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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled study of RAD0001 in the treatment of Angiomyolipoma in patients with either Tuberous Sclerosis Complex (TSC) or Sporadic Lymphangioleiomyomatosis (LAM) Due to EudraCT system limitations, which EMA is aware of, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results

    Summary
    EudraCT number
    2008-002113-48
    Trial protocol
    DE   FR   NL   GB   IT   ES  
    Global end of trial date
    06 Nov 2015

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

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001M2302
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT00790400
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111,
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    06 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Nov 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of Study CRAD001M2302 was to compare the angiomyolipoma response rate of everolimus versus placebo in patients with angiomyolipomata associated with either TSC or sporadic LAM.
    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
    28 Apr 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
    Canada: 5
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Japan: 10
    Country: Number of subjects enrolled
    Netherlands: 13
    Country: Number of subjects enrolled
    Poland: 5
    Country: Number of subjects enrolled
    Russian Federation: 8
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 9
    Country: Number of subjects enrolled
    United States: 32
    Worldwide total number of subjects
    118
    EEA total number of subjects
    63
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    118
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A multicenter trial conducted at 24 sites in 11 countries. As the primary analysis of the core phase of the study favored everolimus over placebo, an open-label extension phase started: patients randomized in placebo were offered to switch on everolimus and those still receiving everolimus at the end of the core phase could continue the treatment.

    Pre-assignment
    Screening details
    The trial had a 2:1 randomization in favor of the everolimus arm. 118 patients were randomized to the core phase of the study. 112 patients received everolimus during core and/or extension phase.

    Period 1
    Period 1 title
    Double-blind Period (Core phase)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Everolimus
    Arm description
    Study drug was given by continuous oral daily dosing of two 5 mg tablets.
    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 is used in 5 mg strength tablets, blister-packed under aluminum foil in units of ten tablets and dosed on a daily basis. It was given by continuous oral daily dosing of two 5 mg tablets.

    Arm title
    Placebo
    Arm description
    Placebo was given by continuous oral daily dosing of two 5 mg tablets.
    Arm type
    Placebo

    Investigational medicinal product name
    Everolimus Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Everolimus Placebo, similar to the Everolimus, was used in 5 mg strength tablets, blister-packed under aluminum foil in units of ten tablets and dosed on a daily basis. It was given by continuous oral daily dosing of two 5 mg tablets.

    Number of subjects in period 1
    Everolimus Placebo
    Started
    79
    39
    Completed
    72
    26
    Not completed
    7
    13
         Progressive disease
    -
    9
         Protocol deviation
    1
    -
         Adverse event, serious fatal
    1
    -
         Abnormal lab value (s)
    1
    -
         Administrative problems
    1
    -
         Adverse event, non-fatal
    2
    4
         Consent withdrawn by subject
    1
    -
    Period 2
    Period 2 title
    Everolimus Period (Core or Extension)
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Everolimus
    Arm description
    Study drug was given by continuous oral daily dosing of two 5 mg tablets.
    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 is used in 5 mg strength tablets, blister-packed under aluminum foil in units of ten tablets and dosed on a daily basis. It was given by continuous oral daily dosing of two 5 mg tablets. tablets.

    Number of subjects in period 2 [1] [2]
    Everolimus
    Started
    72
    Completed
    83
    Not completed
    29
         Protocol deviation
    1
         New treatment
    2
         Adverse event, serious fatal
    1
         Abnormal lab value (s)
    1
         Administrative problems
    2
         Adverse event, non-fatal
    9
         Consent withdrawn by subject
    7
         Disease progression
    5
         Lost to follow-up
    1
    Joined
    40
         Dropped off the study
    7
         Transferred in from other group/arm
    33
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Period 1 was for everolimus & placebo. Period 2 was for anyone who had at least 1 dose of everolimus either in period 1 (started = those on everolimus who completed period 1 & moved to period 2) or in period 2, which contains those who were on placebo in period 1 and switched to everolimus in period 2.
    [2] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: This period includes all the subjects from period 1 who took everolimus plus any other subject who took at least 1 dose of everolimus throughout the duration of the study.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    Study drug was given by continuous oral daily dosing of two 5 mg tablets.

    Reporting group title
    Placebo
    Reporting group description
    Placebo was given by continuous oral daily dosing of two 5 mg tablets.

    Reporting group values
    Everolimus Placebo Total
    Number of subjects
    79 39 118
    Age Categorical
    Units: Subjects
        <30 years
    35 20 55
        ≥ 30 years
    44 19 63
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    32.5 ± 10.37 31 ± 9.64 -
    Gender, Male/Female
    Units: Subjects
        Female
    52 26 78
        Male
    27 13 40
    Subject analysis sets

    Subject analysis set title
    Everolimus randomized (Core period)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Study drug was given by continuous oral daily dosing of two 5 mg tablets.

    Subject analysis set title
    Placebo randomized (Core period)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo was given by continuous oral daily dosing of two 5 mg tablets.

