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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled study of RAD001 in the treatment of patients with subependymal giant cell astrocytomas (SEGA) associated with Tuberous Sclerosis Complex (TSC) Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.

    Summary
    EudraCT number
    		 2007-006997-27
    Trial protocol
    		 BE   IT   GB   DE   NL  
    Global end of trial date
    02 Oct 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Jul 2018
    First version publication date
    07 Jul 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001M2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00789828
    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)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000019-PIP02-07
    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
    02 Oct 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the study was to evaluate the efficacy and safety of everolimus in treating patients with subependymal giant cell astrocytomas (SEGA) associated with tuberous sclerosis complex (TSC).
    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
    10 Aug 2009
    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
    Australia: 2
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Netherlands: 1
    Country: Number of subjects enrolled
    Poland: 19
    Country: Number of subjects enrolled
    Russian Federation: 12
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 67
    Worldwide total number of subjects
    117
    EEA total number of subjects
    33
    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)
    13
    Children (2-11 years)
    61
    Adolescents (12-17 years)
    27
    Adults (18-64 years)
    16
    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 24 centres in 10 countries.

    Pre-assignment
    Screening details
    		 A total of 117 subjects were enrolled and randomized into the core period. Only 111 subjects completing the core period, continued in the open-label extension period of the study.

    Period 1
    Period 1 title
    Core period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor
    Blinding implementation details
    Randomization data were kept strictly confidential and the identity of treatments were concealed by the use of identical study drugs. Unblinding was allowed from randomization to database lock, except in case of patient emergencies and at the conclusion of the study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Everolimus (Core period)
    Arm description
    		 Subjects received oral dose of everolimus 4.5 milligram/square meter (mg/m^2) daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 nanogram/millilitre (ng/mL). Dose adjustments were permitted based on safety and whole blood trough concentrations.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus was administered orally at a starting dose of 4.5 mg/m^2 daily and up-titrated to attain blood trough concentration of 5-15 ng/mL.

    Arm title
    		 Placebo (Core period)
    Arm description
    		 Subjects received oral dose of placebo matching to everolimus daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to everolimus was administered daily via oral route.

    Number of subjects in period 1
    		Everolimus (Core period) Placebo (Core period)
    Started
    78
    39
    Completed
    78
    33
    Not completed
    0
    6
         Consent withdrawn by subject
    -
    4
         Administrative problems
    -
    1
         Lost to follow-up
    -
    1
    Period 2
    Period 2 title
    Extension period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The extension period was open label, hence no blinding was performed.

    Arms
    Arm title
    		 Everolimus (Extension period)
    Arm description
    		 Subjects received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain blood trough concentrations in range of 5-15 ng/mL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    RAD001
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus was administered at a starting dose of 4.5 mg/m^2 daily and up-titrated to attain blood trough concentration of 5-15 ng/mL.

    Number of subjects in period 2
    		Everolimus (Extension period)
    Started
    111
    Completed
    82
    Not completed
    29
         Consent withdrawn by subject
    6
         Disease progression
    1
         New treatment for indication under study
    1
         Adverse event, non-fatal
    10
         Death
    1
         Administrative problems
    7
         Lost to follow-up
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus (Core period)
    Reporting group description
    		 Subjects received oral dose of everolimus 4.5 milligram/square meter (mg/m^2) daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 nanogram/millilitre (ng/mL). Dose adjustments were permitted based on safety and whole blood trough concentrations.

    Reporting group title
    Placebo (Core period)
    Reporting group description
    		 Subjects received oral dose of placebo matching to everolimus daily.

    Reporting group values
    		 Everolimus (Core period) Placebo (Core period) Total
    Number of subjects
    		 78 39 117
    Age categorical
    Units: Subjects
        Age <3 years
    		 13 7 20
        Age 3 to <18 years
    		 55 26 81
        Age ≥ 18 years
    		 10 6 16
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.1 ( 5.9 ) 10.3 ( 7.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 29 21 50
        Male
    		 49 18 67

    End points

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    End points reporting groups
    Reporting group title
    Everolimus (Core period)
    Reporting group description
    		 Subjects received oral dose of everolimus 4.5 milligram/square meter (mg/m^2) daily as an initial starting dose to attain the whole blood trough concentrations in range of 5-15 nanogram/millilitre (ng/mL). Dose adjustments were permitted based on safety and whole blood trough concentrations.

