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    Clinical Trial Results:
    A 12-month, multicenter, open label, randomized, controlled study to evaluate the efficacy, tolerability and safety of early introduction of everolimus, reduced CNI, and early steroid elimination compared to standard CNI, mycophenolate mofetil and steroid regimen in pediatric renal transplant recipients with a 24-month additional safety follow-up

    Summary
    EudraCT number
    		 2010-024381-21
    Trial protocol
    		 HU   BE   FR   DE   NO   IT   Outside EU/EEA   SE   GB   ES  
    Global end of trial date
    24 Sep 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2019
    First version publication date
    04 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001A2314
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01544491
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharmaceuticals AG, 41 613241111, novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000019-PIP06-09
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    24 Sep 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this trial were : 1) To estimate the rate of the composite efficacy endpoint of BPAR, graft loss or death at 12 months post-transplantation in primary pediatric kidney transplant recipients, converted at 4-6 weeks post-transplantation from mycophenolate mofetil + standard TAC regimen and steroids (MMF+sTAC) to everolimus + reduced dose TAC regimen and Steroid withdrawal at 6 months (EVR+rTAC), versus continuation of MMF + standard TAC regimen and steroids. 2) To evaluate renal function, assessed by Glomerular Filtration Rate (eGFR) and estimated by the Schwartz formula (abbreviated) (Schwartz et al 2009), at Month 12.
    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
    17 Aug 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
    Argentina: 3
    Country: Number of subjects enrolled
    Brazil: 13
    Country: Number of subjects enrolled
    France: 11
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    United Kingdom: 14
    Country: Number of subjects enrolled
    Hungary: 6
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    Norway: 8
    Country: Number of subjects enrolled
    Poland: 4
    Country: Number of subjects enrolled
    Spain: 3
    Country: Number of subjects enrolled
    Sweden: 2
    Country: Number of subjects enrolled
    Turkey: 2
    Country: Number of subjects enrolled
    United States: 9
    Worldwide total number of subjects
    106
    EEA total number of subjects
    79
    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)
    2
    Children (2-11 years)
    54
    Adolescents (12-17 years)
    49
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Full Analysis set (FAS) 106 enrolled and randomized patients except misrandomized Per Protocol set (PPS) 90 patients in the FAS without major protocol deviations Safety set (SAF) 106 randomized patients who received at least one dose of study drug

    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
    		 EVR+rTAC
    Arm description
    		 Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant
    Arm type
    		 Experimental

    Investigational medicinal product name
    EverolimusRAD001
    Investigational medicinal product code
    Other name
    Certican, Zortress
    Pharmaceutical forms
    Buccal tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tablets, water-dispersible tablets of 0.1 and 0.25 mg or tablets of 0.25 mg, 0.5 mg, 0.75 mg, or 1.0 mg. When prescribed with TAC: 2.0 mg/m2/dose (maximal initial dose: 0.75 mg bid). Subsequent doses were administered to maintain blood Level C0: 3-8 ng/mL. Given twice daily, 12 hours apart

    Arm title
    		 MMF+sTAC
    Arm description
    		 Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Mycophenolate mofetil
    Investigational medicinal product code
    Other name
    CellCept
    Pharmaceutical forms
    Capsule, Buccal tablet, Oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Capsules; one capsule containing 250 mg, or tablets containing 500 mg. Oral suspension containing 200 mg/mL. Initial recommended dose: 1200 mg/m2/day (max. 1 gr/dose). Subsequent doses were to be reduced to 900 mg/m2/day or lower. As of Month 12 as per center practice. Twice daily, 12 hours apart.

    Number of subjects in period 1
    		EVR+rTAC MMF+sTAC
    Started
    52
    54
    Completed
    47
    51
    Not completed
    5
    3
         Consent withdrawn by subject
    3
    2
         administrative problems
    2
    -
         Lost to follow-up
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    EVR+rTAC
    Reporting group description
    		 Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant

    Reporting group title
    MMF+sTAC
    Reporting group description
    		 Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)

    Reporting group values
    		 EVR+rTAC MMF+sTAC Total
    Number of subjects
    		 52 54 106
    Age, Customized
    Units: Subjects
        1 to <11 years
    		 26 27 53
        11 <= 18 years
    		 26 27 53
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.7 ± 4.9 10.8 ± 4.8 -
    Sex/Gender, Customized
    Units: Subjects
        Male
    		 29 31 60
        Female
    		 23 23 46
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 42 47 89
        Black
    		 1 0 1
        Asian
    		 3 2 5
        Other
    		 6 5 11

