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    Clinical Trial Results:
    Multicenter, open-label, single-arm, safety, tolerability, efficacy and pharmacokinetic study of RAD001 in pediatric de novo renal transplant patients (12-month analysis)

    Summary
    EudraCT number
    		 2005-002372-16
    Trial protocol
    		 ES  
    Global end of trial date
    21 Mar 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Jan 2017
    First version publication date
    04 Jan 2017
    Other versions
    Summary report(s)
    		 CRAD001B351_NovCTR

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001AB351
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    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
    21 Mar 2007
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Mar 2007
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study was conducted in 2 parts: Cohort 1 and Cohort 2. Cohort 1: The main objective of the study was to evaluate the safety and tolerability of RAD001 (everolimus) administered in combination with cyclosporine and corticosteroids in pediatric de novo renal transplant subjects. Cohort 2: The main objective of the study was to evaluate safety and tolerability of concentration-controlled everolimus administered in combination with reduced cyclosporine and corticosteroids in pediatric de novo renal transplant subjects.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 Background immunosuppressive therapy was cyclosporine and corticosteroids. Cyclosporine [6 to 12 milligrams (mg)/Kilograms (kg)/day]was started within 24 hours post-transplantation or pre-transplantation according to the local standard of care. Intravenous (IV) corticosteroids were given pre- or intra-operatively according to local practice at each center. Oral prednisone (or equivalent) (0.1 mg/kg/day)was given according to local practice from Day 1, and continued for at least 6 months.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Aug 2004
    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
    Belgium: 1
    Country: Number of subjects enrolled
    Germany: 10
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    United Kingdom: 4
    Country: Number of subjects enrolled
    United States: 18
    Worldwide total number of subjects
    37
    EEA total number of subjects
    19
    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)
    18
    Adolescents (12-17 years)
    19
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at: Cohort I - 15 centers [United States (6), France (2), Germany (2), Spain (2), Belgium (1), Brazil (1) and United Kingdom (1)]; Cohort II - 3 centers (United States).

    Pre-assignment
    Screening details
    		 A total of 37 subjects were enrolled in the study.

    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was open label study, hence no blinding was performed

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Everolimus (fixed dose), subjects <10 years
    Arm description
    		 All subjects aged less than 10 years and undergone renal transplantation were administered with fixed-dose everolimus 0.8 milligram (mg)/metre (m) ^2 body surface area (BSA) (maximum 1.5 mg) twice-daily (bid), 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner. Cyclosporine was dosed according to trough blood levels based on a conventional down-titration of exposure.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Certican
    Pharmaceutical forms
    Dispersible tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with fixed-dose everolimus 0.8 mg/ m^2 BSA (maximum 1.5 mg) bid, 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner.

    Arm title
    		 Everolimus (fixed dose), subjects 10 to 16 years
    Arm description
    		 All subjects aged 10 to 16 years and undergone renal transplantation were administered with 0.8 mg/m^2 BSA of everolimus (not to exceed 1.5 mg as a single dose independent of BSA) bid, 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner. Cyclosporine was dosed according to trough blood levels based on a conventional down-titration of exposure.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Certican
    Pharmaceutical forms
    Dispersible tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with fixed-dose everolimus 0.8 mg/ m^2 BSA (maximum 1.5 mg) bid, 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner.

    Arm title
    		 Everolimus (concentration-controlled), subjects <10 years
    Arm description
    		 All subjects aged less than 10 years and undergone renal transplantation were administered with initial doses of everolimus at 0.8 mg/ m^2 BSA bid, 12 hours apart, in combination with cyclosporine and corticosteroids followed by administration of everolimus by therapeutic drug monitoring, targeting a blood trough level of > 3 nanogram (ng)/milliliter (mL). Cyclosporine was administered bid by therapeutic drug monitoring targeting reduced cyclosporine trough levels.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Certican
    Pharmaceutical forms
    Tablet, Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with fixed-dose everolimus 0.8 mg/ m^2 BSA (maximum 1.5 mg) bid, 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner.

