-up evaluation or date of death for patients who died or date of graft loss for patients with graft loss. Estimated Kaplan-Meier rates percentages at week 52 have been provided for efficacy failure.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    362
    368
    Units: Percentage
        number (not applicable)
    11.5
    18.2
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Kaplan-Meier survival estimates (percentage) for the rate of patients with the event (Arm 2 minus Arm 1).
    Comparison groups
    Advagraf + MMF + Steroids + Sirolimus v Advagraf + MMF + Steroids
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Treatment difference Arm2-Arm1
    Point estimate
    6.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    1.5
         upper limit
    11.9

    Secondary: Clinical acute rejection

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    End point title
    Clinical acute rejection
    End point description
    The study analysis population for this endpoint consisted of the ITT set. Patients with no events were censored at the date of last follow-up evaluation or date of death for patients who died or date of graft loss for patients with graft loss. Estimated Kaplan-Meier rates at week 52 have been provided for acute rejection.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    362
    368
    Units: Percentage
        number (not applicable)
    7.3
    8.3
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Kaplan-Meier survival estimates (percentage) for the rate of patients with the event (Arm 2 minus Arm 1).
    Comparison groups
    Advagraf + MMF + Steroids v Advagraf + MMF + Steroids + Sirolimus
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Treatment difference Arm2-Arm1
    Point estimate
    1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.9
         upper limit
    4.9

    Secondary: Time to clinical acute rejection

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    End point title
    Time to clinical acute rejection
    End point description
    In time-to-event analysis, time to event/censoring was calculated relative to date of reperfusion, defined as Day 0. The study analysis population for this endpoint consisted of subjects with clinical acute rejection.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    26
    30
    Units: Days
        median (full range (min-max))
    82 (28 to 250)
    86 (28 to 272)
    No statistical analyses for this end point

    Secondary: Biopsy Confirmed Acute Rejection (BCAR)

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    End point title
    Biopsy Confirmed Acute Rejection (BCAR)
    End point description
    The study analysis population for this endpoint consisted of the ITT set. Patients with no events were censored at the date of last follow-up evaluation or date of death for patients who died or date of graft loss for patients with graft loss. A renal biopsy was performed if clinical and/or laboratory signs indicated the occurrence of a rejection episode. The histological evaluation of the biopsy was performed by the local histopathologist following the 07 Banff criteria classification of renal allograft pathology. Acute rejection which was diagnosed as acute antibody-mediated rejection or acute T-cell-mediated rejection (grades I, II or III) according to the 07 Banff criteria was considered to be BCAR. Estimated Kaplan-Meier rates at week 52 have been provided for BCAR. Overall frequency percentage rates have been provided for Antibody-mediated rejections and T-cell-mediated rejection categories.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    362
    368
    Units: Percentage
    number (not applicable)
        BCAR
    4.3
    3.6
        T-cell mediated BCAR
    3.6
    3.3
        Antibody mediated BCAR
    0.3
    0.3
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Kaplan-Meier survival estimates (percentage) for the rate of patients with the event (Arm 2 minus Arm 1).
    Comparison groups
    Advagraf + MMF + Steroids v Advagraf + MMF + Steroids + Sirolimus
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Treatment difference Arm2-Arm1
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.6
         upper limit
    2.3

    Secondary: Time to BCAR

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    End point title
    Time to BCAR
    End point description
    In time-to-event analysis, time to event/censoring will be calculated relative to date of reperfusion, defined as Day 0. The study analysis population for this endpoint consisted of subjects with biopsy confirmed acute rejection.
    End point type
    Secondary
    End point timeframe
    Up to week 52
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    14
    13
    Units: Days
        median (full range (min-max))
    90 (31 to 370)
    89 (37 to 272)
    No statistical analyses for this end point