    Subject analysis set title
    Everolimus (Core and/or Extension period)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients initially randomized in everolimus and patients initially randomized in placebo but who crossed-over to everolimus during extension.

    Subject analysis sets values
    Everolimus randomized (Core period) Placebo randomized (Core period) Everolimus (Core and/or Extension period)
    Number of subjects
    79
    39
    112
    Age Categorical
    Units: Subjects
        <30 years
    35
    20
    49
        ≥ 30 years
    44
    19
    63
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    32.5 ± 10.37
    31 ± 9.64
    33.18 ± 10.287
    Gender, Male/Female
    Units: Subjects
        Female
    52
    26
    73
        Male
    27
    13
    39

    End points

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    End points reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    Study drug was given by continuous oral daily dosing of two 5 mg tablets.

    Reporting group title
    Placebo
    Reporting group description
    Placebo was given by continuous oral daily dosing of two 5 mg tablets.
    Reporting group title
    Everolimus
    Reporting group description
    Study drug was given by continuous oral daily dosing of two 5 mg tablets.

    Subject analysis set title
    Everolimus randomized (Core period)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Study drug was given by continuous oral daily dosing of two 5 mg tablets.

    Subject analysis set title
    Placebo randomized (Core period)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Placebo was given by continuous oral daily dosing of two 5 mg tablets.

    Subject analysis set title
    Everolimus (Core and/or Extension period)
    Subject analysis set type
    Full analysis
    Subject analysis set description
    Patients initially randomized in everolimus and patients initially randomized in placebo but who crossed-over to everolimus during extension.

    Primary: Angiomyolipoma response rate as Per Central Radiology Review

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    End point title
    Angiomyolipoma response rate as Per Central Radiology Review
    End point description
    Angiomyolipoma response defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; there were no kidney increases in volume > 20% from nadir. The patient did not have any angiomyolipoma-related bleeding of ≥ grade 2. For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus.
    End point type
    Primary
    End point timeframe
    From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years
    End point values
    Everolimus randomized (Core period) Placebo randomized (Core period) Everolimus (Core and/or Extension period)
    Number of subjects analysed
    79
    39
    112
    Units: Percentage of Participants
        number (confidence interval 95%)
    41.8 (30.8 to 53.4)
    0 (0 to 9)
    58 (48.3 to 67.3)
    Statistical analysis title
    Superiority Analysis
    Statistical analysis description
    Superiority demonstrated between everolimus & placebo for best overall angiomyolipoma response rate
    Comparison groups
    Placebo randomized (Core period) v Everolimus randomized (Core period)
    Number of subjects included in analysis
    118
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.0001 [1]
    Method
    Cochran-Mantel-Haenszel
    Parameter type
    Clopper-Pearson
    Point estimate
    41.8
    Confidence interval
         level
    95%
         sides
    1-sided
         lower limit
    -
         upper limit
    58.4
    Variability estimate
    Standard deviation
    Notes
    [1] - H0: RREVEROLIMUS ≤ RRPLACEBO versus H1: RREVEROLIMUS > RRPLACEBO where RR is the probability of angiomyolipoma response on everolimus or on placebo. The test at the one-sided 2.5% level, analyzed in the FAS.

    Secondary: Time to Angiomyolipoma Progression as Per Central Radiology Review

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    End point title
    Time to Angiomyolipoma Progression as Per Central Radiology Review
    End point description
    Time to angiomyolipoma progression (TTAP) is defined as time from date of randomization to date of first documented angiomyolipoma progression. Angiomyolipoma progression was defined as one or more of the following: Increase from nadir of ≥ 25% in angiomyolipoma volume to value greater than baseline; the appearance of a new angiomyolipoma ≥ 1.0 cm in longest diameter; an increase from nadir of 20% or more in the volume of either kidney to a value greater than baseline; angiomyolipoma-related bleeding grade ≥ 2. For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma progression is defined starting from the start of everolimus. The baseline means the latest value on or before starting everolimus.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years
    End point values
    Everolimus randomized (Core period) Placebo randomized (Core period) Everolimus (Core and/or Extension period)
    Number of subjects analysed
    79
    39
    112
    Units: months
        median (confidence interval 95%)
    99.99 (99.99 to 999.99)
    11.37 (11.07 to 99.99)
    99.99 (99.99 to 999.99)
    No statistical analyses for this end point

    Secondary: Skin Lesion Response rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)