    Arm title
    		 Everolimus (concentration-controlled), subjects 10 to 16 years
    Arm description
    		 All subjects aged between 10 to 16 years and undergone renal transplantation were administered with initial doses of everolimus at 0.8 mg/m^2 BSA bid, 12 hours apart, in combination with cyclosporine and corticosteroids followed by administration of everolimus by therapeutic drug monitoring, targeting a blood trough level of > 3ng/mL. Cyclosporine was administered targeting reduced cyclosporine trough levels.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Certican
    Pharmaceutical forms
    Dispersible tablet, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered with fixed-dose everolimus 0.8 mg/ m^2 BSA (maximum 1.5 mg) bid, 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner.

    Number of subjects in period 1
    		Everolimus (fixed dose), subjects <10 years Everolimus (fixed dose), subjects 10 to 16 years Everolimus (concentration-controlled), subjects <10 years Everolimus (concentration-controlled), subjects 10 to 16 years
    Started
    10
    9
    6
    12
    Completed
    10
    9
    6
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus (fixed dose), subjects <10 years
    Reporting group description
    		 All subjects aged less than 10 years and undergone renal transplantation were administered with fixed-dose everolimus 0.8 milligram (mg)/metre (m) ^2 body surface area (BSA) (maximum 1.5 mg) twice-daily (bid), 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner. Cyclosporine was dosed according to trough blood levels based on a conventional down-titration of exposure.

    Reporting group title
    Everolimus (fixed dose), subjects 10 to 16 years
    Reporting group description
    		 All subjects aged 10 to 16 years and undergone renal transplantation were administered with 0.8 mg/m^2 BSA of everolimus (not to exceed 1.5 mg as a single dose independent of BSA) bid, 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner. Cyclosporine was dosed according to trough blood levels based on a conventional down-titration of exposure.

    Reporting group title
    Everolimus (concentration-controlled), subjects <10 years
    Reporting group description
    		 All subjects aged less than 10 years and undergone renal transplantation were administered with initial doses of everolimus at 0.8 mg/ m^2 BSA bid, 12 hours apart, in combination with cyclosporine and corticosteroids followed by administration of everolimus by therapeutic drug monitoring, targeting a blood trough level of > 3 nanogram (ng)/milliliter (mL). Cyclosporine was administered bid by therapeutic drug monitoring targeting reduced cyclosporine trough levels.

    Reporting group title
    Everolimus (concentration-controlled), subjects 10 to 16 years
    Reporting group description
    		 All subjects aged between 10 to 16 years and undergone renal transplantation were administered with initial doses of everolimus at 0.8 mg/m^2 BSA bid, 12 hours apart, in combination with cyclosporine and corticosteroids followed by administration of everolimus by therapeutic drug monitoring, targeting a blood trough level of > 3ng/mL. Cyclosporine was administered targeting reduced cyclosporine trough levels.

    Reporting group values
    		 Everolimus (fixed dose), subjects <10 years Everolimus (fixed dose), subjects 10 to 16 years Everolimus (concentration-controlled), subjects <10 years Everolimus (concentration-controlled), subjects 10 to 16 years Total
    Number of subjects
    		 10 9 6 12 37
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 10 0 6 0 16
        Adolescents (12-17 years)
    		 0 9 0 12 21
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 5.7 ( 2.54 ) 13.2 ( 1.72 ) 5.2 ( 2.32 ) 13.8 ( 2.08 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 4 3 2 15
        Male
    		 4 5 3 10 22

    End points

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    End points reporting groups
    Reporting group title
    Everolimus (fixed dose), subjects <10 years
    Reporting group description
    		 All subjects aged less than 10 years and undergone renal transplantation were administered with fixed-dose everolimus 0.8 milligram (mg)/metre (m) ^2 body surface area (BSA) (maximum 1.5 mg) twice-daily (bid), 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner. Cyclosporine was dosed according to trough blood levels based on a conventional down-titration of exposure.