    Secondary: Categories of clinical acute rejections

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    End point title
    Categories of clinical acute rejections
    End point description
    ITT population. Corticosteroid sensitive acute rejection (CSAR): episode treated with new/increased corticosteroids only and has resolved irrespective of any Advagraf/MMF dose changes. Spontaneously resolving acute rejection (SRAR): episode which has not been treated with new/increased corticosteroids, antibodies or any other medication and has resolved irrespective of Advagraf/MMF dose changes. Corticosteroid resistant acute rejection (CRAR): episode which did not resolve following treatment with corticosteroids. Antibody responsive acute rejection (ARAR) episode treated successfully with antibody but no prior steroid administration. Acute rejection episode ongoing unresolved (UAR): episode ongoing/unresolved at graft loss or patient death irrespective of treatment. Other acute rejection (OAR): episode could not be allocated to 1 of the above categories.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    362
    368
    Units: Percentage of participants
    number (not applicable)
        CSAR
    3.6
    5.7
        SRAR
    2.5
    1.4
        CRAR
    1.1
    1.1
        ARAR
    0
    0
        UAR
    0
    0
        OAR
    0
    0
    No statistical analyses for this end point

    Secondary: Delayed graft function (DGF)

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    End point title
    Delayed graft function (DGF)
    End point description
    Delayed graft function is defined as the subject having dialysis for more than one day during the first week post kidney transplantation (Day 1 to Day 7). Kaplan-Meier estimates of delayed graft function. Safety analysis set (SAF) population, the SAF population consisted of all patients who took at least 1 dose of any of the study drugs. The values for Kaplan-Meier estimates of delayed graft function are provided post-randomization.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    362
    368
    Units: Percententage rate
        number (confidence interval 95%)
    11.9 (9 to 15.7)
    11.1 (8.3 to 14.8)
    No statistical analyses for this end point

    Secondary: Subject survival

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    End point title
    Subject survival
    End point description
    Patient survival, defined as the time from the day of the first dose of study drug to the day of death (inclusive). Subjects who were alive at the end of the study or at the date of last evaluation were censored. The study analysis population for this endpoint consisted of the ITT set. Patients with no events were censored at the date of last follow-up evaluation or date of death for patients who died or date of graft loss for patients with graft loss. Estimated Kaplan-Meier rates at week 52 have been provided for subject survival.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    362
    368
    Units: Percentage
        number (confidence interval 95%)
    98.9 (97 to 99.6)
    99.7 (98.1 to 100)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Kaplan-Meier survival estimates (percentage) for the rate of patients with the event (Arm 2 minus Arm 1).
    Comparison groups
    Advagraf + MMF + Steroids v Advagraf + MMF + Steroids + Sirolimus
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Treatment difference Arm2-Arm1
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    2.1

    Secondary: Graft survival

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    End point title
    Graft survival
    End point description
    Graft survival, defined as time from the day of reperfusion to the day of graft loss for patients who were transplanted. The study analysis population for this endpoint consisted of the ITT set. Patients with no events were censored at the date of last follow-up evaluation or date of death for patients who died or date of graft loss for patients with graft loss. Estimated Kaplan-Meier rates at week 52 have been provided for graft survival.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    362
    368
    Units: Percentage
        number (confidence interval 95%)
    97.1 (94.7 to 98.4)
    97.8 (95.6 to 98.9)
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Kaplan-Meier survival estimates (percentage) for the rate of patients with the event (Arm 2 minus Arm 1).
    Comparison groups
    Advagraf + MMF + Steroids v Advagraf + MMF + Steroids + Sirolimus
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Treatment difference Arm2-Arm1
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.6
         upper limit
    3

    Secondary: New Onset Diabetes Mellitus (NODM)

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    End point title
    New Onset Diabetes Mellitus (NODM)
    End point description
    NODM as per American Diabetic Association (ADA) criteria. The study analysis population for this endpoint consisted of the ITT set. Patients with no events were censored at the date of last follow-up evaluation or date of death for patients who died or date of graft loss for patients with graft loss. Estimated Kaplan-Meier rates at week 52 have been provided for NODM.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    362
    368
    Units: Percentage
        number (not applicable)
    8.5
    12.8
    Statistical analysis title
    Statistical analysis 1
    Statistical analysis description
    Kaplan-Meier survival estimates (percentage) for the rate of patients with the event (Arm 2 minus Arm 1).
    Comparison groups
    Advagraf + MMF + Steroids v Advagraf + MMF + Steroids + Sirolimus
    Number of subjects included in analysis
    730
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    Method
    Parameter type
    Treatment difference Arm2-Arm1
    Point estimate
    4.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.9
         upper limit
    9.5

