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    Clinical Trial Results:
    TRON: A randomised, double blind, placebo-controlled study of RAD001 (Everolimus) in the treatment of neurocognitive problems in tuberous sclerosis.

    Summary
    EudraCT number
    		 2011-004854-25
    Trial protocol
    		 GB  
    Global end of trial date
    06 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    10 Nov 2021
    First version publication date
    10 Nov 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    SPON803-10
    Additional study identifiers
    ISRCTN number
    		 ISRCTN09739757
    US NCT number
    		 NCT01954693
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Cardiff University
    Sponsor organisation address
    30-36 Newport Road, Cardiff, United Kingdom, CF24 0DE
    Public contact
    Dr Cheney Drew, Cardiff University, 02920 687243, DrewC5@cardiff.ac.uk
    Scientific contact
    Prof Julian Sampson, Cardiff University, 02920 744050, Sampson@cardiff.ac.uk
    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
    18 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine how effective Everolimus is compared to a placebo for recall memory (remembering events or information) and executive function (the ability to organise thoughts and activities, prioritise tasks, manage time and make decisions) in people with tuberous sclerosis over a 6 month period.
    Protection of trial subjects
    Safety assessments were conducted to ensure ongoing health and wellness of participants as follows: 1) Physical and neurolgiocal examination at screening, baseline, 4, 12 and 24 week assessment points 2) Haematology, Serum Chemistry, spirometry and urine analysis were conducted at each timepoint.
    Background therapy
    		 Tuberous Sclerosis is associated with a number of co-morbid conditions.
    Evidence for comparator
    		 N/A, comparator used in this trial was placebo
    Actual start date of recruitment
    01 Feb 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 38
    Worldwide total number of subjects
    38
    EEA total number of subjects
    38
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    1
    Adults (18-64 years)
    37
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a multi-centre Phase II trial. Recruitment took place in 3 sites: Cardiff, Belfast and Glasgow between 12/FEB/2012 and 06/AUG/2018.

    Pre-assignment
    Screening details
    		 Entry into the study was a two stage process: those likely to be eligible were offered a screening appointment (visit 1) at which fully informed written consent was obtained. A screening assessment including full medical history, current medications, physical examination, together with neurocognitive tests to confirm or refute eligibility.

    Pre-assignment period milestones
    Number of subjects started
    		 67 [1]
    Intermediate milestone: Number of subjects
    Screening: 67
    Number of subjects completed
    		 38

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Consent withdrawn by subject: 1
    Reason: Number of subjects
    		 Not eligible: 28
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Participants were screened for inlcusion in the pre-assignment period but not officially enrolled in the trial at this point.
    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    Randomisation data are kept strictly confidential, and accessible only to authorised personnel until database lock. The drug was supplied by Novartis as open label bulk supplies and sent to St Mary's Pharmaceutical Unit, Cardiff, for packaging and labeling. The participant’s unique identification number and allocation was to be double blinded, so neither the participant, clinician, research psychologist nor the statistician knew which treatment group the participant had been allocated to.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Everolimus
    Arm description
    		 RAD001 (Everolimus) 5mg, administered for 6 months as two oral 2.5 mg tablets once daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    EU/1/09/538/001
    Other name
    Afinitor
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Administration was 2.5mg tablets taken orally once a day. Starting dose of 5mg/day adjusted to achieve trough blood levels of 3-10ng/ml.

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to match
    Investigational medicinal product code
    N/A
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Adminstration was 2 x 2.5mg tablets taken orally, once a day.

    Number of subjects in period 1
    		Everolimus Placebo
    Started
    25
    13
    Visit 3 (week 2)
    24
    12
    Visit 4 (week 4)
    24
    12
    Visit 5 (week 6)
    24
    12
    Visit 6 (week 12)
    24
    12
    Visit 7 (week 24)
    24
    12
    Visit 8 (week 36)
    23 [2]
    12
    Completed
    24
    12
    Not completed
    1
    1
         Consent withdrawn by subject
    1
    1
    Notes
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Participants were screened for inlcusion in the pre-assignment period but not officially enrolled in the trial at this point.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    		 RAD001 (Everolimus) 5mg, administered for 6 months as two oral 2.5 mg tablets once daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo

    Reporting group values
    		 Everolimus Placebo Total
    Number of subjects
    		 25 13 38
    Age categorical
    Units: Subjects
        <50 years
    		 21 10 31
        >= 50 years
    		 4 3 7
    Gender categorical
    Units: Subjects
        Female
    		 14 7 21
        Male
    		 11 6 17
    IQ Level group
    Units: Subjects
        60-79
    		 10 4 14
        80 or more
    		 15 9 24
    Currently on anti-epilepsy drugs
    Units: Subjects
        No
    		 9 4 13
        Yes
    		 16 9 25