    Reporting group title
    Everolimus (fixed dose), subjects 10 to 16 years
    Reporting group description
    		 All subjects aged 10 to 16 years and undergone renal transplantation were administered with 0.8 mg/m^2 BSA of everolimus (not to exceed 1.5 mg as a single dose independent of BSA) bid, 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner. Cyclosporine was dosed according to trough blood levels based on a conventional down-titration of exposure.

    Reporting group title
    Everolimus (concentration-controlled), subjects <10 years
    Reporting group description
    		 All subjects aged less than 10 years and undergone renal transplantation were administered with initial doses of everolimus at 0.8 mg/ m^2 BSA bid, 12 hours apart, in combination with cyclosporine and corticosteroids followed by administration of everolimus by therapeutic drug monitoring, targeting a blood trough level of > 3 nanogram (ng)/milliliter (mL). Cyclosporine was administered bid by therapeutic drug monitoring targeting reduced cyclosporine trough levels.

    Reporting group title
    Everolimus (concentration-controlled), subjects 10 to 16 years
    Reporting group description
    		 All subjects aged between 10 to 16 years and undergone renal transplantation were administered with initial doses of everolimus at 0.8 mg/m^2 BSA bid, 12 hours apart, in combination with cyclosporine and corticosteroids followed by administration of everolimus by therapeutic drug monitoring, targeting a blood trough level of > 3ng/mL. Cyclosporine was administered targeting reduced cyclosporine trough levels.

    Primary: Number of subjects with Adverse Events (AEs) including infections, Serious Adverse Events (SAEs), AE leading to discontinuation and who died

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    End point title
    		 Number of subjects with Adverse Events (AEs) including infections, Serious Adverse Events (SAEs), AE leading to discontinuation and who died [1]
    End point description
    AEs are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards. The analysis was performed on the intent-to-treat (ITT) population defined as all subjects who entered the study, were transplanted, and received at least one dose of study medication.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 450 for on-treatment events (AEs/infection with onset up to 7 days after the premature discontinuation)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for safety end point.
    End point values
    		 Everolimus (fixed dose), subjects <10 years Everolimus (fixed dose), subjects 10 to 16 years Everolimus (concentration-controlled), subjects <10 years Everolimus (concentration-controlled), subjects 10 to 16 years
    Number of subjects analysed
    10
    9
    6
    12
    Units: Subjects
        AEs/Infections
    10
    8
    6
    11
        SAEs
    0
    0
    5
    5
        Deaths
    0
    0
    0
    0
        AEs leading to discontinuation
    1
    0
    0
    1
    No statistical analyses for this end point

    Primary: Number of subjects with hematologic abnormalities based on notable criteria

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    End point title
    		 Number of subjects with hematologic abnormalities based on notable criteria [2]
    End point description
    Subjects with hematologic abnormalities based on notable criteria values outside the defined normal range were graded as laboratory abnormalities. Hematologic parameters for cohort I were: hemoglobin low (< 8.0 gram (g)/deciliter (dL)), platelets low (<=75 *10^9/L), leukocytes low (<= 2.8 *10^9/L), leukocytes high (>=16 *10^9/L) and absolute neutrophils low (<= 1.5 *10^9/L). Hematologic parameters for cohort II were: hemoglobin low (< 5.0 g/dL), platelets high (>=700 *10^9/L), leukocytes low (<= 2.8 *10^9/L), leukocytes high (>= 16 *10^9/L) and absolute neutrophils low (<= 1.5 *10^9/L). The analysis was performed on ITT population.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 450 for on-treatment events (AEs/infection with onset up to 7 days after the premature discontinuation)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for safety end point.
    End point values
    		 Everolimus (fixed dose), subjects <10 years Everolimus (fixed dose), subjects 10 to 16 years Everolimus (concentration-controlled), subjects <10 years Everolimus (concentration-controlled), subjects 10 to 16 years
    Number of subjects analysed
    10
    9
    6
    12
    Units: Subjects
        Hemoglobin low
    4
    1
    1
    0
        Platelets low
    1
    0
    0
    0
        Platelets high
    0
    0
    1
    0
        Leukocytes low
    1
    0
    0
    1
        Leukocytes high
    4
    1
    3
    2
        Absolute neutrophils low
    4
    1
    2
    0
    No statistical analyses for this end point