    End points

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    End points reporting groups
    Reporting group title
    EVR+rTAC
    Reporting group description
    		 Investigational arm : Conversion from MMF to everolimus plus reduced dose tacrolimus and steroids withdrawal at 6 months after transplant

    Reporting group title
    MMF+sTAC
    Reporting group description
    		 Control arm : MMF continuation (in combination with tacrolimus and standard dose steroids)

    Primary: number of participants having reached the composite efficacy endpoint of biopsy-proven acute rejection

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    End point title
    		 number of participants having reached the composite efficacy endpoint of biopsy-proven acute rejection
    End point description
    To estimate the rate of the composite efficacy endpoint of biopsy-proven acute rejection (BPAR), graft loss or death at 12 months post transplantation in primary paediatric kidney transplant recipients converted at 4-6 weeks post-transplantation from MMF + standard TAC regimen and steroids, to everolimus + reduced dose TAC regimen and steroid withdrawal at 6 months, versus continuation of MMF + standard TAC regimen and steroids.
    End point type
    Primary
    End point timeframe
    12 months, 36 months
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: Participants
        12 months
    5
    3
        36 months
    5
    5
    Statistical analysis title
    		 Composite efficacy endpoint analysis at 12 months
    Statistical analysis description
    at 12 months
    Comparison groups
    EVR+rTAC v MMF+sTAC
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 0.9712
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -6.6
         upper limit
    		 6.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.25
    Notes
    [1] - Kaplan-Meier estimates and between treatment differences are estimated using the Kaplan-Meier product-limit formula and 80% confidence intervals derived using standard errors estimated from Greenwood’s formula.
    Statistical analysis title
    		 Composite efficacy endpoint analysis at 36 months
    Statistical analysis description
    36 months
    Comparison groups
    EVR+rTAC v MMF+sTAC
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 [2]
    P-value
    		 = 0.9634
    Method
    		 Logrank
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -7.3
         upper limit
    		 7.7
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.84
    Notes
    [2] - Kaplan-Meier estimates and between treatment differences are estimated using the Kaplan-Meier product-limit formula and 80% confidence intervals derived using standard errors estimated from Greenwood’s formula.

    Primary: To evaluate renal function, assessed by Glomerular Filtration Rate (eGFR) and estimated by the Schwartz formula (abbreviated), at Month 12 and 36

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    End point title
    		 To evaluate renal function, assessed by Glomerular Filtration Rate (eGFR) and estimated by the Schwartz formula (abbreviated), at Month 12 and 36
    End point description
    To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (abbreviated) (Schwartz, 2009).
    End point type
    Primary
    End point timeframe
    12 months and 36 months post-transplantation
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: mL/min/1.73m2
    arithmetic mean (standard error)
        12 months
    76.7 ± 3.66
    71.7 ± 3.56
        36 months
    68.1 ± 3.45
    67.3 ± 3.54
    Statistical analysis title
    		 Renal function analysis at 12 months
    Statistical analysis description
    at 12 months
    Comparison groups
    EVR+rTAC v MMF+sTAC
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 [3]
    P-value
    		 = 0.3455
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (net)
    Point estimate
    5
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -1.8
         upper limit
    		 11.8
    Variability estimate
    Standard error of the mean
    Dispersion value
    5.26
    Notes
    [3] - KM estimates and between treatment differences are estimated using the Kaplan-Meier product-limit formula and 80% confidence intervals derived using standard errors estimated from Greenwood’s formula.
    Statistical analysis title
    		 Renal function analysis at 36 months
    Statistical analysis description
    36 months
    Comparison groups
    EVR+rTAC v MMF+sTAC
    Number of subjects included in analysis
    106
    Analysis specification
    Pre-specified
    Analysis type
    		 [4]
    P-value
    		 = 0.8642
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.8
    Confidence interval
         level
    		 80%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 7.2
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.95
    Notes
    [4] - KM estimates and between treatment differences are estimated using the Kaplan-Meier product-limit formula and 80% confidence intervals derived using standard errors estimated from Greenwood’s formula.