    Secondary: Safety as assessed by recording adverse events, laboratory assessments and vital signs

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    End point title
    Safety as assessed by recording adverse events, laboratory assessments and vital signs
    End point description
    Treatment-emergent adverse events (TEAEs) were defined as those with an onset date occurring on or after randomization (day 28). AEs which changed in severity on/after the date of randomization were included as TEAEs. ITT population.
    End point type
    Secondary
    End point timeframe
    Up to week 52.
    End point values
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Number of subjects analysed
    362
    368
    Units: Participants
        TEAEs
    307
    309
        Drug-related TEAEs
    212
    215
        Deaths
    2
    1
        Serious TEAEs
    158
    148
        Drug-related serious TEAEs
    82
    77
        TEAEs leading to permanent disc. of drug
    22
    48
        Drug-related TEAEs leading to perm. disc. or drug
    16
    39
        Serious TEAEs leading to perm. disc. of drug
    11
    21
        Drug-related serious TEAEs leading to perm. disc.
    7
    16
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs were defined as those with an onset date occurring on or after randomization (day 28). AEs which changed in severity on/after the date of randomization were included as TEAEs.
    Adverse event reporting additional description
    An AE was defined as any untoward medical occurrence in a patient administered a study drug and which did not necessarily have a causal relationship with this treatment. ITT population.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Advagraf + MMF + Steroids
    Reporting group description
    Arm 1 served as the reference arm for the study; the combination of tacrolimus and MMF has a proven efficacy and safety profile.

    Reporting group title
    Advagraf + MMF + Steroids + Sirolimus
    Reporting group description
    Arm 2 Advagraf + MMF(withdrawn on Day 28) + Steroids + Sirolimus(introduced on Day 28) in combination with lower tacrolimus exposure at Day 42 (week 6) was compared to Arm 1.