    Primary: Number of subjects with biochemistry abnormalities based on notable criteria for fixed-dose everolimus

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    End point title
    		 Number of subjects with biochemistry abnormalities based on notable criteria for fixed-dose everolimus [3]
    End point description
    Subjects with biochemistry abnormalities based on notable criteria values outside the defined normal range were graded as laboratory abnormalities by the sponsor. Biochemistry parameters included, liver function: serum glutamic oxaloacetic transaminase aspartate transaminase (SGOT(AST)) high (>= 3 * upper limit of normal (ULN)), serum glutamic pyruvic transaminase alanine transaminase (SGPT(ALT)) high (>= 3 *ULN); renal function: creatinine high (30% increase from previous visit or >= 354 micromole(µmol)/L Day 8 to Week 4 or >= 265 µmol/L after week 4, uric acid high (>= 0.714 millimole(mmol)/L [males] and >= 0.535 mmol/L [females]); lipids:total cholesterol high (>=9.1 mmol/L), triglycerides high (>= 5.6 mmol/L); metabolites and electrolytes: potassium low (<= 3 mmol/L), potassium high (>= 6 mmol/L); enzymes: amylase (>= 2 x ULN), lipase (>= 2 x ULN). The analysis was performed on ITT population.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 450 for on-treatment events (AEs/infection with onset up to 7 days after the premature discontinuation)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for safety end point.
    End point values
    		 Everolimus (fixed dose), subjects <10 years Everolimus (fixed dose), subjects 10 to 16 years Everolimus (concentration-controlled), subjects <10 years Everolimus (concentration-controlled), subjects 10 to 16 years
    Number of subjects analysed
    10
    9
    6
    12
    Units: Subjects
        Liver function: SGOT (AST) high
    1
    0
    1
    1
        Liver function: SGPT (ALT) high
    2
    3
    3
    2
        Renal function: Creatinine high
    4
    3
    5
    3
        Renal function: Uric acid high
    1
    1
    0
    0
        Lipids: Total cholesterol high
    2
    3
    0
    2
        Lipids: Triglycerides high
    1
    2
    0
    1
        Metabolites and electrolytes: Potassium low
    1
    0
    2
    1
        Metabolites and electrolytes: Potassium high
    0
    1
    0
    0
        Metabolites and electrolytes: Magnesium high
    0
    0
    1
    0
        Metabolites and electrolytes: Uric acid high
    0
    0
    1
    0
        Enzymes: Amylase
    1
    0
    0
    1
        Enzymes: Lipase
    5
    2
    0
    0
    No statistical analyses for this end point

    Primary: Number of subjects with urinalysis abnormalities

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    End point title
    		 Number of subjects with urinalysis abnormalities [4]
    End point description
    Subjects with urinalysis abnormalities such as positive urinary glucose and urinary protein post baseline were analyzed. Glucose and protein was determined using dipstick method. The analysis was performed on ITT population.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 450 for on-treatment events (AEs/infection with onset up to 7 days after the premature discontinuation)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for safety end point.
    End point values
    		 Everolimus (fixed dose), subjects <10 years Everolimus (fixed dose), subjects 10 to 16 years Everolimus (concentration-controlled), subjects <10 years Everolimus (concentration-controlled), subjects 10 to 16 years
    Number of subjects analysed
    10
    9
    6
    12
    Units: Subjects
        Positive urinary glucose
    0
    0
    0
    1
        Positive urinary protein
    2
    4
    1
    1
    No statistical analyses for this end point