    Reporting group title
    Placebo (Core period)
    Reporting group description
    		 Subjects received oral dose of placebo matching to everolimus daily.
    Reporting group title
    Everolimus (Extension period)
    Reporting group description
    		 Subjects received oral dose of everolimus 4.5 mg/m^2 daily as an initial starting dose to attain blood trough concentrations in range of 5-15 ng/mL.

    Primary: Percentage of subjects with best overall Subependymal Giant Cell Astrocytomas (SEGA) response

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    End point title
    		 Percentage of subjects with best overall Subependymal Giant Cell Astrocytomas (SEGA) response
    End point description
    Subjects were assessed for SEGA response, defined as 50% reduction from baseline in SEGA volume (where SEGA volume was the sum of the volumes of all target SEGA lesions identified at baseline, and confirmed with a second scan performed approximately 12 weeks later), no unequivocal worsening of non-target SEGA lesions, no new SEGA lesions (≥ 1 cm in longest diameter), and no new or worsening hydrocephalus. Multi-phase brain MRI was utilised to identify SEGA lesions. SEGA response rate was defined as the percentage of subjects whose best overall status was SEGA response as determined by Independent Central Radiology Review. The Kaplan-Meier estimate was used for determining time to SEGA response. The primary analysis was performed in Full Analysis Set (FAS) population, defined as all randomised subjects involved in the study.
    End point type
    Primary
    End point timeframe
    Baseline, Week 12, Week 24, Week 48 (Core period), and annually thereafter up to End of study in the extension period.
    End point values
    		 Everolimus (Core period) Placebo (Core period) Everolimus (Extension period)
    Number of subjects analysed
    78
    39
    111
    Units: Percentage of subjects
        number (confidence interval 95%)
    34.6 (24.2 to 46.2)
    0 (0 to 0.9)
    57.7 (47.9 to 67)
    Statistical analysis title
    		 Response rate difference during core study period
    Statistical analysis description
    Null hypothesis suggested response rate of everolimus to be less than or equal to response rate of placebo. Alternative hypothesis suggested the response rate of everolimus to be greater than placebo. P-value was obtained from the one-sided exact Cochran-Mantel-Haenszel test.
    Comparison groups
    Everolimus (Core period) v Placebo (Core period)
    Number of subjects included in analysis
    117
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.0001
    Method
    		 Cochran-Mantel-Haenszel
    Parameter type
    		 Difference in response rates
    Point estimate
    34.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 15.1
         upper limit
    		 52.4

    Secondary: Change from baseline in frequency of total seizure events per 24 hours at Week 24 in both core and extension period

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    End point title
    		 Change from baseline in frequency of total seizure events per 24 hours at Week 24 in both core and extension period
    End point description
    Seizure frequency per 24 hours was defined as the number of seizures in the electroencephalography (EEG) divided by the number of hours in the EEG, multiplied by 24. Seizure frequency was evaluated using a 24-hour video-EEG. Seizure frequency was listed as missing if the actual EEG recording duration was < 18 hours. The analysis was performed in the FAS population. Missing values were imputed using last observation carried forward approach.
    End point type
    Secondary
    End point timeframe
    Baseline (Core period), Week 24 (Core period), Baseline (Extension period), Week 24 (Extension period)
    End point values
    		 Everolimus (Core period) Placebo (Core period) Everolimus (Extension period)
    Number of subjects analysed
    78
    39
    34
    Units: Seizure frequency
        arithmetic mean (standard deviation)
    -1.24 ( 6.12 )
    -0.24 ( 5.7 )
    -6.07 ( 9.719 )
    No statistical analyses for this end point