    Serious adverse events
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    158 / 362 (43.65%)
    148 / 368 (40.22%)
         number of deaths (all causes)
    4
    1
         number of deaths resulting from adverse events
    1
    1
    Vascular disorders
    Arteriovenous fistula
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 362 (0.00%)
    4 / 368 (1.09%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 362 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphocele
         subjects affected / exposed
    5 / 362 (1.38%)
    8 / 368 (2.17%)
         occurrences causally related to treatment / all
    1 / 5
    4 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Microangiopathy
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         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
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peripheral ischaemia
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Phlebitis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombophlebitis
         subjects affected / exposed
    2 / 362 (0.55%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombosis
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Venous thrombosis limb
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Catheter removal
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrectomy
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Removal of ambulatory peritoneal catheter
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Basal cell carcinoma
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intraductal papilloma of breast
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metastasis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cell carcinoma
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular germ cell cancer
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thyroid cancer
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vulval cancer
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney transplant rejection
         subjects affected / exposed
    15 / 362 (4.14%)
    11 / 368 (2.99%)
         occurrences causally related to treatment / all
    7 / 15
    5 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant rejection
         subjects affected / exposed
    2 / 362 (0.55%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    General physical health deterioration
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired healing
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mucosal haemorrhage
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    3 / 362 (0.83%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ulcer
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Menometrorrhagia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostatitis
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Testicular haemorrhage
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         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
    Arteriovenous fistula thrombosis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Complications of transplanted kidney
         subjects affected / exposed
    6 / 362 (1.66%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device dislocation
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drug misuse
         subjects affected / exposed
    0 / 362 (0.00%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Graft thrombosis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Incisional hernia
         subjects affected / exposed
    0 / 362 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Perinephric collection
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural haemorrhage
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal graft loss
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt blood flow excessive
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt malfunction
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt thrombosis
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent occlusion
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Subdural haemorrhage
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Therapeutic agent toxicity
         subjects affected / exposed
    3 / 362 (0.83%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant failure
         subjects affected / exposed
    3 / 362 (0.83%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric anastomosis complication
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound evisceration
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Antibody test positive
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arteriogram
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial culture positive
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatine increased
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    14 / 362 (3.87%)
    20 / 368 (5.43%)
         occurrences causally related to treatment / all
    7 / 14
    12 / 24
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood glucose increased
         subjects affected / exposed
    0 / 362 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood parathyroid hormone increased
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-reactive protein increased
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Histology abnormal
         subjects affected / exposed
    2 / 362 (0.55%)
    5 / 368 (1.36%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immunosuppressant drug level increased
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver function test abnormal
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Angina pectoris
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    2 / 362 (0.55%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Heart valve incompetence
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sick sinus syndrome
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventricular extrasystoles
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Congenital, familial and genetic disorders
    Gastrointestinal angiodysplasia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    2 / 362 (0.55%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Interstitial lung disease
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    2 / 362 (0.55%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Organising pneumonia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Pleural effusion
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleuritic pain
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary arterial hypertension
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 362 (0.83%)
    4 / 368 (1.09%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary hypertension
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (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
    3 / 362 (0.83%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    2 / 362 (0.55%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    2 / 2
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 362 (0.28%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocythaemia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Brain stem haemorrhage
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lumbar radiculopathy
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post herpetic neuralgia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sciatica
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (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 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Cataract
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinopathy proliferative
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vitreous haemorrhage
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal hernia
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal strangulated hernia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal wall haematoma
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aphthous stomatitis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (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 / 362 (0.83%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    3 / 3
    3 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspepsia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Enterocolitis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastric antral vascular ectasia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernial eventration
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         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
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagitis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (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 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rectal haemorrhage
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    4 / 362 (1.10%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute prerenal failure
         subjects affected / exposed
    0 / 362 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anuria
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dysuria
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Glomerulonephritis membranoproliferative
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematuria
         subjects affected / exposed
    3 / 362 (0.83%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    6 / 362 (1.66%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 7
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperoxaluria
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Kidney fibrosis
         subjects affected / exposed
    1 / 362 (0.28%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephropathy toxic
         subjects affected / exposed
    3 / 362 (0.83%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    3 / 3
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Obstructive uropathy
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Proteinuria
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         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 / 362 (0.28%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal artery thrombosis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    2 / 362 (0.55%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    9 / 362 (2.49%)
