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    Clinical Trial Results:
    A multi-center, randomized, open-label, parallel group study investigating the renal tolerability, efficacy and safety of a CNI-free regimen (everolimus and MPA) versus a CNI-regimen with everolimus in heart transplant recipients

    Summary
    EudraCT number
    		 2007-002671-14
    Trial protocol
    		 DE  
    Global end of trial date
    06 Mar 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2018
    First version publication date
    22 Mar 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001ADE14
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00862979
    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
    06 Mar 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to demonstrate superiority of a CNI-free regimen with respect to the renal function at Month 18 post-transplant, assessed by glomerular filtration rate (GFR) (MDRD method) as compared to the standard CNI-based regimen in HTx patients.
    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
    24 Feb 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 162
    Worldwide total number of subjects
    162
    EEA total number of subjects
    162
    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)
    155
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 232 patients were screened, of these , 193 patients were included in safety set which included 31 non-randomized and 162 randomized. Of these, 145 patients were treated with study medication and had at least 1 post-baseline assessment of the primary outcome variable and included in the Full Analysis Set FAS.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 CNI-regimen
    Arm description
    		 CNI-regimen: cyclosporine A (CyA) or tacrolimus (TAC) with everolimus (EVR) with corticosteroids
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Certican
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.25mg, 0.75mg or 1.0mg based on blood levels (5-10 ng/mL) per day

    Investigational medicinal product name
    tacrolimus
    Investigational medicinal product code
    Other name
    Prograf, TAC
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1 mg, or 5 mg capsule given according to blood levels

    Investigational medicinal product name
    Cyclosporine A
    Investigational medicinal product code
    Other name
    Sandimmun® Optoral, CyA
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg, 25 mg, 50 mg or 100 mg capsule according to blood levels

    Arm title
    		 CNI-free-regimen
    Arm description
    		 CNI-free regimen: everolimus (EVR) with MPA (either MMF or enteric coated mycophenolate sodium (EC-MPS)) and corticosteroids
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Certican
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    0.25mg, 0.75mg or 1.0mg based on blood levels (5-10 ng/mL) per day

    Investigational medicinal product name
    Cyclosporine A
    Investigational medicinal product code
    Other name
    Sandimmun® Optoral, CyA
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg, 25 mg, 50 mg or 100 mg capsule according to blood levels dispense on month 6 to 9 only

    Investigational medicinal product name
    tacrolimus
    Investigational medicinal product code
    Other name
    Prograf, TAC
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg, 1 mg, or 5 mg capsule given according to blood levels dispense on month 6 to 9 only

    Investigational medicinal product name
    Enteric coated mycophenolate sodium
    Investigational medicinal product code
    Other name
    Myfortic, EC-MPS
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    180 mg or 360 mg tablet dosed 1440-2280 mg per day

    Investigational medicinal product name
    mycophenolate mofetil
    Investigational medicinal product code
    Other name
    CellCept, MMF
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250 mg or 500 mg tablets with a dose of 1500-3000 mg per da

    Number of subjects in period 1
    		CNI-regimen CNI-free-regimen
    Started
    84
    78
    Completed
    76
    71
    Not completed
    8
    7
         Adverse event, serious fatal
    -
    1
         Patient withdrew consent
    2
    1
         Adverse event, non-fatal
    6
    3
         Administrative problems
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    CNI-regimen
    Reporting group description
    		 CNI-regimen: cyclosporine A (CyA) or tacrolimus (TAC) with everolimus (EVR) with corticosteroids

    Reporting group title
    CNI-free-regimen
    Reporting group description
    		 CNI-free regimen: everolimus (EVR) with MPA (either MMF or enteric coated mycophenolate sodium (EC-MPS)) and corticosteroids

    Reporting group values
    		 CNI-regimen CNI-free-regimen Total
    Number of subjects
    		 84 78 162
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 81 74 155
        From 65-84 years
    		 3 4 7
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.7 ± 9.7 50.3 ± 9.8 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 11 13 24
        Male
    		 73 65 138

    End points

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    End points reporting groups
    Reporting group title
    CNI-regimen
    Reporting group description
    		 CNI-regimen: cyclosporine A (CyA) or tacrolimus (TAC) with everolimus (EVR) with corticosteroids

    Reporting group title
    CNI-free-regimen
    Reporting group description
    		 CNI-free regimen: everolimus (EVR) with MPA (either MMF or enteric coated mycophenolate sodium (EC-MPS)) and corticosteroids