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    End point title
    Skin Lesion Response rate as Per Investigator (Only Patients With at Least One Skin Lesion at Baseline)
    End point description
    Skin lesion response rate in the double-blind period was determined only among patients with at least one skin lesion at baseline, and is the percentage of this group of patients with a best overall skin lesion response on the Physician’s Global Assessment of Clinical Condition (PGA) of either complete clinical response (CCR) or partial response (PR). A complete clinical response (CCR) requires a grading of 0 indicating the absence of disease (histological confirmation is not required). Grades 1, 2, and 3 constitute partial response, indicating improvement of at least 50 percent, but less than 100 percent improvement. For the everolimus (core/extension periods) treatment group, the baseline means the latest value on or before starting everolimus.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years
    End point values
    Everolimus (Core and/or Extension period)
    Number of subjects analysed
    112
    Units: Percentage of participants
        number (confidence interval 95%)
    68.2 (58.5 to 76.9)
    No statistical analyses for this end point

    Secondary: Percentage of participants with renal impairment

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    End point title
    Percentage of participants with renal impairment
    End point description
    Renal Impairment was measured by glomerular filtration rate which was calculated using the Modification of Diet in Renal Disease formula. Percentage of participants with renal impairment was reported. Severe renal impairment was defined as a GFR of <30ml/min/1.73m2.
    End point type
    Secondary
    End point timeframe
    Day 1 up to 28 days after end of treatment
    End point values
    Everolimus randomized (Core period) Placebo randomized (Core period) Everolimus (Core and/or Extension period)
    Number of subjects analysed
    79
    39
    112
    Units: Percentage of Participants
    number (not applicable)
        Glomerular filtration rate <30 ml/min/1.73m^2
    2.5
    7.7
    7.1
        Glomerular filtration rate≥ 30 ml/min/1.73m^2
    97.5
    92.3
    92.9
    No statistical analyses for this end point

    Secondary: Change From Baseline in plasma angiogenic molecules - Vascular endothelial growth factor (VEGF) marker

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    End point title
    Change From Baseline in plasma angiogenic molecules - Vascular endothelial growth factor (VEGF) marker
    End point description
    Blood samples for biomarker assessment were collected immediately prior to study administration. On-treatment samples was compared to baseline samples with the change from baseline.
    End point type
    Secondary
    End point timeframe
    4 weeks, 12 weeks, 24 weeks, 36 weeks 48 weeks, 60 weeks, 72 weeks
    End point values
    Everolimus randomized (Core period) Placebo randomized (Core period)
    Number of subjects analysed
    79
    39
    Units: pg/mL
    arithmetic mean (standard deviation)
        Week 4 (n:56, 28)
    38.7 ± 141.89
    17.6 ± 57.51
        Week 12 (n:56, 29)
    43.4 ± 60.62
    -6.1 ± 46.28
        Week 24 (n:53, 29)
    31.1 ± 75.83
    -4.3 ± 44.76
        Week 36 (n:26, 18)
    18 ± 45.07
    5.4 ± 24.01
        Week 48 (n:16, 8)
    55.3 ± 80.31
    3.1 ± 34.55
        Week 60 (n:0, 1)
    99.99 ± 999.99
    -4.12 ± 99.99
        Week 72 (n:0, 1)
    99.99 ± 999.99
    -6.1 ± 99.99
    No statistical analyses for this end point

    Secondary: Everolimus Trough Concentrations (Cmin)

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    End point title
    Everolimus Trough Concentrations (Cmin)
    End point description
    Cmin values collected prior to dose administration on the same study day and at 20-28 hours after previous dose, at steady state, and patient did not vomit within 4 hours of previous dose. Samples collected during the first 4 days of dosing were excluded from all analyses.
    End point type
    Secondary
    End point timeframe
    Prior to dosing at weeks 2, 4, 12, 24, 48
    End point values
    Everolimus randomized (Core period)
    Number of subjects analysed
    79
    Units: ng/mL
    arithmetic mean (standard deviation)
        Prior to dosing at Week 2 (n:43)
    7.63 ± 4.32
        Prior to dosing Week 4 (n:44)
    7.72 ± 4.35
        Prior to dosing Week 12 (n:49)
    8.79 ± 6.75
        Prior to dosing Week 24 (n:46)
    9.37 ± 8.83
        Prior to dosing Week 48 (n:15)
    11.49 ± 12.01
    No statistical analyses for this end point

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

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    End point title
    Everolimus blood Concentrations (C2h) at 2 hours post-dose
    End point description
    C2h values collected 1-3 hours after dose administration on the same study day, at steady state, and patient did not vomit between taking previous dose and blood collection. Samples collected during the first 4 days of dosing will be excluded from all analyses.
    End point type
    Secondary
    End point timeframe
    2 hours post-dose administration at Weeks 2, 4, 12, 24, 48
    End point values
    Everolimus randomized (Core period)
    Number of subjects analysed
    79
    Units: ng/mL
    arithmetic mean (standard deviation)
        2 hours post dose administration at Week 2 (n:55)
    33.38 ± 15.66
        2 hours post dose administration at Week 4 (n:49)
    30.89 ± 14.96
        2 hours post dose administration at Week 12 (n:56)
    34.48 ± 15.1
        2 hours post dose administration at Week 24 (n:50)
    39.27 ± 22.25
        2 hours post dose administration at Week 48 (n:14)
    33.2 ± 18.45
    No statistical analyses for this end point