    Secondary: Time to SEGA progression

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    End point title
    		 Time to SEGA progression
    End point description
    Time to SEGA progression was defined as time between randomisation to time to first SEGA progression. SEGA progression was defined as either one or more of the following criteria: 1. increase from nadir of ≥ 25% in SEGA volume to a value greater than baseline SEGA volume (where SEGA volume is the sum of the volumes of all target SEGA lesions identified at baseline, and nadir is the lowest SEGA volume obtained for the subject previously in the trial), 2. unequivocal worsening of non-target SEGA lesions, 3. appearance of new SEGA lesion ≥ 1.0 cm in longest diameter, 4. new or worsening hydrocephalus. The analysis was performed in the FAS population. Here "Number of subjects analysed" signifies the subjects assessed for time to SEGA progression during the study for each arm, respectively. The median TTSP based on central radiology review was not reached in any treatment arms; Here, 99999.9 represents not applicable data because EudraCT system is not accepting "NA" for not available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 48 after start of study treatment, and annually thereafter up to End of study
    End point values
    		 Everolimus (Core period) Placebo (Core period) Everolimus (Extension period)
    Number of subjects analysed
    78 [1]
    39 [2]
    111 [3]
    Units: Months
        median (confidence interval 95%)
    99999.9 (-99999.9 to 99999.9)
    99999.9 (-99999.9 to 99999.9)
    99999.9 (-99999.9 to 99999.9)
    Notes
    [1] - Median was not reached as no subject experienced disease progression during core period.
    [2] - Median was not reached as only 6 subjects experienced disease progression during core period.
    [3] - Median was not reached as no subject experienced disease progression during extension period.
    No statistical analyses for this end point

    Secondary: Time to SEGA response

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    End point title
    		 Time to SEGA response [4]
    End point description
    Subjects were assessed for time to SEGA response, defined as 50% reduction from baseline in SEGA volume (where SEGA volume was the sum of the volumes of all target SEGA lesions identified at baseline, and confirmed with a second scan performed approximately 12 weeks later), no unequivocal worsening of non-target SEGA lesions, no new SEGA lesions (≥ 1 cm in longest diameter), and no new or worsening hydrocephalus. Multi-phase brain MRI was utilised to identify SEGA lesions. SEGA response rate was defined as the percentage of subjects whose best overall status was SEGA response as determined by Independent Central Radiology Review. The Kaplan-Meier estimate was used for determining time to SEGA response. The analysis was performed in the FAS population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 48 after start of study treatment, and annually thereafter up to End of study
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to evaluate the active treatment (everolimus) arms only.
    End point values
    		 Everolimus (Core period) Everolimus (Extension period)
    Number of subjects analysed
    27
    64
    Units: Months
        median (confidence interval 95%)
    2.99 (2.79 to 5.36)
    5.32 (3.02 to 5.59)
    No statistical analyses for this end point

    Secondary: Duration of SEGA response

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    End point title
    		 Duration of SEGA response [5]
    End point description
    Duration of SEGA response was defined as time from the date of the first documented SEGA response until date of first documented SEGA progression. Duration of SEGA response was evaluated only for subjects who achieved a SEGA response. The time to SEGA progression was censored if SEGA progression was not observed before the first to occur out of (i) analysis cut-off date (ii) the date when systemic anti-SEGA medication is started, (iii) the date of a SEGA-related surgery or (iv) the date of death. Since, no case of SEGA progression was observed in core study which resulted in censored duration of SEGA response. Only 5 SEGA responders experienced a SEGA progression in extension period. The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies the subjects assessed for SEGA progression during the study for each arm, respectively. Here, 99999.9 represents not applicable data becasue EudraCT system is not accepting "NA" for not available data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 48 after start of study treatment, and annually thereafter up to End of study
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to evaluate the active treatment (everolimus) arms only.
    End point values
    		 Everolimus (Core period) Everolimus (Extension period)
    Number of subjects analysed
    27 [6]
    5 [7]
    Units: Months
        median (confidence interval 95%)
    99999.9 (-99999.9 to 99999.9)
    99999.9 (-99999.9 to 99999.9)
    Notes
    [6] - Median was not achieved as no case of SEGA progression was observed.
    [7] - Median was not achieved as only 5 events of SEGA progression were observed.
    No statistical analyses for this end point

    Secondary: Time to SEGA worsening

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    End point title
    		 Time to SEGA worsening
    End point description
    Time to SEGA worsening was defined as the time from the start of everolimus to date of the first SEGA worsening. SEGA worsening was defined as either; increase from nadir of ≥ 25% in SEGA volume or unequivocal worsening of non-target SEGA lesions, or appearance of new SEGA lesion ≥ 1.0 cm in longest diameter, or new or worsening hydrocephalus. The median value was not reached in either treatment arm of core period as SEGA worsening was observed in less subjects (everolimus - 7 and placebo - 8). The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies the subjects assessed for time to SEGA worsening during the study for each arm, respectively. Here, 99999.9 represents not applicable data because EudraCT system is not accepting "NA" for not available/not applicable data.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 12, Week 24, Week 48 after start of study treatment, and annually thereafter up to End of study
    End point values
    		 Everolimus (Core period) Placebo (Core period) Everolimus (Extension period)
    Number of subjects analysed
    7 [8]
    8 [9]
    40
    Units: Months
        median (confidence interval 95%)
    99999.9 (-99999.9 to 99999.9)
    99999.9 (-99999.9 to 99999.9)
    55.72 (55.72 to 99999.9)
    Notes
    [8] - Median was not achieved as only 7 events of SEGA progression were observed.
    [9] - Median was not achieved as only 8 events of SEGA progression were observed.
    No statistical analyses for this end point

