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    Clinical Trial Results:
    A national, multi-center, randomized, open label study to evaluate the efficacy and safety of everolimus combined with enteric-coated mycophenolate sodium compared to the standard treatment combining tacrolimus and enteric-coated mycophenolate sodium in de novo liver transplant recipients

    Summary
    EudraCT number
    		 2012-000137-39
    Trial protocol
    		 FR  
    Global end of trial date
    26 Mar 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001HFR02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01625377
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    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
    26 Mar 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to evaluate whether Certican® combined with Myfortic® led to better kidney function, compared to standard treatment combining tacrolimus and Myfortic®, in de novo liver transplant patients, between randomization and 6 months after transplantation. Renal function was assessed by the estimated glomerular filtration rate (eGFR) (abbreviated Modification of Diet in Renal Disease [aMDRD] formula).
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    07 Dec 2012
    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
    France: 188
    Worldwide total number of subjects
    188
    EEA total number of subjects
    188
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    168
    From 65 to 84 years
    20
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Total 188 patients were randomized

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Tacrolimus
    Arm description
    		 From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Basiliximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Basiliximab was supplied to the participating centers as marketed, i.e. in packs containing one vial of 20-mg powder, and water for injection (WFI). 20 mg at D0 and D4

    Investigational medicinal product name
    tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Arm 1: tacrolimus (C06-10 ng/ml) from D3-D5 post-transplantation to month 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to month 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation tomonth 6 post-transplantation. Arm 2 : tacolimus (C0 6-10 ng/ml) from D3-D5 post-transplantation to

    Investigational medicinal product name
    Corticosteroids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of oral corticosteroid therapy was at the discretion of the centers according to their usual practice

    Investigational medicinal product name
    Mycophenolic Acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose of 1440 mg/day from transplantation to month 6 post-transplantation

    Arm title
    		 Everolimus (RAD001)
    Arm description
    		 From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Basiliximab
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Basiliximab was supplied to the participating centers as marketed, i.e. in packs containing one vial of 20-mg powder, and water for injection (WFI). 20 mg at D0 and D4

    Investigational medicinal product name
    everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    everolimus (C0 6-10 ng/ml) from randomization to month 6 post-transplantation

    Investigational medicinal product name
    Corticosteroids
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Administration of oral corticosteroid therapy was at the discretion of the centers according to their usual practice

    Investigational medicinal product name
    Mycophenolic Acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Dose of 1440 mg/day from transplantation to month 6 post-transplantation

    Number of subjects in period 1
    		Tacrolimus Everolimus (RAD001)
    Started
    95
    93
    Safety set of population
    94
    90
    Intent to treat population
    93
    90
    Completed
    88
    71
    Not completed
    7
    22
         Adverse event, serious fatal
    1
    1
         Administrative Problem
    1
    1
         Graft loss
    1
    -
         Adverse event, non-fatal
    3
    16
         Unsatisfactory therapeutic effect
    -
    1
         Abnormal laboratory values
    1
    -
         Protocol deviation
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tacrolimus
    Reporting group description
    		 From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids

    Reporting group title
    Everolimus (RAD001)
    Reporting group description
    		 From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).

    Reporting group values
    		 Tacrolimus Everolimus (RAD001) Total
    Number of subjects
    		 95 93 188
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 85 83 168
        From 65-84 years
    		 10 10 20
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 55.5 ± 8.24 56.5 ± 8.59 -
    Gender, Male/Female
    Units: Participants
        Female
    		 14 14 28
        Male
    		 81 79 160

    End points

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    End points reporting groups
    Reporting group title
    Tacrolimus
    Reporting group description
    		 From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids

    Reporting group title
    Everolimus (RAD001)
    Reporting group description
    		 From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post-transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).