    Secondary: Duration of angiomyolipoma response - only Everolimus patients with angiomyolipoma response

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    End point title
    Duration of angiomyolipoma response - only Everolimus patients with angiomyolipoma response
    End point description
    Duration of angiomyolipoma response was defined as the time from the date of the first documented angiomyolipoma response until the date of the first documented angiomyolipoma progression . Angiomyolipoma response was defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; there were no kidney increases in volume > 20% from nadir. The patient did not have any angiomyolipoma-related bleeding of ≥ grade 2.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years
    End point values
    Everolimus (Core and/or Extension period)
    Number of subjects analysed
    65
    Units: months
        median (confidence interval 95%)
    99.99 (99.99 to 999.99)
    No statistical analyses for this end point

    Secondary: Time to angiomyolipoma response - only Everolimus patients with angiomyolipoma response

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    End point title
    Time to angiomyolipoma response - only Everolimus patients with angiomyolipoma response
    End point description
    Time to angiomyolipoma response was defined as the time from the date of randomization until the date of the first documented angiomyolipoma response. Angiomyolipoma response defined as the combination of the following criteria: reduction in angiomyolipoma volume of ≥ 50% relative to baseline, where angiomyolipoma volume was sum of volumes of all target lesions identified at baseline, and with a confirmatory scan performed approximately 12 weeks later (no sooner than 8 weeks later); no new angiomyolipoma lesions ≥ 1.0 cm in longest diameter were identified; no kidney increases in volume > 20% from nadir; no angiomyolipoma-related bleeding of ≥ grade 2. For the everolimus (core/extension periods) treatment group, the time to angiomyolipoma response is from the start of everolimus. The baseline in the response definition means the latest value on or before starting everolimus.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to 5.7 years
    End point values
    Everolimus (Core and/or Extension period)
    Number of subjects analysed
    65
    Units: months
        median (confidence interval 95%)
    2.89 (2.79 to 3.19)
    No statistical analyses for this end point

    Secondary: Duration of skin lesion response - only Everolimus patients with best overall skin lesion response of Complete clinical response (CCR) or Partial response (PR)

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    End point title
    Duration of skin lesion response - only Everolimus patients with best overall skin lesion response of Complete clinical response (CCR) or Partial response (PR)
    End point description
    Duration of skin lesion response is defined as the time from the date of the first skin lesion response until the date of the first skin lesion progression, according to the PGA (physician’s global assessment of clinical condition). A progression is when the disease is worse than at baseline evaluation by >=25% or more.
    End point type
    Secondary
    End point timeframe
    From date of randomization until the earliest date of first documented AML progression, date of further anti-AML medication (including open-label Everolimus)/surgery or up to about 5.7 years
    End point values
    Everolimus (Core and/or Extension period)
    Number of subjects analysed
    73
    Units: months
        median (confidence interval 95%)
    99.99 (99.99 to 999.99)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Randomized to everolimus
    Reporting group description
    Randomized to everolimus

    Reporting group title
    Randomized to placebo and crossed-over to everolimus
    Reporting group description
    Randomized to placebo and crossed-over to everolimus

    Reporting group title
    Randomized to placebo and never crossed-over to everolimus
    Reporting group description
    Randomized to placebo and never crossed-over to everolimus