    Secondary: Percentage of subjects with skin lesions assessed using Physician's global assessement overall score

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    End point title
    		 Percentage of subjects with skin lesions assessed using Physician's global assessement overall score
    End point description
    Skin lesions included hypomelanotic macules, the shagreen patch, periungual or subungual fibromas, facial angiofibromas and/or forehead plaques. Response was evaluated using the Physician’s Global Assessment of Clinical Condition (PGA) on a 7-point scale: Grade 0 = complete clinical response, indicated absence of disease, Grade 1, 2, and 3 = partial response, indicated improvements of ≥ 50% but < 100%, Grade 4, 5 = stable disease, indicated some or no improvements of 25% - < 50% and 6 = progressive disease, indicated worse than at baseline evaluation by > 25%. Response rate was determined for subjects with ≥ 1 skin lesion at baseline, defined as the percentage of subjects with overall status as complete clinical response or partial response. The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies the subjects assessed for skin lesion response during the study for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Start at Week 12 and every 12 weeks thereafter up to End of study
    End point values
    		 Everolimus (Core period) Placebo (Core period) Everolimus (Extension period)
    Number of subjects analysed
    72
    38
    105
    Units: Percentage of subjects
        median (confidence interval 95%)
    41.7 (30.2 to 53.9)
    10.5 (2.9 to 24.8)
    58.1 (48.1 to 67.7)
    No statistical analyses for this end point

    Secondary: Duration of skin lesion response

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    End point title
    		 Duration of skin lesion response [10]
    End point description
    Duration of skin lesion response was defined as the time from the first skin lesion response until the first skin lesion progression, defined as worsening of lesion by > 25% or more from baseline. The analysis was performed in the FAS population. Here, "Number of subjects analysed" signifies the subjects assessed for skin lesion response during the study for each arm, respectively. Here, 99999.9 represents not applicable data becasue EudraCT system is not accepting "NA" for not available/not applicable data.
    End point type
    Secondary
    End point timeframe
    Start at Week 12 and every 12 weeks thereafter up to End of study
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to evaluate the active treatment (everolimus) arms only.
    End point values
    		 Everolimus (Core period) Everolimus (Extension period)
    Number of subjects analysed
    30 [11]
    61 [12]
    Units: Months
        median (confidence interval 95%)
    99999.9 (-99999.9 to 99999.9)
    99999.9 (-99999.9 to 99999.9)
    Notes
    [11] - Median was not achieved as no case of skin lesion was observed.
    [12] - Median was not achieved as no case of skin lesion was observed.
    No statistical analyses for this end point

    Secondary: Everolimus blood concentration (C2h) at 2 hours post dose

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    End point title
    		 Everolimus blood concentration (C2h) at 2 hours post dose [13]
    End point description
    The subjects were assessed for everolimus blood concentration at 2 hours time point after dose administration on the same day, if the subject did not vomit between previous dose and blood sample collection. Tandem liquid chromatography-mass spectrometry method was used for evaluation. C2h values were categorized as < 20 ng/mL, 20-50 ng/mL, and > 50 ng/mL, concentrations below the lower limit of quantification were entered as 0 ng/mL. The analysis was performed in the Safety Set population (Only evaluable PK Samples), defined as subjects who received at least one dose of the double-blind study drug, with a valid post baseline assessment. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively. Here, the value 99999.9 in the field represents not available estimable. Here, 99999.9 represents not applicable data becasue EudraCT system is not accepting "NA" for not available/not applicable data.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1-3 hours (Post dose)
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to evaluate the active treatment (everolimus) arms only.
    End point values
    		 Everolimus (Core period) Everolimus (Extension period)
    Number of subjects analysed
    78
    111
    Units: Nanogram(s)/millilitre
    arithmetic mean (standard deviation)
        Week 6 (n= 37, 47)
    27.52 ( 15.24 )
    27.74 ( 16.202 )
        Week 24 (n= 11, 13)
    38.7 ( 15.76 )
    39.25 ( 14.662 )
        Week 48 (n= 1, 3)
    23.2 ( 99999.9 )
    49.73 ( 28.884 )
        Week 96 (n= 0, 6)
    99999.9 ( 99999.9 )
    31.63 ( 21.902 )
        Week 144 (n= 0, 6)
    99999.9 ( 99999.9 )
    26.33 ( 11.908 )
        Week 240 (n= 0, 0)
    99999.9 ( 99999.9 )
    99999.9 ( 99999.9 )
    No statistical analyses for this end point