    Primary: Change from baseline (randomization) in renal function

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    End point title
    		 Change from baseline (randomization) in renal function
    End point description
    Change in renal function was measured by change in glomerular filtration rate (GFR). GFR calculated using the abbreviated modification of diet in renal disease (aMDRD) formula. GFR in mL/min/1.73m^2 for men of non-black ethnicity: 186 * [C/88]^-1.154 * [A]^-0.023*G*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.
    End point type
    Primary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    93
    90
    Units: mL/min/1.73m^2
        least squares mean (standard error)
    -13.29 ± 2.75
    1.05 ± 2.81
    Statistical analysis title
    		 Treatments comparison in eGFR change
    Comparison groups
    Everolimus (RAD001) v Tacrolimus
    Number of subjects included in analysis
    183
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -14.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -21.34
         upper limit
    		 -7.34

    Secondary: Number of patients with treatment failures

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    End point title
    		 Number of patients with treatment failures
    End point description
    Incidence of treatment failures, assessed with composite criterion including treated biopsy proven acute rejection (tBPAR) with a rejection activity index (RAI) according to Banff classification >3, graft loss or death at 6 months. Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft.
    End point type
    Secondary
    End point timeframe
    At week 12 and week 24
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    93
    90
    Units: Patients
        week 12, Treatment failures - NO
    91
    88
        week 12, Treatment failures - YES
    2
    2
        week 24, Treatment failures - NO
    89
    81
        week 24, Treatment failures - YES
    4
    9
    No statistical analyses for this end point

    Secondary: Number of patients with treated or not treated Biopsy proven acute rejection (BPAR)

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    End point title
    		 Number of patients with treated or not treated Biopsy proven acute rejection (BPAR)
    End point description
    Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy.
    End point type
    Secondary
    End point timeframe
    at 12 week and 24 week
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    93
    90
    Units: Patients
        Week 12, Treated BPAR
    2
    2
        Week 12, Not treated BPAR
    0
    0
        Week 24, Treated BPAR
    2
    8
        Week 24, Not Treated BPAR
    0
    1
    No statistical analyses for this end point

    Secondary: Number of patients reported with different categories of severity of BPAR according to Banff classification

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    End point title
    		 Number of patients reported with different categories of severity of BPAR according to Banff classification
    End point description
    Biopsy proven acute rejection was defined as a clinically suspected acute rejection confirmed by biopsy. The severity of BPAR was categorized as : Mild (Banff grade I, RAI = 4 and 5) Moderate (Banff grade II, RAI = 6 and 7) Severe (Banff grade III, RAI = 8 and 9) Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted.
    End point type
    Secondary
    End point timeframe
    at 12 week and 24 week
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    93
    90
    Units: Patients
        Week 12: Mild
    1
    1
        Week 12: Moderate
    1
    1
        Week 12: Severe
    0
    0
        Week 24: Mild
    1
    5
        Week 24: Moderate
    1
    3
        Week 24: Sever
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with treated or untreated BPAR with RAI score greater than 3

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    End point title
    		 Number of patients with treated or untreated BPAR with RAI score greater than 3
    End point description
    Biopsy proven acute rejection (BPAR) was defined as a clinically suspected acute rejection confirmed by biopsy. The Banff Rejection Activity Index (RAI) comprises 3 components scored from 0 to 3: venous endothelial inflammation; bile duct inflammation damage; and portal inflammation; the scores are combined to an overall score (the RAI) ranging from 0 to 9. An overall score of 0-3 is considered indeterminate, score of 4-5 is mild acute, score of 6-7 is moderate acute , and score of 8-9 is severe acute. Only the episode with the highest total RAI score for each participant was counted. The patients with treated or untreated BPAR having RAI score > 3 were reported in this end point.
    End point type
    Secondary
    End point timeframe
    At 24 weeks
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    93
    90
    Units: Patients
        Not Treated BPAR: RAI score >3
    0
    0
        Not Treated BPAR: Missing RAI score
    0
    1
        Treated BPAR: RAI score >3
    2
    8
    No statistical analyses for this end point

    Secondary: Number of patients with death or graft loss

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    End point title
    		 Number of patients with death or graft loss
    End point description
    The graft was presumed to be lost on the day the patient was registered again on the waiting list, or the day he/she received a new graft.
    End point type
    Secondary
    End point timeframe
    at week 24
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    93
    90
    Units: Patients
        Graft Loss
    1
    0
        Death
    1
    1
    No statistical analyses for this end point