    Serious adverse events
    Randomized to everolimus Randomized to placebo and crossed-over to everolimus Randomized to placebo and never crossed-over to everolimus
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 79 (35.44%)
    17 / 33 (51.52%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    1
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Haemodynamic instability
         subjects affected / exposed
    0 / 79 (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
    Hypertension
         subjects affected / exposed
    0 / 79 (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
    Hypertensive crisis
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Thrombosis
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Angiomyolipoma
         subjects affected / exposed
    0 / 79 (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
    Nasal sinus cancer
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    General disorders and administration site conditions
    Adverse drug reaction
         subjects affected / exposed
    0 / 79 (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
    Fatigue
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 79 (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
    Aggression
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Alcohol abuse
         subjects affected / exposed
    0 / 79 (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
    Anxiety
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Hallucination
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric decompensation
         subjects affected / exposed
    0 / 79 (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
    Psychogenic seizure
         subjects affected / exposed
    0 / 79 (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
    Psychotic disorder
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Reproductive system and breast disorders
    Breast hypoplasia
         subjects affected / exposed
    0 / 79 (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
    Endometrial hyperplasia
         subjects affected / exposed
    0 / 79 (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
    Ovarian cyst
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    2 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Ovarian cyst ruptured
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Toxicity to various agents
         subjects affected / exposed
    1 / 79 (1.27%)
    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 creatinine increased
         subjects affected / exposed
    2 / 79 (2.53%)
    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
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 79 (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
    Cardiovascular insufficiency
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Bronchospasm
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Haemoptysis
         subjects affected / exposed
    0 / 79 (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
    Pleuritic pain
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    2 / 79 (2.53%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Bone marrow oedema
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Complex regional pain syndrome
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    1 / 79 (1.27%)
    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 / 1
    0 / 0
    0 / 0
    Diplegia
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    3 / 79 (3.80%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Generalised tonic-clonic seizure
         subjects affected / exposed
    2 / 79 (2.53%)
    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
    Hydrocephalus
         subjects affected / exposed
    0 / 79 (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
    Syncope
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Transient ischaemic attack
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Eye disorders
    Visual acuity reduced
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    0 / 79 (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 adhesions
         subjects affected / exposed
    0 / 79 (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
    Abdominal compartment syndrome
         subjects affected / exposed
    0 / 79 (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
    Abdominal hernia
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Colitis
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Constipation
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Diarrhoea
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Diarrhoea haemorrhagic
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Gastric ulcer
         subjects affected / exposed
    0 / 79 (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
    Ileal perforation
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intestinal perforation
         subjects affected / exposed
    0 / 79 (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
    Salivary gland calculus
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Volvulus
         subjects affected / exposed
    0 / 79 (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
    Vomiting
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal failure acute
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Renal failure chronic
         subjects affected / exposed
    0 / 79 (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
    Renal haemorrhage
         subjects affected / exposed
    0 / 79 (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
    Renal impairment
         subjects affected / exposed
    0 / 79 (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
    Hepatobiliary disorders
    Bile duct stenosis
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Skin and subcutaneous tissue disorders
    Angioedema
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 79 (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
    Chondropathy
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Joint effusion
         subjects affected / exposed
    2 / 79 (2.53%)
    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
    Rhabdomyolysis
         subjects affected / exposed
    0 / 79 (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
    Spinal osteoarthritis
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Gout
         subjects affected / exposed
    1 / 79 (1.27%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Appendicitis
         subjects affected / exposed
    2 / 79 (2.53%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 79 (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
    Bronchopneumonia
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Campylobacter gastroenteritis
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Erysipelas
         subjects affected / exposed
    0 / 79 (0.00%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 79 (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
    Gastrointestinal infection
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Incision site infection
         subjects affected / exposed
    0 / 79 (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
    Peritonitis