    Secondary: Composite efficacy endpoint

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    End point title
    		 Composite efficacy endpoint
    End point description
    To evaluate the proportion of patients with the following efficacy events: Biopsy Proven Acute Rejection (BPAR), graft loss or death. The efficacy events will be descriptively summarized by treatment group.
    End point type
    Secondary
    End point timeframe
    at 12 and 36 months post-transplantation
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: participants
        month 12 composite efficacy endpoint
    5
    3
        graft loss 12 months
    0
    0
        death 12 months
    0
    0
        acute rejection 12 months
    5
    4
        treated acute rejection 12 months
    5
    4
        Biopsy proven acute rejection 12 months
    5
    3
        treated Biopsy proven acute rejection 12 months
    5
    3
        month 36 composite efficacy endpoint
    5
    5
        graft loss 36 months
    1
    2
        death 36 months
    0
    0
        acute rejection 36 months
    5
    7
        Biopsy proven acute rejection 36 months
    5
    5
        treated Biopsy proven acute rejection 36 months
    5
    5
    No statistical analyses for this end point

    Secondary: To evaluate the severity of BPAR (all BPAR) (Banff 2009)

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    End point title
    		 To evaluate the severity of BPAR (all BPAR) (Banff 2009)
    End point description
    T-cell mediated rejection severity : Type IA - Significant interstitial infiltration (> 25% of parenchyma) and foci of moderate tubulitis (> 4 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IB - Significant interstitial infiltration (> 25% of parenchyma) and foci of severe tubulitis (> 10 mononuclear cells/tubular cross section or group of 10 tubular cells). Type IIA - Mild to moderate intimal arteritis Type IIB - Severe intimal arteritis comprising > 25% of the lumenal area Type III - Transmural (full vessel wall thickness) arteritis and/or arterial fibrinoid change and necrosis of medial smooth muscle cells (with accompanying lymphocytic inflammation)
    End point type
    Secondary
    End point timeframe
    month 12, month 36
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: participants
        month 12 grade IA
    3
    1
        month 12 grade IB
    1
    0
        month 12 grade IIA
    0
    2
        month 12 grade IIB
    0
    0
        month 12 grade III
    0
    0
        month 36 grade IA
    3
    1
        month 36 grade IB
    2
    0
        month 36 grade IIA
    0
    1
        month 36 grade IIB
    0
    1
        month 36 grade III
    0
    1
    No statistical analyses for this end point

    Secondary: To evaluate the time to event of BPAR

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    End point title
    		 To evaluate the time to event of BPAR
    End point description
    Time to incidence of Event, given in terms of number of participants with an Event according to time interval up to 36 months
    End point type
    Secondary
    End point timeframe
    36 months
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: participants
        day 1-7
    0
    0
        day 8-14
    0
    0
        day 15-28
    1
    0
        day 29-56
    0
    0
        day 57-84
    0
    0
        day 85-150
    2
    2
        day 151- 240
    0
    0
        day 241-330
    1
    2
        day 331- 510
    0
    1
        day 511-690
    1
    0
        day 691-870
    0
    0
        day 871-1050
    0
    0
        after day 1050
    0
    0
    No statistical analyses for this end point

    Secondary: Incidence of biopsy proven antibody mediated rejection.

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    End point title
    		 Incidence of biopsy proven antibody mediated rejection.
    End point description
    To evaluate the proportion of patients with the following efficacy events: biopsy proven antibody mediated rejection/Steroid resistant BPAR and BPAR treated with T cell depleting therapy.
    End point type
    Secondary
    End point timeframe
    at 12 and 36 months post-transplantation
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: participants
        patients with BPAR at 12 months
    7
    8
        BPAR Steroid resistant,12 months
    1
    0
        BPAR, T Cell depleting therapy 12 months
    1
    1
        patients with BPAR at 36 months
    6
    12
        BPAR Steroid resistant,36 months
    1
    2
        BPAR, T Cell depleting therapy 36 months
    2
    1
    No statistical analyses for this end point

    Secondary: Chronic allograft nephropathy / interstitial fibrosis and tubular atrophy

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    End point title
    		 Chronic allograft nephropathy / interstitial fibrosis and tubular atrophy
    End point description
    To evaluate the proportion of patients with chronic allograft nephropathy (interstitial fibrosis and tubular atrophy, IF/TA) by histopathology and its progression.The term chronic allograft nephropathy was used inappropriately in the protocol and therefore, replaced by interstitial fibrosis and tubular atrophy
    End point type
    Secondary
    End point timeframe
    at 12 and 36 months post-transplantation.
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: participants
        12 months
    3
    3
        36 months
    11
    7
    No statistical analyses for this end point