    Primary: Number of subjects with clinically significant changes in vital signs and electrocardiogram (ECG)

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    End point title
    		 Number of subjects with clinically significant changes in vital signs and electrocardiogram (ECG) [5]
    End point description
    Subjects were evaluated for abnormal vital signs and ECG parameters. Vital signs like blood pressure (BP): systolic blood pressure (SBP) (>=140 millimeter of mercury (mmHg) and diastolic blood pressure (DBP) (>=90 mmHg) outside baseline range were graded as clinically significant vital signs. The analysis was performed on ITT population.
    End point type
    Primary
    End point timeframe
    From Day 1 to Day 450 for on-treatment events (AEs/infection with onset up to 7 days after the premature discontinuation)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive analysis was planned to be reported for safety end point.
    End point values
    		 Everolimus (fixed dose), subjects <10 years Everolimus (fixed dose), subjects 10 to 16 years Everolimus (concentration-controlled), subjects <10 years Everolimus (concentration-controlled), subjects 10 to 16 years
    Number of subjects analysed
    10
    9
    6
    12
    Units: Subjects
        SBP
    5
    7
    3
    9
        DBP
    7
    5
    4
    6
        ECG
    0
    0
    1
    4
    No statistical analyses for this end point

    Secondary: Number of subjects with biopsy-proven acute rejection/graft loss/death/lost to follow-up within 12 months of the study

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    End point title
    		 Number of subjects with biopsy-proven acute rejection/graft loss/death/lost to follow-up within 12 months of the study
    End point description
    Efficacy failure was determined as biopsy-proven acute rejection/graft loss/death/lost to follow-up. Graft loss was defined as graft failure, including death due to graft failure. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 381
    End point values
    		 Everolimus (fixed dose), subjects <10 years Everolimus (fixed dose), subjects 10 to 16 years Everolimus (concentration-controlled), subjects <10 years Everolimus (concentration-controlled), subjects 10 to 16 years
    Number of subjects analysed
    10
    9
    6
    12
    Units: Subjects
        Biopsy-proven acute rejection
    0
    3
    0
    0
        Graft loss
    0
    0
    0
    0
        Death
    0
    0
    0
    0
        Loss to follow-up
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of subjects with clinically confirmed acute rejection, antibody treated acute rejection, allograft nephropathy, chronic rejection, delayed graft function within 12 months of the study

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    End point title
    		 Number of subjects with clinically confirmed acute rejection, antibody treated acute rejection, allograft nephropathy, chronic rejection, delayed graft function within 12 months of the study
    End point description
    Efficacy of everolimus in the prevention of chronic allograft rejection (chronic graft dysfunction) was determined as clinically confirmed acute rejection/biopsy-proven acute rejection/antibody treated acute rejection/biopsy-proven chronic allograft nephropathy/clinically confirmed chronic rejection and delayed graft function. Delayed graft function was defined as need for dialysis within 7 days post-transplantation. The analysis was performed on ITT population.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 381
    End point values
    		 Everolimus (fixed dose), subjects <10 years Everolimus (fixed dose), subjects 10 to 16 years Everolimus (concentration-controlled), subjects <10 years Everolimus (concentration-controlled), subjects 10 to 16 years
    Number of subjects analysed
    10
    9
    6
    12
    Units: Subjects
        Clinically confirmed acute rejection
    0
    3
    0
    0
        Antibody treated acute rejection
    0
    0
    0
    0
        Biopsy-proven chronic allograft nephropathy
    2
    1
    0
    0
        Clinically confirmed chronic rejection
    1
    1
    0
    0
        Delayed graft function
    1
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious Adverse Events are monitored from date of First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV). All other adverse events are monitored from First Subject First Treatment until LSLV.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    0.0
    Reporting groups
    Reporting group title
    Age Group <10 years
    Reporting group description
    		 All subjects aged less than 10 years and undergone renal transplantation were administered with fixed-dose everolimus 0.8 mg/m ^2 BSA (maximum 1.5 mg) b.i.d, 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner. Cyclosporine was dosed according to trough blood levels based on a conventional down-titration of exposure.