    14 / 368 (3.80%)
         occurrences causally related to treatment / all
    4 / 9
    7 / 19
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    6 / 362 (1.66%)
    5 / 368 (1.36%)
         occurrences causally related to treatment / all
    3 / 6
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tubulointerstitial nephritis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteral disorder
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteral polyp
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric obstruction
         subjects affected / exposed
    2 / 362 (0.55%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ureteric stenosis
         subjects affected / exposed
    5 / 362 (1.38%)
    6 / 368 (1.63%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral disorder
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urethral obstruction
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary fistula
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary incontinence
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary retention
         subjects affected / exposed
    2 / 362 (0.55%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract obstruction
         subjects affected / exposed
    2 / 362 (0.55%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinoma
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (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 / 362 (0.28%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (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
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neck pain
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteitis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal osteoarthritis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    Hyperparathyroidism
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Anorexia
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    3 / 362 (0.83%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 362 (0.28%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    0 / 1
    3 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic foot
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercalcaemia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperlipidaemia
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypervolaemia
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Insulin-requiring type 2 diabetes mellitus
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal abscess
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis bacterial
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BK virus infection
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacterial pyelonephritis
         subjects affected / exposed
    2 / 362 (0.55%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter intestinal infection
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridial infection
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus gastritis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus gastroenteritis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    19 / 362 (5.25%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    14 / 19
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ecthyma
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocarditis enterococcal
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia bacteraemia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia sepsis
         subjects affected / exposed
    2 / 362 (0.55%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    5 / 362 (1.38%)
    5 / 368 (1.36%)
         occurrences causally related to treatment / all
    2 / 5
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    9 / 362 (2.49%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    5 / 10
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis astroviral
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis clostridial
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis norovirus
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis salmonella
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Herpes zoster ophthalmic
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Human polyomavirus infection
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected cyst
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infected lymphocele
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    2 / 362 (0.55%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parotitis
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 362 (1.38%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    3 / 6
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Pneumonia bacterial
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia cytomegaloviral
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia klebsiella
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia streptococcal
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polyomavirus-associated nephropathy
         subjects affected / exposed
    3 / 362 (0.83%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    2 / 3
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    7 / 362 (1.93%)
    4 / 368 (1.09%)
         occurrences causally related to treatment / all
    2 / 7
    5 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    4 / 362 (1.10%)
    8 / 368 (2.17%)
         occurrences causally related to treatment / all
    3 / 7
    4 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis chronic
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal cyst infection
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    0 / 362 (0.00%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Shunt infection
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Streptococcal bacteraemia
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Typhoid fever
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (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
         subjects affected / exposed
    2 / 362 (0.55%)
    3 / 368 (0.82%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection bacterial
         subjects affected / exposed
    2 / 362 (0.55%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection enterococcal
         subjects affected / exposed
    2 / 362 (0.55%)
    5 / 368 (1.36%)
         occurrences causally related to treatment / all
    1 / 2
    2 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection fungal
         subjects affected / exposed
    0 / 362 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection pseudomonal
         subjects affected / exposed
    1 / 362 (0.28%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection staphylococcal
         subjects affected / exposed
    1 / 362 (0.28%)
    0 / 368 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    5 / 362 (1.38%)
    1 / 368 (0.27%)
         occurrences causally related to treatment / all
    2 / 5
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 362 (0.00%)
    2 / 368 (0.54%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Advagraf + MMF + Steroids Advagraf + MMF + Steroids + Sirolimus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    284 / 362 (78.45%)
    284 / 368 (77.17%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    21 / 362 (5.80%)
    20 / 368 (5.43%)
         occurrences all number
    21
    22
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    19 / 362 (5.25%)
    13 / 368 (3.53%)
         occurrences all number
    19
    13
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 362 (6.35%)
    14 / 368 (3.80%)
         occurrences all number
    25
    14
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    17 / 362 (4.70%)
    22 / 368 (5.98%)
         occurrences all number
    18
    25
    Leukopenia
         subjects affected / exposed
    44 / 362 (12.15%)
    9 / 368 (2.45%)
         occurrences all number
    49
    9
    Nervous system disorders
    Tremor
         subjects affected / exposed
    28 / 362 (7.73%)
    26 / 368 (7.07%)
         occurrences all number
    30
    26
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    42 / 362 (11.60%)
    66 / 368 (17.93%)
         occurrences all number
    47
    75
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    45 / 362 (12.43%)
    34 / 368 (9.24%)
         occurrences all number
    60
    40
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    6 / 362 (1.66%)
    21 / 368 (5.71%)
         occurrences all number
    6
    21
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    13 / 362 (3.59%)
    23 / 368 (6.25%)
         occurrences all number
    13
    25
    Dyslipidaemia
         subjects affected / exposed
    20 / 362 (5.52%)
    22 / 368 (5.98%)
         occurrences all number
    20
    22
    Hypercholesterolaemia
         subjects affected / exposed
    13 / 362 (3.59%)
    22 / 368 (5.98%)
         occurrences all number
    13
    24
    Hyperlipidaemia
         subjects affected / exposed
    12 / 362 (3.31%)
    23 / 368 (6.25%)
         occurrences all number
    12
    23
    Infections and infestations
    Cytomegalovirus infection
         subjects affected / exposed
    26 / 362 (7.18%)
    11 / 368 (2.99%)
         occurrences all number
    28
    11
    Escherichia urinary tract infection
         subjects affected / exposed
    36 / 362 (9.94%)
    19 / 368 (5.16%)
         occurrences all number
    51
    23
    Nasopharyngitis
         subjects affected / exposed
    29 / 362 (8.01%)
    29 / 368 (7.88%)
         occurrences all number
    40
    33
    Urinary tract infection
         subjects affected / exposed
    18 / 362 (4.97%)
    19 / 368 (5.16%)
         occurrences all number
    22
    20
    Urinary tract infection bacterial
         subjects affected / exposed
    31 / 362 (8.56%)
    16 / 368 (4.35%)
         occurrences all number
    39
    24
    Urinary tract infection enterococcal
         subjects affected / exposed
    18 / 362 (4.97%)
    23 / 368 (6.25%)
         occurrences all number
    22
    25

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Dec 2010
    The protocol amendment was signed prior to the first-patient-in date.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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