    Secondary: Everolimus trough concentrations (Cmin) at 24 hours after last dose

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    End point title
    		 Everolimus trough concentrations (Cmin) at 24 hours after last dose [14]
    End point description
    The subjects were assessed for everolimus trough concentration (Cmin) at 24 hours time point after previous dose administration, at a steady state following 5 days of consistent dosing, if the subject did not vomit within 4 hours of previous dose. Tandem liquid chromatography-mass spectrometry method was used for evaluation. Cmin values were categorized as <5 ng/mL, 5-10 ng/mL, and >10 ng/mL, concentrations below the lower limit of quantification were entered as 0 ng/mL. The analysis was performed in the Safety Set population. The 'n' signifies those subjects evaluable for this measure at specified time points for each group, respectively.Here, 99999.9 represents not applicable data becasue EudraCT system is not accepting "NA" for not available/not applicable data.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 20-28 hours (Post-dose)
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The end point was planned to evaluate the active treatment (everolimus) arms only.
    End point values
    		 Everolimus (Core period) Everolimus (Extension period)
    Number of subjects analysed
    78
    111
    Units: Nanogram(s)/millilitre
    arithmetic mean (standard deviation)
        Week 6 (n= 64, 94)
    5.8 ( 3.68 )
    6.09 ( 3.708 )
        Week 24 (n= 64, 89)
    6.59 ( 3.43 )
    6.86 ( 3.504 )
        Week 48 (n= 23, 86)
    7.28 ( 3.11 )
    7.07 ( 3.214 )
        Week 72 (n= 4, 92)
    6.08 ( 2.19 )
    7.25 ( 3.66 )
        Week 96 (n= 0, 83)
    99999.9 ( 99999.9 )
    7.09 ( 3.697 )
        Week 144 (n= 0, 69)
    99999.9 ( 99999.9 )
    7.28 ( 3.35 )
        Week 240 (n= 0, 13)
    99999.9 ( 99999.9 )
    5.85 ( 2.507 )
    No statistical analyses for this end point

    Secondary: Percentage of subjects with renal impairment during core period

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    End point title
    		 Percentage of subjects with renal impairment during core period
    End point description
    Renal function was assessed using glomerular filtration rate (GFR) based on age measure; Modification of Diet in Renal Disease (MDRD) formula for subjects aged 18 years or older, defined as GFR equal to 32788*(serum creatinine (micromol/L)^-1.154)*(age^-0.203 )*(0.742, if female)*(1.210, if black), and Schwartz formula for subjects less than 18 years defined as GFR equal to 0.41*height (cm)/ Serum creatinine (mg/dL). Subjects with severe renal impairment defined as GFR < 30 mL/min/1.73 m^2 and subjects with National Cancer Institute’s Common Terminology Criteria for Adverse Events (NCI-CTCAE) grade 3/4 serum creatinine were reported. The analysis was performed in the SAF population. Here, "Number of subjects analysed" signifies the subjects assessed for renal function during the study for each arm, respectively.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 28 days after end of treatment (Core period)
    End point values
    		 Everolimus (Core period) Placebo (Core period)
    Number of subjects analysed
    78
    39
    Units: Percentage of subjects
    number (not applicable)
        Grade 3 or 4
    0
    0
        Grade 1 or 2
    3.8
    0
        Grade 0
    96.2
    100
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Subject First Visit (FSFV) until Last Subject Last Visit (LSLV). All adverse events reported in this record are from date of First Subject First Treatment until LSLV.
    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
    17.0
    Reporting groups
    Reporting group title
    Everolimus (Core + Extension period)
    Reporting group description
    		 Subjects who recieved Everolimu both in core and extension period.

    Reporting group title
    Placebo (Core) + Everolimus (Extention)
    Reporting group description
    		 All patietns who recieved placebo in core, entered the open-lable extension to recieve everolimus.