         subjects affected / exposed
    0 / 79 (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
    1 / 79 (1.27%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Sepsis
         subjects affected / exposed
    0 / 79 (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
    0 / 79 (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
    Urinary tract infection
         subjects affected / exposed
    1 / 79 (1.27%)
    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
    Viral infection
         subjects affected / exposed
    0 / 79 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Randomized to everolimus Randomized to placebo and crossed-over to everolimus Randomized to placebo and never crossed-over to everolimus
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    79 / 79 (100.00%)
    33 / 33 (100.00%)
    5 / 6 (83.33%)
    Vascular disorders
    Circulatory collapse
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Haematoma
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Hypertension
         subjects affected / exposed
    22 / 79 (27.85%)
    12 / 33 (36.36%)
    0 / 6 (0.00%)
         occurrences all number
    24
    15
    0
    Lymphoedema
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    4
    3
    0
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Seasonal allergy
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Fatigue
         subjects affected / exposed
    17 / 79 (21.52%)
    13 / 33 (39.39%)
    1 / 6 (16.67%)
         occurrences all number
    22
    15
    1
    Influenza like illness
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 33 (15.15%)
    1 / 6 (16.67%)
         occurrences all number
    2
    13
    1
    Malaise
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Oedema peripheral
         subjects affected / exposed
    16 / 79 (20.25%)
    10 / 33 (30.30%)
    0 / 6 (0.00%)
         occurrences all number
    31
    19
    0
    Pyrexia
         subjects affected / exposed
    11 / 79 (13.92%)
    6 / 33 (18.18%)
    1 / 6 (16.67%)
         occurrences all number
    16
    7
    1
    Psychiatric disorders
    Affective disorder
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Aggression
         subjects affected / exposed
    1 / 79 (1.27%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    Anxiety
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    5
    1
    0
    Depression
         subjects affected / exposed
    8 / 79 (10.13%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    9
    4
    0
    Insomnia
         subjects affected / exposed
    6 / 79 (7.59%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    7
    1
    0
    Mood swings
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    Sleep disorder
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    3
    5
    0
    Reproductive system and breast disorders
    Amenorrhoea
         subjects affected / exposed
    16 / 79 (20.25%)
    6 / 33 (18.18%)
    0 / 6 (0.00%)
         occurrences all number
    30
    8
    0
    Dysmenorrhoea
         subjects affected / exposed
    3 / 79 (3.80%)
    1 / 33 (3.03%)
    1 / 6 (16.67%)
         occurrences all number
    3
    5
    1
    Menorrhagia
         subjects affected / exposed
    11 / 79 (13.92%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    23
    2
    0
    Menstruation irregular
         subjects affected / exposed
    11 / 79 (13.92%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    11
    4
    0
    Metrorrhagia
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    6
    4
    0
    Ovarian cyst
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    7
    4
    0
    Vaginal haemorrhage
         subjects affected / exposed
    7 / 79 (8.86%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    13
    13
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 79 (0.00%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Fall
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Incision site pain
         subjects affected / exposed
    0 / 79 (0.00%)
    0 / 33 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    0
    1
    Laceration
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    Procedural pain
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 33 (6.06%)
    1 / 6 (16.67%)
         occurrences all number
    2
    2
    1
    Investigations
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    10 / 79 (12.66%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    14
    8
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    9 / 79 (11.39%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    14
    10
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    10 / 79 (12.66%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    11
    7
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    11 / 79 (13.92%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    22
    5
    0
    Blood cholesterol increased
         subjects affected / exposed
    11 / 79 (13.92%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    12
    9
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    3 / 79 (3.80%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    4
    9
    0
    Blood creatinine increased
         subjects affected / exposed
    4 / 79 (5.06%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    7
    5
    0
    Blood fibrinogen increased
         subjects affected / exposed
    4 / 79 (5.06%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    4
    5
    0
    Blood lactate dehydrogenase increased
         subjects affected / exposed
    9 / 79 (11.39%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    15
    4
    0
    Blood phosphorus decreased
         subjects affected / exposed
    6 / 79 (7.59%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    7
    2
    0
    Blood triglycerides increased
         subjects affected / exposed
    10 / 79 (12.66%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    10
    7
    0
    C-reactive protein increased
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Carbon monoxide diffusing capacity decreased
         subjects affected / exposed
    7 / 79 (8.86%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    8
    1
    0
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    5
    1
    0
    Haemoglobin decreased
         subjects affected / exposed
    11 / 79 (13.92%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    14
    5
    0
    International normalised ratio increased
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    4
    3
    0
    Low density lipoprotein increased
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Weight decreased
         subjects affected / exposed
    7 / 79 (8.86%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    7
    4
    0
    Weight increased
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    White blood cell count decreased
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Tachycardia
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Congenital, familial and genetic disorders
    Hamartoma
         subjects affected / exposed
    1 / 79 (1.27%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    2
    2
    0
    Cough