    Secondary: Proteinuria (urinary protein/creatinine ratio)

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    End point title
    		 Proteinuria (urinary protein/creatinine ratio)
    End point description
    The urinary protein/creatinine ratio will be descriptively summarized by treatment group at each visit. The incidence rate of patients with proteinuria will be categorized in <0.2 g/mg/mg, 0.2<2.0 mg/mg and ≥ 2.0 mg/mg and summarized by treatment groups at each visit.
    End point type
    Secondary
    End point timeframe
    at 12 and 36 months post-transplantation
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: participants
        Baseline < 200mg/g
    1
    2
        Baseline 200 - < 2000 mg/g
    12
    12
        Baseline >= 2000 mg/g
    14
    15
        Month 12 < 200mg/g
    19
    28
        Month 12 200 - < 2000 mg/g
    13
    11
        Month 12 >= 2000 mg/g
    0
    0
        Month 36 < 200mg/g
    23
    23
        Month 36 200 - < 2000 mg/g
    10
    11
        Month 36 >= 2000 mg/g
    1
    0
    No statistical analyses for this end point

    Secondary: Growth/development : weight, height, BMI : change from baseline

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    End point title
    		 Growth/development : weight, height, BMI : change from baseline
    End point description
    evaluation of the potential effects upon the bone growth. The mean Z-score change from randomization is summarized. The Z-score represents the percentile Z(p) of the normal distribution where p denotes the percent of patients in the reference population (of same age and gender) with a value lower than or equal to the value measured.
    End point type
    Secondary
    End point timeframe
    month 12 , month 36 post transplantation.
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: z score
    arithmetic mean (standard deviation)
        Height month 12
    0.37 ± 0.625
    0.20 ± 0.537
        Height month 36
    0.72 ± 1.131
    0.39 ± 0.776
        Weight month 12
    0.30 ± 0.732
    0.42 ± 0.747
        Weight month 36
    0.61 ± 0.987
    0.82 ± 1.268
        BMI month 12
    0.00 ± 0.716
    0.24 ± 0.980
        BMI month 36
    0.02 ± 0.860
    0.47 ± 1.231
    No statistical analyses for this end point

    Secondary: Evaluation of evolution of renal allograft function over time

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    End point title
    		 Evaluation of evolution of renal allograft function over time
    End point description
    results given as eGFR values by time interval
    End point type
    Secondary
    End point timeframe
    baseline, 6 months, 12 months , 24 months, 36 months
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: ml/min/1.73m2
    arithmetic mean (standard deviation)
        baseline
    14.2 ± 11.38
    13.1 ± 15.62
        month 6
    76.6 ± 28.29
    68.3 ± 21.02
        month 12
    76.9 ± 21.61
    67.8 ± 23.57
        month 24
    72.9 ± 28.43
    68.6 ± 23.26
        month 36
    68.2 ± 21.60
    69.6 ± 20.01
    No statistical analyses for this end point

    Secondary: To evaluate renal function, assessed by Glomerular Filtration Rate (eGFR) and estimated by the Schwartz formula (extended), at Month 12

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    End point title
    		 To evaluate renal function, assessed by Glomerular Filtration Rate (eGFR) and estimated by the Schwartz formula (extended), at Month 12
    End point description
    To evaluate renal function assessed by Glomerular Filtration Rate (eGFR) estimated by the Schwartz Formula (extended) (Schwartz, 2009). Results given as change from randomization
    End point type
    Secondary
    End point timeframe
    12 months post-transplantation
    End point values
    		 EVR+rTAC MMF+sTAC
    Number of subjects analysed
    52
    54
    Units: mL/min/1.73m2
        arithmetic mean (standard deviation)
    4.6 ± 11.94
    -0.0 ± 23.92
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    up to 36 months
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    EVR+rTAC
    Reporting group description
    		 EVR+rTAC

    Reporting group title
    MMF+sTAC
    Reporting group description
    		 MMF+sTAC