    Reporting group title
    Placebo (Core period, No extension)
    Reporting group description
    		 Subects who recieved placebo in core , did not enter the extnesion period of open-label everolimus

    Serious adverse events
    		 Everolimus (Core + Extension period) Placebo (Core) + Everolimus (Extention) Placebo (Core period, No extension)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 78 (42.31%)
    17 / 33 (51.52%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Raynaud's phenomenon
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 33 (6.06%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    5 / 7
    1 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asphyxia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary pneumatocele
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Agitation
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foreign body aspiration
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Complex partial seizures
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Convulsion
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 33 (3.03%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 6
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Drooling
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epilepsy
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile convulsion
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Grand mal convulsion
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Partial seizures
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lymphadenopathy
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Large intestinal ulcer
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mouth ulceration
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Focal segmental glomerulosclerosis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Patellofemoral pain syndrome
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tendon disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Acinetobacter bacteraemia
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Adenovirus infection
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ear infection bacterial
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Epstein-Barr virus infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Febrile infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    5 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    2 / 5
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    4 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected bites
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Laryngitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Meningitis viral
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nasopharyngitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Otitis media
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pertussis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    11 / 78 (14.10%)
    5 / 33 (15.15%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    9 / 14
    2 / 5
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory tract infection viral
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sinusitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Everolimus (Core + Extension period) Placebo (Core) + Everolimus (Extention) Placebo (Core period, No extension)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    77 / 78 (98.72%)
    33 / 33 (100.00%)
    6 / 6 (100.00%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    11 / 78 (14.10%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    11
    2
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Fatigue
         subjects affected / exposed
    16 / 78 (20.51%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    17
    3
    0
    Pyrexia
         subjects affected / exposed
    25 / 78 (32.05%)
    7 / 33 (21.21%)
    2 / 6 (33.33%)
         occurrences all number
    89
    24
    3
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    5 / 78 (6.41%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    9
    5
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    5 / 78 (6.41%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    23 / 78 (29.49%)
    10 / 33 (30.30%)
    1 / 6 (16.67%)
         occurrences all number
    46
    13
    1
    Epistaxis
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    17
    5
    0
    Nasal congestion
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Oropharyngeal pain
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    6
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    7
    3
    0
    Psychiatric disorders
    Abnormal behaviour
         subjects affected / exposed
    6 / 78 (7.69%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    0
    Aggression
         subjects affected / exposed
    10 / 78 (12.82%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    13
    5
    0
    Agitation
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    6
    1
    0
    Anxiety
         subjects affected / exposed
    10 / 78 (12.82%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    12
    3
    0
    Insomnia
         subjects affected / exposed
    11 / 78 (14.10%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    15
    4
    0
    Irritability
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    6
    1
    0
    Obsessive-compulsive disorder
         subjects affected / exposed
    5 / 78 (6.41%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    Sleep disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    Blood cholesterol increased
         subjects affected / exposed
    11 / 78 (14.10%)
    3 / 33 (9.09%)
    1 / 6 (16.67%)
         occurrences all number
    15
    3
    1
    Blood fibrinogen decreased
         subjects affected / exposed
    5 / 78 (6.41%)
    6 / 33 (18.18%)
    0 / 6 (0.00%)
         occurrences all number
    5
    6
    0
    Blood glucose increased
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    6 / 78 (7.69%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    0
    0
    Blood triglycerides increased
         subjects affected / exposed
    7 / 78 (8.97%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    0
    0
    Carbon dioxide decreased
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    International normalised ratio increased