         subjects affected / exposed
    21 / 79 (26.58%)
    7 / 33 (21.21%)
    2 / 6 (33.33%)
         occurrences all number
    28
    9
    2
    Dyspnoea
         subjects affected / exposed
    3 / 79 (3.80%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    Epistaxis
         subjects affected / exposed
    10 / 79 (12.66%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    12
    3
    0
    Lymphangioleiomyomatosis
         subjects affected / exposed
    1 / 79 (1.27%)
    1 / 33 (3.03%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    1
    Nasal congestion
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 33 (3.03%)
    1 / 6 (16.67%)
         occurrences all number
    3
    1
    1
    Oropharyngeal pain
         subjects affected / exposed
    13 / 79 (16.46%)
    6 / 33 (18.18%)
    1 / 6 (16.67%)
         occurrences all number
    19
    13
    1
    Pneumothorax
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Productive cough
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Rhinitis allergic
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    2
    3
    0
    Rhinorrhoea
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    5
    0
    0
    Sinus congestion
         subjects affected / exposed
    2 / 79 (2.53%)
    1 / 33 (3.03%)
    1 / 6 (16.67%)
         occurrences all number
    2
    1
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    9 / 79 (11.39%)
    6 / 33 (18.18%)
    0 / 6 (0.00%)
         occurrences all number
    16
    7
    0
    Leukopenia
         subjects affected / exposed
    9 / 79 (11.39%)
    7 / 33 (21.21%)
    0 / 6 (0.00%)
         occurrences all number
    20
    17
    0
    Lymphopenia
         subjects affected / exposed
    5 / 79 (6.33%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    14
    11
    0
    Neutropenia
         subjects affected / exposed
    7 / 79 (8.86%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    15
    11
    0
    Thrombocytopenia
         subjects affected / exposed
    6 / 79 (7.59%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    11
    4
    0
    Nervous system disorders
    Convulsion
         subjects affected / exposed
    8 / 79 (10.13%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    11
    15
    0
    Dizziness
         subjects affected / exposed
    9 / 79 (11.39%)
    4 / 33 (12.12%)
    1 / 6 (16.67%)
         occurrences all number
    10
    5
    1
    Epilepsy
         subjects affected / exposed
    3 / 79 (3.80%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    Headache
         subjects affected / exposed
    26 / 79 (32.91%)
    15 / 33 (45.45%)
    0 / 6 (0.00%)
         occurrences all number
    54
    34
    0
    Lethargy
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Migraine
         subjects affected / exposed
    9 / 79 (11.39%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    19
    1
    0
    Peripheral sensory neuropathy
         subjects affected / exposed
    0 / 79 (0.00%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Petit mal epilepsy
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    4
    10
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    6
    7
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    13 / 79 (16.46%)
    5 / 33 (15.15%)
    2 / 6 (33.33%)
         occurrences all number
    17
    12
    2
    Abdominal pain upper
         subjects affected / exposed
    7 / 79 (8.86%)
    4 / 33 (12.12%)
    1 / 6 (16.67%)
         occurrences all number
    7
    9
    1
    Aphthous stomatitis
         subjects affected / exposed
    19 / 79 (24.05%)
    12 / 33 (36.36%)
    1 / 6 (16.67%)
         occurrences all number
    57
    27
    1
    Constipation
         subjects affected / exposed
    8 / 79 (10.13%)
    6 / 33 (18.18%)
    1 / 6 (16.67%)
         occurrences all number
    10
    6
    1
    Dental caries
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Diarrhoea
         subjects affected / exposed
    17 / 79 (21.52%)
    11 / 33 (33.33%)
    1 / 6 (16.67%)
         occurrences all number
    27
    20
    1
    Dyspepsia
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    Flatulence
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    5
    3
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    4
    0
    0
    Mouth ulceration
         subjects affected / exposed
    15 / 79 (18.99%)
    4 / 33 (12.12%)
    1 / 6 (16.67%)
         occurrences all number
    33
    13
    1
    Nausea
         subjects affected / exposed
    18 / 79 (22.78%)
    7 / 33 (21.21%)
    2 / 6 (33.33%)
         occurrences all number
    35
    14
    2
    Stomatitis
         subjects affected / exposed
    41 / 79 (51.90%)
    10 / 33 (30.30%)
    0 / 6 (0.00%)
         occurrences all number
    105
    14
    0
    Toothache
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    7
    6
    0
    Vomiting
         subjects affected / exposed
    18 / 79 (22.78%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    37
    9
    0
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 33 (9.09%)
    1 / 6 (16.67%)
         occurrences all number
    7
    4
    1
    Leukocyturia
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Proteinuria
         subjects affected / exposed
    11 / 79 (13.92%)
    10 / 33 (30.30%)
    0 / 6 (0.00%)
         occurrences all number
    16
    28
    0
    Renal pain
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    3
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    25 / 79 (31.65%)
    11 / 33 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    34
    15
    0
    Alopecia
         subjects affected / exposed
    7 / 79 (8.86%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    7
    2
    0
    Dermatitis
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    4
    9
    0
    Dermatitis acneiform
         subjects affected / exposed
    6 / 79 (7.59%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    13
    1
    0
    Dry skin
         subjects affected / exposed
    8 / 79 (10.13%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    8
    5
    0
    Eczema
         subjects affected / exposed
    11 / 79 (13.92%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    14
    4
    0
    Papule
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    Pigmentation disorder
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    Pruritus
         subjects affected / exposed
    8 / 79 (10.13%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    10
    5
    0
    Rash
         subjects affected / exposed
    5 / 79 (6.33%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    7
    3
    0
    Rash pruritic
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    1
    5
    0
    Skin mass
         subjects affected / exposed
    0 / 79 (0.00%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    13 / 79 (16.46%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    19
    3
    0
    Back pain
         subjects affected / exposed
    12 / 79 (15.19%)
    14 / 33 (42.42%)
    0 / 6 (0.00%)
         occurrences all number
    18
    16
    0
    Flank pain
         subjects affected / exposed
    5 / 79 (6.33%)
    5 / 33 (15.15%)