    Primary: Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18

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    End point title
    		 Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18
    End point description
    Calculated Glomerular Filtration Rate (cGFR) Using Modification of Diet in Renal Disease (MDRD) Formula at Month 18 cGFR (in mL/min/1.73 m2) = 186.3*(C-1.154)*(A-0.203)*G*R where C = the serum concentration of creatinine (mg/dL), A = age (years), G = 0.742 when gender is female, otherwise G = 1, R = 1.21 when race is black, otherwise R = 1.
    End point type
    Primary
    End point timeframe
    Month 18
    End point values
    		 CNI-regimen CNI-free-regimen
    Number of subjects analysed
    69
    65
    Units: mL/min
        arithmetic mean (standard deviation)
    54.2 ± 17.9
    66.9 ± 23.0
    Statistical analysis title
    		 cGFR using MDRD Formula at Month 18
    Comparison groups
    CNI-regimen v CNI-free-regimen
    Number of subjects included in analysis
    134
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -11.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.5
         upper limit
    		 -6.1

    Secondary: Occurrence of treatment failures from Month 6 to 9 and Month 9 to 18

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    End point title
    		 Occurrence of treatment failures from Month 6 to 9 and Month 9 to 18
    End point description
    Treatment failure was defined as composite endpoint of biopsy proven acute rejection of ISHLT 1990 grade ≥ 3A resp. ISHLT 2004 grade ≥ 2R, acute rejection episodes associated with hemodynamic compromise, graft loss / re-transplant, death, loss to follow up (at least one condition must be present). If participant had an occurrence in each period it was counted for each period.
    End point type
    Secondary
    End point timeframe
    Month 6 to Month 9; Month 9 to Month 18
    End point values
    		 CNI-regimen CNI-free-regimen
    Number of subjects analysed
    74
    74
    Units: Occurences
        Month 6 to Month 9 Treatment failure-all reasons
    1
    4
        Month 9 to Month 18 Treatment failure-all reasons
    3
    15
    Statistical analysis title
    		 Occurrence of treatment failures from Month 6 to 9
    Statistical analysis description
    Month 6 to Month 9
    Comparison groups
    CNI-regimen v CNI-free-regimen
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.203
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [1] - difference
    Statistical analysis title
    		 Occurrence of treatment failures from Month 9-18
    Statistical analysis description
    Month 9 to Month 18
    Comparison groups
    CNI-regimen v CNI-free-regimen
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.002
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [2] - difference

    Secondary: Occurrence of major cardiac events (MACE) from Month 6 to 18

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    End point title
    		 Occurrence of major cardiac events (MACE) from Month 6 to 18
    End point description
    Major cardiac events (MACE) was defined as one of the following: any death, myocardial infarction, coronary artery bypass grafting
    End point type
    Secondary
    End point timeframe
    Month 6 to Month 18
    End point values
    		 CNI-regimen CNI-free-regimen
    Number of subjects analysed
    74
    71
    Units: Occurences
        Myocardial infarction|
    1
    0
        Death|
    0
    1
    No statistical analyses for this end point

    Secondary: Calculated Glomerular Filtration Rate (cGFR) according to Cockcroft-Gault at Month 12 and 18

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    End point title
    		 Calculated Glomerular Filtration Rate (cGFR) according to Cockcroft-Gault at Month 12 and 18
    End point description
    Calculated Glomerular Filtration Rate (cGFR) according to Cockcroft-Gault at Month 12 and 18. For men: GFR=(140-Age) x Body weight (kg) / 72 x Serum Creatinine (mg/dl) For women: GFR=0.85 (140 -Age) x Body weight(kg)/ 72 x Serum Creatinine (mg/dl)
    End point type
    Secondary
    End point timeframe
    Month 12 and 18
    End point values
    		 CNI-regimen CNI-free-regimen
    Number of subjects analysed
    74
    71
    Units: mL/min
    arithmetic mean (standard deviation)
        Month 12 n=68, 62|
    54.2 ± 19.7
    69.8 ± 23.4
        Month 18 n=69, 65|
    54.2 ± 17.9
    66.9 ± 23.00
    Statistical analysis title
    		 cGFR according to Cockcroft-Gault at Month 12
    Statistical analysis description
    Month 12
    Comparison groups
    CNI-regimen v CNI-free-regimen
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -19.6
         upper limit
    		 -8.3
    Statistical analysis title
    		 cGFR according to Cockcroft-Gault at Month 18
    Statistical analysis description
    Month 18
    Comparison groups
    CNI-regimen v CNI-free-regimen
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -11.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.5
         upper limit
    		 -6.1