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    Low density lipoprotein increased
         subjects affected / exposed
    6 / 78 (7.69%)
    2 / 33 (6.06%)
    1 / 6 (16.67%)
         occurrences all number
    7
    2
    1
    Neutrophil count decreased
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    8
    1
    0
    Weight decreased
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    6
    1
    0
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    3 / 78 (3.85%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    3
    5
    0
    Excoriation
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    Fall
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 33 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    2
    0
    2
    Hand fracture
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Laceration
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Limb injury
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 33 (3.03%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    1
    Lip injury
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 33 (3.03%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    1
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    31 / 78 (39.74%)
    13 / 33 (39.39%)
    4 / 6 (66.67%)
         occurrences all number
    85
    19
    4
    Dizziness
         subjects affected / exposed
    6 / 78 (7.69%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    6
    5
    0
    Epilepsy
         subjects affected / exposed
    3 / 78 (3.85%)
    2 / 33 (6.06%)
    1 / 6 (16.67%)
         occurrences all number
    3
    2
    3
    Headache
         subjects affected / exposed
    13 / 78 (16.67%)
    6 / 33 (18.18%)
    1 / 6 (16.67%)
         occurrences all number
    20
    10
    1
    Migraine with aura
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    8
    1
    0
    Neutropenia
         subjects affected / exposed
    8 / 78 (10.26%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    15
    6
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    Vertigo
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 78 (6.41%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    9
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    5 / 78 (6.41%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    6
    4
    0
    Constipation
         subjects affected / exposed
    11 / 78 (14.10%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    15
    2
    0
    Dental caries
         subjects affected / exposed
    5 / 78 (6.41%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    6
    2
    0
    Diarrhoea
         subjects affected / exposed
    21 / 78 (26.92%)
    7 / 33 (21.21%)
    0 / 6 (0.00%)
         occurrences all number
    44
    12
    0
    Enteritis
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    6
    0
    1
    Mouth ulceration
         subjects affected / exposed
    33 / 78 (42.31%)
    6 / 33 (18.18%)
    0 / 6 (0.00%)
         occurrences all number
    87
    32
    0
    Nausea
         subjects affected / exposed
    7 / 78 (8.97%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    10
    1
    0
    Oral pain
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    Stomatitis
         subjects affected / exposed
    29 / 78 (37.18%)
    21 / 33 (63.64%)
    1 / 6 (16.67%)
         occurrences all number
    137
    49
    1
    Vomiting
         subjects affected / exposed
    24 / 78 (30.77%)
    6 / 33 (18.18%)
    1 / 6 (16.67%)
         occurrences all number
    43
    12
    2
    Toothache
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    18 / 78 (23.08%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    18
    5
    0
    Dermatitis
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Dry skin
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    5
    1
    0
    Eczema
         subjects affected / exposed
    5 / 78 (6.41%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    Rash
         subjects affected / exposed
    12 / 78 (15.38%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    22
    2
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Pain in extremity
         subjects affected / exposed
    6 / 78 (7.69%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    11
    0
    0
    Infections and infestations
    Abscess
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Body tinea
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Bronchitis
         subjects affected / exposed
    14 / 78 (17.95%)
    5 / 33 (15.15%)
    1 / 6 (16.67%)
         occurrences all number
    28
    6
    2
    Cellulitis
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    0
    Conjunctivitis
         subjects affected / exposed
    7 / 78 (8.97%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    10
    6
    0
    Croup infectious
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    0
    Ear infection
         subjects affected / exposed
    14 / 78 (17.95%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    22
    10
    0
    Fungal infection
         subjects affected / exposed
    0 / 78 (0.00%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Gastroenteritis
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    Gastroenteritis viral
         subjects affected / exposed
    9 / 78 (11.54%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    12
    8
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Gastrointestinal viral infection
         subjects affected / exposed
    4 / 78 (5.13%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    Influenza
         subjects affected / exposed
    6 / 78 (7.69%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    8
    2
    0
    Laryngitis
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    30 / 78 (38.46%)
    15 / 33 (45.45%)
    1 / 6 (16.67%)
         occurrences all number
    59
    21
    1
    Oral candidiasis
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    3
    0
    3
    Otitis media
         subjects affected / exposed
    16 / 78 (20.51%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    31
    9
    0
    Pharyngitis
         subjects affected / exposed
    12 / 78 (15.38%)
    7 / 33 (21.21%)
    0 / 6 (0.00%)
         occurrences all number
    39
    22