    Serious adverse events
    		 EVR+rTAC MMF+sTAC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 52 (0.00%)
    0 / 54 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 EVR+rTAC MMF+sTAC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    46 / 52 (88.46%)
    48 / 54 (88.89%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 54 (5.56%)
         occurrences all number
    1
    4
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 52 (13.46%)
    6 / 54 (11.11%)
         occurrences all number
    9
    7
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    14 / 52 (26.92%)
    11 / 54 (20.37%)
         occurrences all number
    55
    27
    Fatigue
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 54 (3.70%)
         occurrences all number
    3
    4
    Pain
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 54 (5.56%)
         occurrences all number
    3
    3
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    11 / 52 (21.15%)
    10 / 54 (18.52%)
         occurrences all number
    20
    23
    Oropharyngeal pain
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 54 (5.56%)
         occurrences all number
    3
    3
    Investigations
    Blood creatinine increased
         subjects affected / exposed
    3 / 52 (5.77%)
    6 / 54 (11.11%)
         occurrences all number
    6
    7
    Hepatic enzyme increased
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 54 (1.85%)
         occurrences all number
    3
    1
    Weight decreased
         subjects affected / exposed
    0 / 52 (0.00%)
    5 / 54 (9.26%)
         occurrences all number
    0
    7
    Weight increased
         subjects affected / exposed
    5 / 52 (9.62%)
    2 / 54 (3.70%)
         occurrences all number
    5
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    10 / 52 (19.23%)
    11 / 54 (20.37%)
         occurrences all number
    17
    13
    Tremor
         subjects affected / exposed
    1 / 52 (1.92%)
    4 / 54 (7.41%)
         occurrences all number
    1
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    10 / 52 (19.23%)
    11 / 54 (20.37%)
         occurrences all number
    11
    12
    Iron deficiency anaemia
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 54 (0.00%)
         occurrences all number
    4
    0
    Leukopenia
         subjects affected / exposed
    6 / 52 (11.54%)
    6 / 54 (11.11%)
         occurrences all number
    8
    7
    Neutropenia
         subjects affected / exposed
    2 / 52 (3.85%)
    10 / 54 (18.52%)
         occurrences all number
    2
    12
    Polycythaemia
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 54 (0.00%)
         occurrences all number
    3
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    5 / 52 (9.62%)
    5 / 54 (9.26%)
         occurrences all number
    6
    5
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 52 (13.46%)
    6 / 54 (11.11%)
         occurrences all number
    10
    9
    Abdominal pain upper
         subjects affected / exposed
    6 / 52 (11.54%)
    5 / 54 (9.26%)
         occurrences all number
    8
    11
    Aphthous ulcer
         subjects affected / exposed
    9 / 52 (17.31%)
    1 / 54 (1.85%)
         occurrences all number
    14
    3
    Constipation
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 54 (3.70%)
         occurrences all number
    3
    3
    Diarrhoea
         subjects affected / exposed
    13 / 52 (25.00%)
    16 / 54 (29.63%)
         occurrences all number
    23
    31
    Mouth ulceration
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 54 (3.70%)
         occurrences all number
    7
    2
    Nausea
         subjects affected / exposed
    4 / 52 (7.69%)
    4 / 54 (7.41%)
         occurrences all number
    6
    4
    Vomiting
         subjects affected / exposed
    10 / 52 (19.23%)
    8 / 54 (14.81%)
         occurrences all number
    25
    23
    Skin and subcutaneous tissue disorders
    Dermatitis diaper
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 54 (0.00%)
         occurrences all number
    5
    0
    Pruritus
         subjects affected / exposed
    0 / 52 (0.00%)
    4 / 54 (7.41%)
         occurrences all number
    0
    6
    Rash
         subjects affected / exposed
    5 / 52 (9.62%)
    2 / 54 (3.70%)
         occurrences all number
    9
    2
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 54 (5.56%)
         occurrences all number
    3
    3
    Proteinuria
         subjects affected / exposed
    4 / 52 (7.69%)
    2 / 54 (3.70%)
         occurrences all number
    4
    2
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 54 (1.85%)
         occurrences all number
    4
    1
    Infections and infestations
    BK virus infection
         subjects affected / exposed
    4 / 52 (7.69%)
    8 / 54 (14.81%)
         occurrences all number
    6
    9
    Bronchitis
         subjects affected / exposed
    2 / 52 (3.85%)
    4 / 54 (7.41%)
         occurrences all number
    2
    6
    Cystitis
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 54 (1.85%)