    Secondary: Change from baseline (randomization) in serum creatinine

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    End point title
    		 Change from baseline (randomization) in serum creatinine
    End point description
    Change in serum creatinine concentrations from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    93
    90
    Units: µmol/L
        arithmetic mean (standard deviation)
    7.2 ± 36
    -1.3 ± 38.53
    No statistical analyses for this end point

    Secondary: Change from baseline (randomization) in urine protein/creatinine ratio

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    End point title
    		 Change from baseline (randomization) in urine protein/creatinine ratio
    End point description
    Change in urine protein/creatinine ratio from baseline (randomization) to week 24 post-randomization was one of the efficacy assessments of renal function. Baseline was Day 28 visit.
    End point type
    Secondary
    End point timeframe
    Baseline, week 24
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    64
    61
    Units: mg/mmol
        arithmetic mean (standard deviation)
    -2.3 ± 27.89
    21.9 ± 92
    No statistical analyses for this end point

    Secondary: Change from baseline (randomization) in Creatinine clearance estimated using the adjusted Cockcroft-Gault formula

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    End point title
    		 Change from baseline (randomization) in Creatinine clearance estimated using the adjusted Cockcroft-Gault formula
    End point description
    Creatinine clearance by the Cockcroft-Gault formula is computed in mL/min/1.73m^2 from the creatinine clearance in mL/min by multiplying it by 1.73 and dividing it by the body surface area Baseline was Day 28 visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    93
    90
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    -9 ± 30.63
    0.7 ± 25.65
    No statistical analyses for this end point

    Secondary: Change from baseline (randomization) in glomerular filtration rate estimated by abbreviated modification of diet in renal disease (MDRD) formula

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    End point title
    		 Change from baseline (randomization) in glomerular filtration rate estimated by abbreviated modification of diet in renal disease (MDRD) formula
    End point description
    Change in glomerular filtration rate was calculated using the MDRD abbreviated formula. GFR in mL/min/1.73m^2 for men of non-black ethnicity: 186 * [C/88]^-1.154 * [A]^-0.023*G*R ; C = serum creatinine (in μmol/L); A = Age (in years). G = 0.742 when the patient is a women; Otherwise G=1 R= 1.21 when the patient was of black ethnicity; Otherwise R = 1 Baseline was Day 28 visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    93
    90
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    -11.8 ± 34.01
    0.1 ± 32.59
    No statistical analyses for this end point

    Secondary: Change from baseline (randomization) in glomerular filtration rate estimated by CKD-EPI formula

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    End point title
    		 Change from baseline (randomization) in glomerular filtration rate estimated by CKD-EPI formula
    End point description
    GFR estimated by using the Chronic kidney disease- epidemiology (CKD-EPI) formula: eGFR (mL/min/1.73m^2) = 141 * min(C/K,1)^ α * max(C/K,1)^-1.209 * 0.993^A * 1.1018 (if male) * 1.159 (if black) where C = serum creatinine (in mg/dL) ; A = Age (in years); K = 0.7 for women and 0.9 for men; α = -0.329 for women and -0.411 for men. Baseline was Day 28 visit.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 24
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    93
    90
    Units: mL/min/1.73m^2
        arithmetic mean (standard deviation)
    -6.9 ± 20.11
    2.4 ± 22.18
    No statistical analyses for this end point

    Secondary: Number of patients in different stages of chronic kidney diseases according to the K/DOQI classification system

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    End point title
    		 Number of patients in different stages of chronic kidney diseases according to the K/DOQI classification system
    End point description
    Kidney disease outcomes quality initiative (K/DOQI) classification is based on glomerular filtration rate (GFR), abbreviated MDRD formula (mL/min/1.73m^2) : Stage 1 : GFR >= 90; Stage 2 = GFR was between 60-89; Stage 3 = GFR was between 30-59 ; Stage 4 = GFR was between 15-29; Stage 5 = GFR was < 15 (or dialysis)
    End point type
    Secondary
    End point timeframe
    At Week 24
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    86
    74
    Units: Patients
        Stage 1
    24
    41
        Stage 2
    34
    29
        Stage 3
    28
    4
        Stage 4
    0
    0
        Stage 5
    0
    0
    No statistical analyses for this end point

    Secondary: Number of patients with any adverse events, serious adverse events, death and premature discontinuation