    End points

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    End points reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    		 RAD001 (Everolimus) 5mg, administered for 6 months as two oral 2.5 mg tablets once daily.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo

    Primary: Memory functioning

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    End point title
    		 Memory functioning
    End point description
    The primary outcome for this study is memory functioning, with improved memory functioning classed as a one SD response on any of the following memory tests Complex Figure test and List Learning test from the BIRT Memory and Information Processing Battery, Spatial Working Memory (SWM) and Stockings of Cambridge (SOC) from the CANTAB, and Telephone search dual task from the Test of Everyday Attention.
    End point type
    Primary
    End point timeframe
    Between baseline and Visit 7 (week 24 / 6 months)
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    24
    12
    Units: Improved memory functioning
        Yes - improved by one SD
    20
    9
        No - did not improve by one SD
    3
    3
    Statistical analysis title
    		 Primary outcome
    Statistical analysis description
    The hypothesis for the primary analysis of the primary outcome in TRON was to observe a 15% learning effect in the placebo group and that an improvement of 35% or more in the Everolimus group would provide sufficient evidence for further investigation of Everolimus as a treatment for TAND. A one sample chi-squared test was used to determine whether the proportion of patients in the intervention group who improve their recall memory at 6 months by one SD was at least 0.35.
    Comparison groups
    Placebo v Everolimus
    Number of subjects included in analysis
    36
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 = 0.077 [2]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - A one-sample χ2 test for improvement to 95% (derived from adding the hypothesised 20-percentage point increase to the observed 75% improvement from baseline to 6 months in the Placebo arm) in the Everolimus arm provides a p-value of 0.077, implying no evidence to suggest that the observed proportion of 87.0% in Everolimus is different to the hypothesised 95%. This indicates no statistically significant difference between observing 95.0% or 87.0% improvement in the Everolimus arm given the data.
    [2] - A one-sample χ2 test for improvement to 95% (derived from adding the hypothesised 20-percentage point increase to the observed 75% improvement from baseline to 6 months in the Placebo arm) in the Everolimus arm provides a p-value of 0.077.

    Secondary: CANTAB Rapid Visual Information Processing - Standard score

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    End point title
    		 CANTAB Rapid Visual Information Processing - Standard score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months follow-up
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    11
    Units: standard score
    number (not applicable)
        1SD improvement
    1
    0
    Statistical analysis title
    		 1-sample chi-squared test
    Statistical analysis description
    A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected). A one sample chi-squared test will be used to determine whether the proportion of patients in the Ever
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 < 0.001
    Method
    		 1-sided chi-squared
    Confidence interval
    Notes
    [3] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected). A one sample chi-squared test will be used to determine whether the proportion of patients in the Ever

    Secondary: CANTAB - Spatial span

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    End point title
    		 CANTAB - Spatial span
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    23
    12
    Units: Span length
    number (not applicable)
        1SD improvement
    2
    2
    Statistical analysis title
    		 1 sample chi-squared
    Statistical analysis description
    A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected). A one sample chi-squared test will be used to determine whether the proportion of patients in the Ever
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    35
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval

    Secondary: QOLIE - Seizure worry

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    End point title
    		 QOLIE - Seizure worry
    End point description
    End point type
    Secondary
    End point timeframe
    baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    11
    Units: score
    number (not applicable)
        1SD improvement
    2
    1
    Statistical analysis title
    		 1-sample chi-square
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [4] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: QOLIE- Overall Quality of Life

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    End point title
    		 QOLIE- Overall Quality of Life
    End point description
    End point type
    Secondary
    End point timeframe
    baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    11
    Units: score
    number (not applicable)
        1SD improvement
    1
    1
    Statistical analysis title
    		 1 sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [5] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: QOLIE -Fatigue

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    End point title
    		 QOLIE -Fatigue
    End point description
    End point type
    Secondary
    End point timeframe
    baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    11
    Units: score
    number (not applicable)
        1SD improvement
    2
    1
    Statistical analysis title
    		 1 sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [6] - A one sample chi-squared test was used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: QOLIE - Cognitive functioning

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    End point title
    		 QOLIE - Cognitive functioning
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    11
    Units: score
    number (not applicable)
        1 SD improvement
    4
    2
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.003
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [7] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: QOLIE - Medication effects

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    End point title
    		 QOLIE - Medication effects
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    11
    Units: score
    number (not applicable)
        1SD improvement
    3
    1
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [8] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: QOLIE - Social functioning

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    End point title
    		 QOLIE - Social functioning
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    11
    Units: score
    number (not applicable)
        1SD improvement
    4
    1
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [9]
    P-value
    		 = 0.003
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [9] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: QOLIE - Overall score

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    End point title
    		 QOLIE - Overall score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    11
    Units: score
    number (not applicable)
        1SD improvement
    3
    0
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [10] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: Symptoms Checklist 90 (SCL-90R) - Somatization