         occurrences all number
    6
    1
    Cytomegalovirus infection
         subjects affected / exposed
    3 / 52 (5.77%)
    3 / 54 (5.56%)
         occurrences all number
    4
    4
    Cytomegalovirus viraemia
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 54 (5.56%)
         occurrences all number
    0
    3
    Ear infection
         subjects affected / exposed
    1 / 52 (1.92%)
    5 / 54 (9.26%)
         occurrences all number
    1
    5
    Epstein-Barr viraemia
         subjects affected / exposed
    3 / 52 (5.77%)
    2 / 54 (3.70%)
         occurrences all number
    3
    2
    Epstein-Barr virus infection
         subjects affected / exposed
    7 / 52 (13.46%)
    2 / 54 (3.70%)
         occurrences all number
    8
    2
    Gastroenteritis
         subjects affected / exposed
    4 / 52 (7.69%)
    5 / 54 (9.26%)
         occurrences all number
    5
    6
    Influenza
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 54 (1.85%)
         occurrences all number
    3
    1
    Nasopharyngitis
         subjects affected / exposed
    16 / 52 (30.77%)
    6 / 54 (11.11%)
         occurrences all number
    45
    20
    Oral herpes
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 54 (5.56%)
         occurrences all number
    2
    4
    Otitis media
         subjects affected / exposed
    4 / 52 (7.69%)
    1 / 54 (1.85%)
         occurrences all number
    6
    1
    Pharyngitis
         subjects affected / exposed
    6 / 52 (11.54%)
    1 / 54 (1.85%)
         occurrences all number
    6
    1
    Rhinitis
         subjects affected / exposed
    7 / 52 (13.46%)
    5 / 54 (9.26%)
         occurrences all number
    15
    10
    Sinusitis
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 54 (5.56%)
         occurrences all number
    1
    3
    Tonsillitis
         subjects affected / exposed
    3 / 52 (5.77%)
    8 / 54 (14.81%)
         occurrences all number
    3
    9
    Upper respiratory tract infection
         subjects affected / exposed
    8 / 52 (15.38%)
    6 / 54 (11.11%)
         occurrences all number
    10
    9
    Urinary tract infection
         subjects affected / exposed
    13 / 52 (25.00%)
    15 / 54 (27.78%)
         occurrences all number
    20
    30
    Metabolism and nutrition disorders
    Acidosis
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 54 (5.56%)
         occurrences all number
    2
    5
    Hypertriglyceridaemia
         subjects affected / exposed
    4 / 52 (7.69%)
    2 / 54 (3.70%)
         occurrences all number
    4
    2
    Hypokalaemia
         subjects affected / exposed
    3 / 52 (5.77%)
    1 / 54 (1.85%)
         occurrences all number
    3
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 52 (0.00%)
    4 / 54 (7.41%)
         occurrences all number
    0
    5
    Iron deficiency
         subjects affected / exposed
    6 / 52 (11.54%)
    0 / 54 (0.00%)
         occurrences all number
    7
    0
    Metabolic acidosis
         subjects affected / exposed
    3 / 52 (5.77%)
    0 / 54 (0.00%)
         occurrences all number
    3
    0
    Obesity
         subjects affected / exposed
    2 / 52 (3.85%)
    3 / 54 (5.56%)
         occurrences all number
    2
    3
    Vitamin D deficiency
         subjects affected / exposed
    3 / 52 (5.77%)
    4 / 54 (7.41%)
         occurrences all number
    3
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Feb 2013
    The purpose of this amendment was a) to update inclusion / exclusion criteria, and b) to allow the choice between two induction options (Simulect or no induction) to optimize patient enrollment, c) to introduce an interim analysis for the purpose of regulatory data submission.
    03 Jun 2014
    The purpose of this amendment was a) to replace the analysis introduced in the protocol amendment v02, dated 19-Feb-2013 by a 12 Month analysis in a subset of at least 30 patients for the purpose of regulatory data submission, and b) to introduce a standardized definition for the assessment of New Onset Diabetes Mellitus (NODM) which will be applied to all ongoing and new RAD001 clinical trials.
    11 Feb 2015
    The purpose of this amendment was to comply with the European Medicines Agency request to amend all Novartis clinical trials where Cellcept® (mycophenolate mofetil - MMF) and Myfortic™ (enteric-coated formulation of mycophenolate sodium (EC-MPS)) are used as Investigational Medicinal Product (IMP). The following new warnings regarding the risks of hypogammaglobulinemia and bronchiectasis had to be provided to all investigators and patients participating in the study
    14 Jul 2016
    In response to the French Health Authorities (HA) request, the protocol was updated with the recent notifications for use of mycophenolate based on EMA’s recommendation published on 23 Oct 2015, and the Dear Health Care Professional Letter (DHCPL) for CellCept that was distributed by F. Hoffmann-La Roche AG on 10-Nov-2015.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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