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    End point title
    		 Number of patients with any adverse events, serious adverse events, death and premature discontinuation
    End point description
    Baseline was Day 28 visit. This endpoint reports patients with total adverse events (any), serious adverse events, death and premature discontinuation.
    End point type
    Secondary
    End point timeframe
    Baseline to 24 weeks
    End point values
    		 Tacrolimus Everolimus (RAD001)
    Number of subjects analysed
    94
    90
    Units: Patients
        Any Adverse events
    85
    81
        Serious Adverse events
    28
    42
        Death
    1
    2
        At least one AE led to premature discontinuation
    4
    18
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All Adverse events are reported in this record from First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Everolimus (RAD001)
    Reporting group description
    		 From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : everolimus (recommended starting dose of 2 mg/day, then adjusted to achieve the target 6 ≤ C0 ≤ 10 ng/mL, until W24) + mycophenolic acid 1440 mg/d ± oral corticosteroids. The dose of tacrolimus was reduced by 50% twice: at the introduction of everolimus and at week 8 post transplantation. Tacrolimus had to be finally discontinued in week 12 post-transplantation (by week 16 at the latest).

    Reporting group title
    Tacrolimus
    Reporting group description
    		 From transplantation to randomization: Basiliximab (20mg) at Day 0 and Day 4 + tacrolimus (C0 6-10 ng/ml) from Day 3-Day 5 + mycophenolic acid 1440 mg/d ± oral corticosteroids. From randomization to month 6 : tacrolimus (C0 6-10 ng/ml) + mycophenolic acid 1440 mg/d ± oral corticosteroids