    Reporting group title
    Age Group 10 to 16 years
    Reporting group description
    		 All subjects aged 10 to 16 years and undergone renal transplantation were administered with 0.8 mg/m^2 BSA of everolimus (not to exceed 1.5 mg as a single dose independent of BSA) b.i.d, 12 hours apart after cyclosporine and corticosteroids administration and at least one hour prior to or after breakfast or dinner. Cyclosporine was dosed according to trough blood levels based on a conventional down-titration of exposure.

    Serious adverse events
    		 Age Group <10 years Age Group 10 to 16 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 6 (83.33%)
    5 / 12 (41.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoproliferative disorder
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (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
    Pyrexia
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abdominal distension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (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 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Peritonitis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Bladder distension
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (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
    Otitis media
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         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
    		 Age Group <10 years Age Group 10 to 16 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 6 (100.00%)
    10 / 12 (83.33%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    4 / 6 (66.67%)
    4 / 12 (33.33%)
         occurrences all number
    4
    4
    Hypotension
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Lymphocele
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Generalised oedema
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    3
    Pain
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 12 (0.00%)
         occurrences all number
    3
    0
    Pyrexia
         subjects affected / exposed
    4 / 6 (66.67%)
    4 / 12 (33.33%)
         occurrences all number
    5
    3
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Genital erythema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Scrotal oedema
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Scrotal swelling
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 12 (25.00%)
         occurrences all number
    6
    5
    Epistaxis
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Nasal congestion
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Pharyngolaryngeal pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    Pulmonary oedema
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Rhinorrhoea
         subjects affected / exposed
    4 / 6 (66.67%)
    3 / 12 (25.00%)
         occurrences all number
    7
    7
    Sinus congestion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Tachypnoea
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    3
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    4
    Blood creatinine increased
         subjects affected / exposed
    0 / 6 (0.00%)
    3 / 12 (25.00%)
         occurrences all number
    0
    2
    Blood potassium decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Blood triglycerides increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    Cytomegalovirus test positive
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Heart rate increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Immunosuppressant drug level increased
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Urine output decreased
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Graft complication
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Incision site pain
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Incisional hernia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Lower limb fracture
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Post procedural discharge
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Procedural pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Skin laceration
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Cardiomegaly
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Left ventricular hypertrophy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Tachycardia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Coordination abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Dizziness
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Headache
         subjects affected / exposed
    1 / 6 (16.67%)
    4 / 12 (33.33%)
         occurrences all number
    1
    5
    Lethargy
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Tremor
         subjects affected / exposed
    0 / 6 (0.00%)
    5 / 12 (41.67%)
         occurrences all number
    0
    5
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Eye disorders
    Eye swelling
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Ocular hyperaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Vision blurred
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Abdominal pain
         subjects affected / exposed
    3 / 6 (50.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    2
    Constipation
         subjects affected / exposed
    4 / 6 (66.67%)
    2 / 12 (16.67%)
         occurrences all number
    4
    3
    Diarrhoea
         subjects affected / exposed
    1 / 6 (16.67%)
    3 / 12 (25.00%)
         occurrences all number
    4
    2
    Epigastric discomfort
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Gingival hyperplasia
         subjects affected / exposed
    3 / 6 (50.00%)
    6 / 12 (50.00%)
         occurrences all number
    3
    8
    Ileus
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Inguinal hernia
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Melaena