    Secondary: Serum Creatinine at Month 6, 8, 9, 10 12 and 18

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    End point title
    		 Serum Creatinine at Month 6, 8, 9, 10 12 and 18
    End point description
    Serum Creatinine is an indicator of renal function measured in the blood
    End point type
    Secondary
    End point timeframe
    Month 6, 8, 9, 10 12 and 18
    End point values
    		 CNI-regimen CNI-free-regimen
    Number of subjects analysed
    74
    71
    Units: μmol/L
    arithmetic mean (standard deviation)
        Month 6|
    1.53 ± 0.49
    1.49 ± 0.51
        Month 8 n=73, 70|
    1.44 ± 0.41
    1.27 ± 0.35
        Month 9 n=74, 70|
    1.58 ± 0.75
    1.24 ± 0.32
        Month 10 n=74, 70|
    1.53 ± 0.53
    1.20 ± 0.30
        Month 12 n=74, 70|
    1.53 ± 0.52
    1.22 ± 0.33
        Month 18|
    1.50 ± 0.50
    1.27 ± 0.44
    No statistical analyses for this end point

    Secondary: Reciprocal Creatinine Slope between Month 6 and Month 18

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    End point title
    		 Reciprocal Creatinine Slope between Month 6 and Month 18
    End point description
    Reciprocal Creatinine Slope is an indication of renal function over time with a higher slope value indicating an improvement in renal function.
    End point type
    Secondary
    End point timeframe
    Between Month 6 and Month 18
    End point values
    		 CNI-regimen CNI-free-regimen
    Number of subjects analysed
    74
    71
    Units: 1/serum vs time
        arithmetic mean (standard deviation)
    0.045 ± 0.364
    0.403 ± 1.863
    Statistical analysis title
    		 Reciprocal Creatinine Slope between Month 6&18
    Comparison groups
    CNI-regimen v CNI-free-regimen
    Number of subjects included in analysis
    145
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.008
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    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 reported in this record are from date of 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
    20.0
    Reporting groups
    Reporting group title
    CNI-Regimen
    Reporting group description
    		 CNI-Regimen

    Reporting group title
    CNI-free-regimen
    Reporting group description
    		 CNI-free-regimen