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    End point title
    		 Symptoms Checklist 90 (SCL-90R) - Somatization
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    12
    Units: score
    number (not applicable)
        1SD improvement
    3
    2
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 other [11]
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [11] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: SCL-90R - Obsessive-Compulsive

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    End point title
    		 SCL-90R - Obsessive-Compulsive
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    18
    11
    Units: score
    number (not applicable)
        1SD improvement
    1
    1
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [12] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other [13]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [13] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: SCL-90R - Interpersonal Sensitivity

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    End point title
    		 SCL-90R - Interpersonal Sensitivity
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    19
    10
    Units: score
    number (not applicable)
        1SD improvement
    2
    0
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    		 other [14]
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [14] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: SCL-90R - Depression

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    End point title
    		 SCL-90R - Depression
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    20
    11
    Units: score
    number (not applicable)
        1SD improvement
    1
    1
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other [15]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [15] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: SCL-90R - Anxiety

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    End point title
    		 SCL-90R - Anxiety
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    20
    11
    Units: score
    number (not applicable)
        1SD improvement
    2
    3
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other [16]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [16] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: SCL-90R - Hostility

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    End point title
    		 SCL-90R - Hostility
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    20
    11
    Units: score
    number (not applicable)
        1SD improvement
    3
    1
    Statistical analysis title
    		 1SD improvement
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other [17]
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [17] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: SCL-90R - Phobic Anxiety

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    End point title
    		 SCL-90R - Phobic Anxiety
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    11
    Units: score
    number (not applicable)
        1SD improvement
    1
    0
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [18]
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [18] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: SCL-90R - Paranoid Ideation

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    End point title
    		 SCL-90R - Paranoid Ideation
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    22
    11
    Units: score
    number (not applicable)
        1SD improvement
    1
    0
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other [19]
    P-value
    		 = 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [19] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: SCL-90R - Psychoticism

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    End point title
    		 SCL-90R - Psychoticism
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    21
    10
    Units: score
    number (not applicable)
        1SD improvement
    1
    1
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 other [20]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [20] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Secondary: SCL-90R - Global Severity Index

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    End point title
    		 SCL-90R - Global Severity Index
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to 6 months
    End point values
    		 Everolimus Placebo
    Number of subjects analysed
    17
    8
    Units: score
    number (not applicable)
        1SD improvement
    1
    0
    Statistical analysis title
    		 1-sample chi-squared
    Comparison groups
    Everolimus v Placebo
    Number of subjects included in analysis
    25
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [21]
    P-value
    		 < 0.001
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [21] - A one sample chi-squared test will be used to determine whether the proportion of patients in the Everolimus group who improve at six months by at least one SD is significantly greater than what is expected (the null hypothesis of equal proportions is rejected).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse Events were monitored from baseline to study end and AEs ongoing on completion of the study were followed up as clinically indicated.
    Adverse event reporting additional description
    Patients entered into the study were encouraged from the outset to contact the clinical team at the time of an adverse event occurring. In addition, at each visit, AEs that might have occurred since the previous visit were reported.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.1
    Reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    		 Includes participants randomsied to receive Everolimus

    Reporting group title
    Placebo
    Reporting group description
    		 This includes all participants randomised to the placebo group