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    2 / 6 (33.33%)
    3 / 12 (25.00%)
         occurrences all number
    2
    3
    Vomiting
         subjects affected / exposed
    3 / 6 (50.00%)
    3 / 12 (25.00%)
         occurrences all number
    5
    5
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 12 (33.33%)
         occurrences all number
    0
    7
    Dermatitis diaper
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Hirsutism
         subjects affected / exposed
    5 / 6 (83.33%)
    7 / 12 (58.33%)
         occurrences all number
    6
    10
    Pruritus
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    1
    3
    Rash
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Rash papular
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Rash pruritic
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Skin odour abnormal
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Enuresis
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Haematuria
         subjects affected / exposed
    3 / 6 (50.00%)
    1 / 12 (8.33%)
         occurrences all number
    3
    1
    Hydronephrosis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Renal hydrocele
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Urethral disorder
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Urethral pain
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Vesicoureteric reflux
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Cushingoid
         subjects affected / exposed
    4 / 6 (66.67%)
    8 / 12 (66.67%)
         occurrences all number
    4
    10
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 6 (0.00%)
    4 / 12 (33.33%)
         occurrences all number
    0
    4
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Infections and infestations
    BK virus infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Fungal infection
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Oral herpes
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    2 / 6 (33.33%)
    0 / 12 (0.00%)
         occurrences all number
    2
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Rhinitis
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 6 (50.00%)
    5 / 12 (41.67%)
         occurrences all number
    7
    9
    Urinary tract infection
         subjects affected / exposed
    4 / 6 (66.67%)
    2 / 12 (16.67%)
         occurrences all number
    8
    2
    Varicella
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Viral infection
         subjects affected / exposed
    4 / 6 (66.67%)
    1 / 12 (8.33%)
         occurrences all number
    4
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Fluid overload
         subjects affected / exposed
    1 / 6 (16.67%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    Fluid retention
         subjects affected / exposed
    1 / 6 (16.67%)
    2 / 12 (16.67%)
         occurrences all number
    1
    3
    Hypercholesterolaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Hyperglycaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    Hyperlipidaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    2
    Hypokalaemia
         subjects affected / exposed
    1 / 6 (16.67%)
    1 / 12 (8.33%)
         occurrences all number
    1
    1
    Hypomagnesaemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    2
    Hypophosphataemia
         subjects affected / exposed
    0 / 6 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Jun 2000
    • Dosing guidelines were amended so that study drug could be taken with or without food, with the exception of visit days with PK profile blood sample collection. • No restrictions on the kind of food or fluid taken after administration of study medication or for meals were required, except that grapefruit or grapefruit juice was not allowed. This amendment was issued prior to the recruitment of the first subject to Cohort II, therefore the actual Cohort II protocol incorporated these amendments.
    30 Apr 2001
    Based on findings of possible cyclosporine-related nephrotoxicity in related studies, cyclosporine target levels were reduced, everolimus drug level targeting was introduced (in place of fixed dosing per BSA) and renal function were more closely monitored as follows: • Cyclosporine levels were progressively lowered to 50-100 ng/mL by Month 3. • Everolimus trough levels were maintained at ≥ 3 ng/mL. • Blood samples for serum creatinine, blood urea nitrogen, everolimus and cyclosporine trough levels were collected regularly. This amendment was issued prior to the recruitment of the first subject to Cohort II, therefore the actual Cohort II protocol incorporated these amendments.
    09 Jul 2001
    This amendment applied only to Cohort I subjects: • Blood samples were to be obtained every 6 months for the determination of endocrine parameters (follicle stimulating hormone, luteinizing hormone, testosterone [boys and girls]) and safety or drug effects, and included retrospective analysis of stored blood samples taken since the start of the study. • Sexual maturity was to be assessed at each scheduled visit using Tanner staging, if possible. In boys, testicular volume was also to be assessed every 6 months.
    04 Feb 2004
    This amendment applied only to Cohort II subjects: • An additional blood sample was added to each study visit for the determination of the endocrine parameters (follicle stimulating hormone and luteinizing hormone in males and females; testosterone in males only). • Sexual maturity was to be assessed at each visit using Tanner staging in males and females. In males, testicular volume was also to be assessed every 6 months. This amendment was issued prior to the recruitment of the first subject to Cohort II, therefore the actual Cohort II protocol incorporated these amendments.

    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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