    Serious adverse events
    		 CNI-Regimen CNI-free-regimen
    Total subjects affected by serious adverse events
         subjects affected / exposed
    40 / 84 (47.62%)
    29 / 78 (37.18%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    B-CELL LYMPHOMA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BLADDER CANCER
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PLASMACYTOMA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PROSTATE CANCER RECURRENT
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    ANEURYSM
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ANGIOPATHY
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEEP VEIN THROMBOSIS
         subjects affected / exposed
    3 / 84 (3.57%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HYPERTENSION
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    MEDICAL DEVICE REMOVAL
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    CHEST PAIN
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHILLS
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FATIGUE
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PYREXIA
         subjects affected / exposed
    0 / 84 (0.00%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STENOSIS
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (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
    HEART TRANSPLANT REJECTION
         subjects affected / exposed
    3 / 84 (3.57%)
    7 / 78 (8.97%)
         occurrences causally related to treatment / all
    0 / 3
    7 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Reproductive system and breast disorders
    BENIGN PROSTATIC HYPERPLASIA
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    DYSPNOEA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY EMBOLISM
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PULMONARY MASS
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLAMMATORY MARKER INCREASED
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WEIGHT INCREASED
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    ACETABULUM FRACTURE
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LUMBAR VERTEBRAL FRACTURE
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VASCULAR PSEUDOANEURYSM
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    ATRIAL FIBRILLATION
         subjects affected / exposed
    0 / 84 (0.00%)
    3 / 78 (3.85%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    ATRIAL FLUTTER
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CORONARY ARTERY STENOSIS
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    LEFT VENTRICULAR DYSFUNCTION
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PERICARDIAL EFFUSION
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SINUS TACHYCARDIA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TACHYCARDIA
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    MYOCLONIC EPILEPSY
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (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
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SYNCOPE
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    EYE PAIN
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GLAUCOMA
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         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 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    APHTHOUS ULCER
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COLITIS ISCHAEMIC
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIARRHOEA
         subjects affected / exposed
    1 / 84 (1.19%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INGUINAL HERNIA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    NAUSEA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    VOMITING
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    CHOLECYSTITIS
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS ACUTE
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLECYSTITIS CHRONIC
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHOLELITHIASIS
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    ANGIOEDEMA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETIC FOOT
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SKIN HAEMORRHAGE
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    ACUTE KIDNEY INJURY
         subjects affected / exposed
    2 / 84 (2.38%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CHRONIC KIDNEY DISEASE
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HAEMATURIA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL ARTERY STENOSIS
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (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
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    RENAL IMPAIRMENT
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (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
    1 / 84 (1.19%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (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
    BACK PAIN
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOARTHRITIS
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OSTEOPOROSIS
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    ANAL ABSCESS
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPERGILLOMA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ASPERGILLUS INFECTION
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERAEMIA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    BACTERIAL INFECTION
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CAMPYLOBACTER GASTROENTERITIS
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (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
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    CYTOMEGALOVIRUS INFECTION
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DEVICE RELATED INFECTION
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIABETIC GANGRENE
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    DIVERTICULITIS
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ENDOCARDITIS
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    ESCHERICHIA INFECTION
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    FEBRILE INFECTION
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS
         subjects affected / exposed
    2 / 84 (2.38%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS NOROVIRUS
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GASTROENTERITIS SALMONELLA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    GROIN INFECTION
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    H1N1 INFLUENZA
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES SIMPLEX
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER
         subjects affected / exposed
    1 / 84 (1.19%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    HERPES ZOSTER INFECTION NEUROLOGICAL
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTED LYMPHOCELE
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTION
         subjects affected / exposed
    3 / 84 (3.57%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFECTIOUS PLEURAL EFFUSION
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    OTITIS EXTERNA
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMOCYSTIS JIROVECII PNEUMONIA
         subjects affected / exposed
    2 / 84 (2.38%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    PNEUMONIA
         subjects affected / exposed
    6 / 84 (7.14%)
    2 / 78 (2.56%)
         occurrences causally related to treatment / all
    1 / 6
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    SEPTIC SHOCK
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    TUBERCULOSIS
         subjects affected / exposed
    1 / 84 (1.19%)
    0 / 78 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    URETERITIS
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         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
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    WOUND INFECTION
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 84 (0.00%)
    1 / 78 (1.28%)
         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
    		 CNI-Regimen CNI-free-regimen
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    74 / 84 (88.10%)
    65 / 78 (83.33%)
    Vascular disorders
    HYPERTENSION
         subjects affected / exposed
    9 / 84 (10.71%)
    3 / 78 (3.85%)
         occurrences all number
    11
    3
    General disorders and administration site conditions
    FATIGUE
         subjects affected / exposed
    3 / 84 (3.57%)
    4 / 78 (5.13%)
         occurrences all number
    4
    4
    OEDEMA
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 78 (2.56%)
         occurrences all number
    5
    2
    OEDEMA PERIPHERAL
         subjects affected / exposed
    17 / 84 (20.24%)
    20 / 78 (25.64%)
         occurrences all number
    21
    21
    PYREXIA
         subjects affected / exposed
    8 / 84 (9.52%)
    5 / 78 (6.41%)
         occurrences all number
    11
    5
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    4 / 84 (4.76%)
    5 / 78 (6.41%)
         occurrences all number
    6
    6
    DYSPNOEA
         subjects affected / exposed
    8 / 84 (9.52%)
    5 / 78 (6.41%)
         occurrences all number
    10
    5
    Investigations
    BLOOD CREATININE INCREASED
         subjects affected / exposed
    5 / 84 (5.95%)
    1 / 78 (1.28%)
         occurrences all number
    5
    1
    C-REACTIVE PROTEIN INCREASED
         subjects affected / exposed
    5 / 84 (5.95%)
    3 / 78 (3.85%)
         occurrences all number
    5
    3
    Cardiac disorders
    SINUS TACHYCARDIA
         subjects affected / exposed
    3 / 84 (3.57%)
    5 / 78 (6.41%)
         occurrences all number
    3
    6
    TACHYCARDIA
         subjects affected / exposed
    8 / 84 (9.52%)
    7 / 78 (8.97%)
         occurrences all number
    9
    7
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    5 / 84 (5.95%)
    7 / 78 (8.97%)
         occurrences all number
    6
    9
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    6 / 84 (7.14%)
    7 / 78 (8.97%)
         occurrences all number
    6
    7
    LEUKOPENIA
         subjects affected / exposed
    10 / 84 (11.90%)
    10 / 78 (12.82%)
         occurrences all number
    11
    13
    Gastrointestinal disorders
    APHTHOUS ULCER
         subjects affected / exposed
    4 / 84 (4.76%)
    5 / 78 (6.41%)
         occurrences all number
    4
    5
    DIARRHOEA
         subjects affected / exposed
    11 / 84 (13.10%)
    5 / 78 (6.41%)
         occurrences all number
    11
    6
    NAUSEA
         subjects affected / exposed
    10 / 84 (11.90%)
    6 / 78 (7.69%)
         occurrences all number
    10
    7
    VOMITING
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 78 (2.56%)
         occurrences all number
    7
    2
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    3 / 84 (3.57%)
    6 / 78 (7.69%)
         occurrences all number
    3
    6
    RASH
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 78 (2.56%)
         occurrences all number
    6
    2
    Endocrine disorders
    HYPERTHYROIDISM
         subjects affected / exposed
    6 / 84 (7.14%)
    4 / 78 (5.13%)
         occurrences all number
    6
    4
    Musculoskeletal and connective tissue disorders
    MUSCLE SPASMS
         subjects affected / exposed
    7 / 84 (8.33%)
    1 / 78 (1.28%)
         occurrences all number
    7
    1
    MYALGIA
         subjects affected / exposed
    6 / 84 (7.14%)
    1 / 78 (1.28%)
         occurrences all number
    6
    1
    OSTEOPOROSIS
         subjects affected / exposed
    2 / 84 (2.38%)
    5 / 78 (6.41%)
         occurrences all number
    3
    5
    PAIN IN EXTREMITY
         subjects affected / exposed
    5 / 84 (5.95%)
    1 / 78 (1.28%)
         occurrences all number
    5
    1
    Infections and infestations
    BRONCHITIS
         subjects affected / exposed
    8 / 84 (9.52%)
    3 / 78 (3.85%)
         occurrences all number
    8
    3
    CYTOMEGALOVIRUS INFECTION
         subjects affected / exposed
    11 / 84 (13.10%)
    4 / 78 (5.13%)
         occurrences all number
    14
    4
    NASOPHARYNGITIS
         subjects affected / exposed
    23 / 84 (27.38%)
    12 / 78 (15.38%)
         occurrences all number
    35
    15
    ORAL HERPES
         subjects affected / exposed
    2 / 84 (2.38%)
    5 / 78 (6.41%)
         occurrences all number
    2
    5
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 84 (1.19%)
    4 / 78 (5.13%)
         occurrences all number
    1
    5
    Metabolism and nutrition disorders
    HYPERCHOLESTEROLAEMIA
         subjects affected / exposed
    7 / 84 (8.33%)
    3 / 78 (3.85%)
         occurrences all number
    7
    3
    HYPERLIPIDAEMIA
         subjects affected / exposed
    9 / 84 (10.71%)
    5 / 78 (6.41%)
         occurrences all number
    9
    5
    HYPERTRIGLYCERIDAEMIA
         subjects affected / exposed
    8 / 84 (9.52%)
    6 / 78 (7.69%)
         occurrences all number
    8
    6
    HYPERURICAEMIA
         subjects affected / exposed
    5 / 84 (5.95%)
    2 / 78 (2.56%)
         occurrences all number
    5
    2
    HYPOKALAEMIA
         subjects affected / exposed
    7 / 84 (8.33%)
    13 / 78 (16.67%)
         occurrences all number
    7
    13