    Serious adverse events
    		 Everolimus Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 13 (15.38%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Seizure cluster
    Additional description: Increased seiure frequency requiring hopitilisation
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
    Additional description: Recurrence of previous suicidal ideation prior to participation in trial.
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Everolimus Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 25 (84.00%)
    8 / 13 (61.54%)
    Vascular disorders
    epistaxis
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Surgical and medical procedures
    Weight loss diet
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Oedema extremities
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Flu like symptoms
         subjects affected / exposed
    6 / 25 (24.00%)
    0 / 13 (0.00%)
         occurrences all number
    9
    0
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract infection
         subjects affected / exposed
    7 / 25 (28.00%)
    4 / 13 (30.77%)
         occurrences all number
    6
    10
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Elevated Creatine Phosphokinase
         subjects affected / exposed
    0 / 25 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    High liver enzymes
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    High IMP level
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Burns first degree
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 25 (8.00%)
    2 / 13 (15.38%)
         occurrences all number
    3
    2
    Seizure
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Dizziness
         subjects affected / exposed
    1 / 25 (4.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    Dysgeusia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    hypersomnolence
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    drop attacks
    Additional description: Increase in frequency
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Neutropenia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 13 (0.00%)
         occurrences all number
    3
    0
    Eye disorders
    blurred vision
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Oral Mucositis
         subjects affected / exposed
    13 / 25 (52.00%)
    2 / 13 (15.38%)
         occurrences all number
    32
    2
    Diarrhoea
         subjects affected / exposed
    3 / 25 (12.00%)
    2 / 13 (15.38%)
         occurrences all number
    3
    2
    Inguinal hernia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Toothache
         subjects affected / exposed
    3 / 25 (12.00%)
    0 / 13 (0.00%)
         occurrences all number
    4
    0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    skin rash
         subjects affected / exposed
    3 / 25 (12.00%)
    1 / 13 (7.69%)
         occurrences all number
    4
    1
    Renal and urinary disorders
    Urinary incontinence
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Proteinuria
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Back pain
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Chest wall pain
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Skin infection
         subjects affected / exposed
    5 / 25 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    6
    0
    Otitis externa
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0
    Paronychia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypophosphatemia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    30 Oct 2011
    • Postponement of appointments in event of seizures (p40, 7.0) • All patients to have Hepatitis B and C screening prior to randomization (p29; 5.1.1, p41; 7.1). Any positive results go to GP for further confirmatory tests. • Patients will not be tested for HIV but will be excluded if known to be HIV seropositive (p30; 5.1.2)
    20 Dec 2011
    • Exclusion criterion regarding potent inhibitors of CYP3A4 • Development Safety Update Reports have now replaced Annual Safety Reports. • MHRA must approve all amendments to protocol before implementation and notified at the time an Urgent Safety Measure is taken
    01 Feb 2012
    • Cardiff will deliver the packed open labeled drug and placebo to the pharmacy at the University Hospital of Wales for dispensing • Randomisation details • Treatment blinding details • Unblinding section • The SRS listed is now the SRS-A • In the event of a positive result, participants will be referred for appropriate counselling and further management via their GP. • Dipstick Urinalysis will also be carried out at weeks 2, 6, 36 • SAEs to be reported to Novartis within one business day. Unblinding will be carried out by SEWTU before the SAE is passed to Novartis • Inclusion of Nominated person details • ‘EDTA anticoagulated tube marked with patient name, hospital and trial number, date/time of sample collection’ – changed to PID/DOB and initials
    04 Oct 2012
    • Trial Steering Committee now referred to as Study Steering Committee (SSC) to avoid confusion with Tuberous Sclerosis Complex (TSC) • Addition of the NART premorbid test as a secondary outcome measure • Addition of Co-investigators • Alteration to dosing modifications in case of toxicities to bring in line with the SmPC. Specifically with regard to Grade 2&3 • Out dated reference to ECG and electrocardiogram were removed
    02 Feb 2013
    • Inclusion of Co investigators details to TRON • Substantial Amendment: Imaging study • Inclusion of Brain DTI MR scan in assessment schedule • Inclusion of Brain DTI MR Scan on Visit 2 & Visit 7 in TRON flow chart
    15 Feb 2013
    Addition of detail on informed consent. The SRS-A will no longer be undertaken at visit 4, the VABS-2 will no longer be undertaken at visit 6. (see table 2)
    26 Feb 2013
    • Revision of data analysis in sub-study following Novartis review
    07 Nov 2013
    • Addition of new wording for SAE section • Change of Trial Manager
    06 May 2014
    • Amendment of exclusion criteria for Previous Brain Neurosurgery so those who have had SEGA (sub-ependymal giant cell astrocytoma) surgery or radiosurgery over 5 years ago are now eligible
    25 Sep 2014
    • Removal of the Social Responsiveness Scale - Adult, and the Social Communication Questionnaire (SCQ) at 3 month interview
    05 Jan 2015
    • One eligibility criteria has been altered as it was felt to be overly stringent. Previously, individuals were required to have a score of -2 standard deviations (SD) on any one of the primary outcomes in order to be eligible to take part. This has been adjusted to approximately -1.5 SD. • Entry criteria regarding kidney function has also been updated in light of new evidence. • Wording in relation to IMP dispensing has been refined in order to make it more clear as to when and how participants might be prescribed an increase in dose.
    06 Aug 2015
    • Section 1.2.6 addition of new marketing authorization for Everolimus for the treatment of renal angiomyolipoma in TSC • Section 7.2 Addition of the need for fasted bloods to be repeated if it was not possible to do them at a planned study visit. • Section 7.4 Addition of provision for blood to be drawn and submitted for pharmacokinetic analysis by participant’s GP • Section 9.2 update for procedures for receiving safety information from Novartis.
    02 Mar 2016
    • Addition to text (where relevant) of the new research sites at Belfast City Hospital and Queen Elizabeth University Hospital, Glasgow and removal of specific references to Cardiff and/or University Hos[ital Wales as the only research site. • Section 6.2: Change to the process of Patient Identification Number allocation from assignation the point of consent to assignation at the point of confirmation of attendance to eligibility assessment appointment. • Section 6.3: Addition of process for randomization for new sites

    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.
    Different versions of the TEA were used between baseline and primary endpoint. These are scored differently, so direct comparison is difficult. Participants entered on the basis of the TEA were excluded in a sensitivity analysis.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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