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    15 / 78 (19.23%)
    2 / 33 (6.06%)
    1 / 6 (16.67%)
         occurrences all number
    24
    4
    1
    Pneumonia
         subjects affected / exposed
    12 / 78 (15.38%)
    3 / 33 (9.09%)
    1 / 6 (16.67%)
         occurrences all number
    16
    3
    1
    Respiratory tract infection
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    9
    1
    0
    Respiratory tract infection viral
         subjects affected / exposed
    7 / 78 (8.97%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    17
    4
    0
    Rhinitis
         subjects affected / exposed
    8 / 78 (10.26%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    10
    3
    0
    Sinusitis
         subjects affected / exposed
    17 / 78 (21.79%)
    4 / 33 (12.12%)
    1 / 6 (16.67%)
         occurrences all number
    35
    8
    1
    Tracheitis
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    23 / 78 (29.49%)
    7 / 33 (21.21%)
    3 / 6 (50.00%)
         occurrences all number
    35
    13
    3
    Urinary tract infection
         subjects affected / exposed
    7 / 78 (8.97%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    13
    4
    0
    Varicella
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    Viral infection
         subjects affected / exposed
    6 / 78 (7.69%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    9
    3
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 33 (3.03%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    12 / 78 (15.38%)
    6 / 33 (18.18%)
    0 / 6 (0.00%)
         occurrences all number
    16
    7
    0
    Dehydration
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 33 (3.03%)
    2 / 6 (33.33%)
         occurrences all number
    2
    1
    2
    Hypercholesterolaemia
         subjects affected / exposed
    11 / 78 (14.10%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    12
    3
    0
    Hyperlipidaemia
         subjects affected / exposed
    6 / 78 (7.69%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    7
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2009
    The requirement of target lesion volume increase above the baseline value for defining progression was added. The exclusion criterion of prior brain surgery was removed, and renal disease was allowed. Skin lesion response scans were allowed to carry out in 12 weeks after initial response and the screening period was increased from 14 to 21 days
    02 Apr 2010
    - Target everolimus concentration range was modified from 10-15 ng/mL to 5-15 ng/mL, two additional dose levels (10.67 mg/m^2 and 14.22 mg/m^2) were added. - Stricter guidance with respect to changes in endocrine hormone levels and hepatitis virus screening was implemented. - The screening period for the study was extended from 21 to 28 days. - Added endocrine blood testing (testosterone, LH, FSH and Estradiol) at screening and subsequent timepoints accorindg to age an gender - Added Tanner staging to assess sexual maturation at screening and subsequent timepoints accorinding to age
    11 Jan 2011
    Evaluation of any potential effects of everolimus on growth and development in the pediatric population was allowed. The definition and safety recommendations concerning hepatitis B virus (HBV) reactivation and hepatitis C virus (HCV) flare were modified.
    23 Feb 2011
    All subjects have endocrine testing at baseline or at their next scheduled visit (if no prior endocrine testing had been done). Endocrine blood sampling was completed annually until the subject's 10th birthday and every 12 weeks thereafter.
    05 Mar 2012
    As part of this amendment, a full pharmacokinetic (PK) profile was collected from subjects currently active in the study. New PK collection time-points were added.
    22 Aug 2012
    - Changed inclusion criteria to include highly effective contraceptive measures instead of adequate contraceptive measures. - Added secondary amenorrhea as an identified risk of study drug. Added information on management of secondary amenorrhea. - Added detailed description of highly effective contraceptive measures. - Added completion of hormone evaluations when amenorrhea is seen between scheduled assessments. - Revised 2 tables: - Urine pregnancy testing frequency increased from every 12 weeks to every 4 weeks.  - Serum pregnancy test added to End of Treatment evaluation.  - Additional menstrual history and pregnancy history information collected. Will conduct monthly monitoring of menstrual status.  - Added collection of biological parental height to assist us in the evaluation of patient’s growth and development. - Section revised to include - Urine pregnancy testing frequency increased from every 12 weeks to every 4 weeks. Serum pregnancy test added to End of Treatment evaluation.  - Parental height subsection added. Data will be used to evaluation patient’s growth and development. - Revised endocrine testing section to include reproductive history. Additional medical information on reproductive history will be collected. - Additional safety language for pregnancies added - Added data collection language regarding the results from at home urine pregnancy to be recorded on patient diaries for source documentation only.
    15 Jan 2013
    - In the section, Amendment (date 22-Aug-2012), Changes to the protocol, the following paragraph is deleted: “This amendment is required for patient safety (i.e. necessary to eliminate immediate hazards to the trial patients International Conference on Harmonization GCP 3.3.8). Therefore it will be implemented prior to IRB/IEC approval, but will be sent for approval as well.” - In the section, Amendment (date 22-Aug-2012), Changes to the protocol, the following paragraph is added: “The changes described in this amended protocol require IRB/EC approval prior to implementation. In addition, if the changes herein affect the Informed Consent, sites are required to update and submit for approval a revised Informed Consent that takes into account the changes described in this amended protocol.”

    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.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/CtrdWeb/home.novfor complete trial results.
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    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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