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Apr 2010
    Amendment 1: Clarification of the involvement of a CRO
    22 Nov 2012
    Amendment 2: Clarification of exclusion criteria misunderstandings. Criteria missing from the synopsis or protocol text but mentioned in the corresponding part were completed The required time frames for SAE reporting were clarified. The study outline table was adapted to clearly indicate the timely application of medication.
    22 Jan 2015
    Amendment 3: The stopping rules for MPA were amended to clearly follow the recommendations given in a dear healthcare professional letter issued for CellCept® by Roche on 12-Dec-2014. This information was added to the sections Study drug administration, Permitted study drug adjustments, Premature patient withdrawal from study treatment, and Dose reduction of everolimus and MPA. Two exclusion criteria were amended for enhanced study feasibility in line with clinical praxis and patients’ de facto condition: -Exclusion criterion 10 (enrollment) and exclusion criterion 4 (baseline) were modified to allow for inclusion of patients with leukocytes ≥ 3000/mm3  -Exclusion criterion 17 (enrollment) was removed.
    25 Nov 2015
    Amendment 4: Enrollment was to be terminated by 31-Dec-2015 due to slow recruitment and the inability to achieve the planned sample size in a considerable amount of time. At the time of preparation of this amendment, n = 160 patients had been randomized. A comment was added to Section 10.8. (Sample size calculation) In response to German Health Authority’s request, the protocol was modified to implement most recent notifications for use of MPA based on the dear health care professional letter (DHCPL) that was sent out for CellCept® by Roche 10-Nov-2015. The novel safety information were added to section 6.5.1. (Study drug administration). Additional pregnancy β-hCG tests were implemented into section 7 (Visit schedule and assessments) and into the assessment schedule (Table 7-1) and are mandatory for all female patients of child bearing potential at screening, baseline, switch and every study visit.

    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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