    Serious adverse events
    		 Everolimus (RAD001) Tacrolimus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    42 / 90 (46.67%)
    28 / 94 (29.79%)
         number of deaths (all causes)
    2
    1
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Arterial stenosis
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lymphoedema
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Diabetes mellitus management
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Drain removal
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia repair
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Device dislocation
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Generalised oedema
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General physical health deterioration
         subjects affected / exposed
    2 / 90 (2.22%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperthermia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Systemic inflammatory response syndrome
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Liver transplant rejection
         subjects affected / exposed
    5 / 90 (5.56%)
    3 / 94 (3.19%)
         occurrences causally related to treatment / all
    3 / 5
    1 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transplant rejection
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Social circumstances
    Physical disability
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (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 respiratory distress syndrome
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (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
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asphyxia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung disorder
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Anastomotic stenosis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biliary anastomosis complication
         subjects affected / exposed
    5 / 90 (5.56%)
    4 / 94 (4.26%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver graft loss
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Post procedural bile leak
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Spinal fracture
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular pseudoaneurysm
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound evisceration
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Agranulocytosis
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anaemia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    3 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombotic microangiopathy
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ascites
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 90 (1.11%)
    4 / 94 (4.26%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangiolitis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Biloma
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic artery stenosis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholestasis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis
         subjects affected / exposed
    1 / 90 (1.11%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic vein stenosis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic vein thrombosis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatitis cholestatic
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Jaundice
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatorenal syndrome
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatocellular injury
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver disorder
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nodular regenerative hyperplasia
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Purpura
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    3 / 90 (3.33%)
    4 / 94 (4.26%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure acute
         subjects affected / exposed
    2 / 90 (2.22%)
    2 / 94 (2.13%)
         occurrences causally related to treatment / all
    1 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 90 (2.22%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoporotic fracture
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Chondrocalcinosis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal wall abscess
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abscess oral
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cholangitis suppurative
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Campylobacter infection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cytomegalovirus infection
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic infection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infectious pleural effusion
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Liver abscess
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lung infection
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oral infection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumococcal infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    5 / 90 (5.56%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic arthritis staphylococcal
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 90 (1.11%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinusitis aspergillus
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Soft tissue infection
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus
         subjects affected / exposed
    1 / 90 (1.11%)
    0 / 94 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus inadequate control
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 90 (0.00%)
    1 / 94 (1.06%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus (RAD001) Tacrolimus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    64 / 90 (71.11%)
    68 / 94 (72.34%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 90 (7.78%)
    12 / 94 (12.77%)
         occurrences all number
    7
    13
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    12 / 90 (13.33%)
    7 / 94 (7.45%)
         occurrences all number
    12
    7
    Neutropenia
         subjects affected / exposed
    9 / 90 (10.00%)
    14 / 94 (14.89%)
         occurrences all number
    11
    15
    Lymphopenia
         subjects affected / exposed
    4 / 90 (4.44%)
    6 / 94 (6.38%)
         occurrences all number
    4
    7
    Leukopenia
         subjects affected / exposed
    10 / 90 (11.11%)
    8 / 94 (8.51%)
         occurrences all number
    10
    9
    Pancytopenia
         subjects affected / exposed
    5 / 90 (5.56%)
    1 / 94 (1.06%)
         occurrences all number
    5
    1
    Thrombocytopenia
         subjects affected / exposed
    8 / 90 (8.89%)
    10 / 94 (10.64%)
         occurrences all number
    8
    10
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    7 / 90 (7.78%)
    6 / 94 (6.38%)
         occurrences all number
    7
    6
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    6 / 90 (6.67%)
    16 / 94 (17.02%)
         occurrences all number
    7
    18
    Aphthous stomatitis
         subjects affected / exposed
    8 / 90 (8.89%)
    0 / 94 (0.00%)
         occurrences all number
    9
    0
    Abdominal pain
         subjects affected / exposed
    3 / 90 (3.33%)
    5 / 94 (5.32%)
         occurrences all number
    3
    5
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    24 / 90 (26.67%)
    12 / 94 (12.77%)
         occurrences all number
    24
    13
    Hepatocellular injury
         subjects affected / exposed
    16 / 90 (17.78%)
    4 / 94 (4.26%)
         occurrences all number
    16
    4
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    3 / 90 (3.33%)
    11 / 94 (11.70%)
         occurrences all number
    4
    12
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    5 / 90 (5.56%)
    6 / 94 (6.38%)
         occurrences all number
    6
    7
    Metabolism and nutrition disorders
    Dyslipidaemia
         subjects affected / exposed
    7 / 90 (7.78%)
    1 / 94 (1.06%)
         occurrences all number
    7
    1
    Hyperglycaemia
         subjects affected / exposed
    6 / 90 (6.67%)
    5 / 94 (5.32%)
         occurrences all number
    6
    5
    Hyperkalaemia
         subjects affected / exposed
    7 / 90 (7.78%)
    3 / 94 (3.19%)
         occurrences all number
    7
    6
    Hypokalaemia
         subjects affected / exposed
    11 / 90 (12.22%)
    2 / 94 (2.13%)
         occurrences all number
    13
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 May 2012
    - The study design was amended to have a more gradual elimination of tacrolimus in the everolimus (RAD001) group: the dose of tacrolimus was reduced by 50% twice (D0 and in W8 post-transplantation). Tacrolimus had to be fully discontinued in W12 post-transplantation when the everolimus (RAD001) C0 was within the target ranges or by Visit 10 (W16) at the latest. Prior to protocol amendment 1, the dose of tacrolimus was reduced by 50% upon everolimus (RAD001) initiation, then fully discontinued when the everolimus (RAD001) C0 was within the target ranges (when possible at Visit 6, W6), and by Visit 7 (W8) at the latest. - The exclusion/non-eligibility criteria were modified or completed based on the investigators' comments, to focus more precisely the concerned patient population: henceforth, patients transplanted for primary biliary cirrhosis were excluded; patients with BMI ≥35 (formely, ≥32) were excluded; patients with platelet count <50,000 /mm3 (formely, <75,000 /mm3) were non eligible for randomization.
    19 Sep 2013
    - Following investigators' request, the day of initiation of tacrolimus was modified from D5 post-transplantation to D3-D5 post-transplantation, to ensure the patients’ best healthcare. - The exclusion criterion 7, alpha-fetoprotein > 1000 ng/mL was restricted to patients with hepatocellular carcinoma, as the dosage of this parameter was not medically relevant for all patients. Both above changes were to apply only to patients who did not already started tacrolimus treatment (Visit 3, D5 post-transplantation) or did not have completed already the laboratory assessments of the screening visit (Visit 1, D-7 pre-transplantation).

    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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