    1 / 6 (16.67%)
         occurrences all number
    7
    8
    1
    Muscle spasms
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 33 (6.06%)
    1 / 6 (16.67%)
         occurrences all number
    2
    3
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 79 (1.27%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    1
    4
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 79 (2.53%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    4
    5
    0
    Myalgia
         subjects affected / exposed
    7 / 79 (8.86%)
    5 / 33 (15.15%)
    1 / 6 (16.67%)
         occurrences all number
    12
    5
    1
    Neck pain
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    1
    3
    0
    Pain in extremity
         subjects affected / exposed
    5 / 79 (6.33%)
    7 / 33 (21.21%)
    0 / 6 (0.00%)
         occurrences all number
    5
    10
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 79 (10.13%)
    6 / 33 (18.18%)
    0 / 6 (0.00%)
         occurrences all number
    8
    6
    0
    Hypercholesterolaemia
         subjects affected / exposed
    29 / 79 (36.71%)
    11 / 33 (33.33%)
    0 / 6 (0.00%)
         occurrences all number
    40
    23
    0
    Hyperglycaemia
         subjects affected / exposed
    3 / 79 (3.80%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    3
    7
    0
    Hyperlipidaemia
         subjects affected / exposed
    10 / 79 (12.66%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    19
    6
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    8 / 79 (10.13%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    8
    7
    0
    Hypokalaemia
         subjects affected / exposed
    2 / 79 (2.53%)
    5 / 33 (15.15%)
    0 / 6 (0.00%)
         occurrences all number
    2
    5
    0
    Hypophosphataemia
         subjects affected / exposed
    15 / 79 (18.99%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    26
    4
    0
    Iron deficiency
         subjects affected / exposed
    7 / 79 (8.86%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    7
    2
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    9 / 79 (11.39%)
    9 / 33 (27.27%)
    1 / 6 (16.67%)
         occurrences all number
    11
    13
    1
    Cellulitis
         subjects affected / exposed
    2 / 79 (2.53%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    3
    4
    0
    Conjunctivitis
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    5
    2
    0
    Ear infection
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    5
    1
    0
    Folliculitis
         subjects affected / exposed
    4 / 79 (5.06%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    4
    1
    0
    Furuncle
         subjects affected / exposed
    4 / 79 (5.06%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    4
    2
    0
    Gastroenteritis
         subjects affected / exposed
    9 / 79 (11.39%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    9
    4
    0
    Gastroenteritis viral
         subjects affected / exposed
    4 / 79 (5.06%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    6
    0
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    1
    2
    0
    Gingivitis
         subjects affected / exposed
    2 / 79 (2.53%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    3
    3
    0
    Influenza
         subjects affected / exposed
    8 / 79 (10.13%)
    3 / 33 (9.09%)
    1 / 6 (16.67%)
         occurrences all number
    8
    4
    1
    Nasopharyngitis
         subjects affected / exposed
    36 / 79 (45.57%)
    19 / 33 (57.58%)
    1 / 6 (16.67%)
         occurrences all number
    102
    58
    2
    Oral candidiasis
         subjects affected / exposed
    1 / 79 (1.27%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    3
    2
    0
    Oral herpes
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    14
    2
    0
    Otitis externa
         subjects affected / exposed
    0 / 79 (0.00%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    0
    4
    0
    Otitis media
         subjects affected / exposed
    6 / 79 (7.59%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    13
    4
    0
    Periodontitis
         subjects affected / exposed
    6 / 79 (7.59%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    7
    0
    0
    Pharyngitis
         subjects affected / exposed
    5 / 79 (6.33%)
    1 / 33 (3.03%)
    0 / 6 (0.00%)
         occurrences all number
    6
    1
    0
    Pharyngitis streptococcal
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    8
    0
    0
    Pneumonia
         subjects affected / exposed
    6 / 79 (7.59%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    7
    2
    0
    Rash pustular
         subjects affected / exposed
    7 / 79 (8.86%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    8
    3
    0
    Respiratory tract infection
         subjects affected / exposed
    5 / 79 (6.33%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    5
    2
    0
    Respiratory tract infection viral
         subjects affected / exposed
    5 / 79 (6.33%)
    0 / 33 (0.00%)
    0 / 6 (0.00%)
         occurrences all number
    8
    0
    0
    Rhinitis
         subjects affected / exposed
    7 / 79 (8.86%)
    6 / 33 (18.18%)
    1 / 6 (16.67%)
         occurrences all number
    12
    7
    1
    Sinusitis
         subjects affected / exposed
    11 / 79 (13.92%)
    4 / 33 (12.12%)
    1 / 6 (16.67%)
         occurrences all number
    27
    10
    1
    Tonsillitis
         subjects affected / exposed
    1 / 79 (1.27%)
    6 / 33 (18.18%)
    0 / 6 (0.00%)
         occurrences all number
    1
    6
    0
    Tooth abscess
         subjects affected / exposed
    7 / 79 (8.86%)
    2 / 33 (6.06%)
    0 / 6 (0.00%)
         occurrences all number
    10
    2
    0
    Tooth infection
         subjects affected / exposed
    4 / 79 (5.06%)
    3 / 33 (9.09%)
    0 / 6 (0.00%)
         occurrences all number
    5
    3
    0
    Upper respiratory tract infection
         subjects affected / exposed
    15 / 79 (18.99%)
    4 / 33 (12.12%)
    0 / 6 (0.00%)
         occurrences all number
    24
    10
    0
    Urinary tract infection
         subjects affected / exposed
    25 / 79 (31.65%)
    12 / 33 (36.36%)
    1 / 6 (16.67%)
         occurrences all number
    50
    23
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Mar 2010
    Amendment 1 was issued after the inclusion of 21% of patients and introduced the following changes: Allowed assessment of angiomyolipomas to be carried out by CT scan as well as by MRI with the condition that the same imaging modality for assessment of the kidneys must be used throughout the trial for each individual patient; Patients who met pre-specified criteria at BL would now be screened for hepatitis B (HBV) and hepatitis C (HCV) at BL, using the following tests: HBV DNA, HBV surface antigen, HBV surface antibody, HBV core antibody, HCV RNA-PCR. Hepatitis B and C management guidelines were added for patients who are active prior to the implementation of Amendment 1; Harmonized the visit window for all visits; Added revised table of p-glycoprotein substrates, inhibitors, and inducers; Added provision for an End of Treatment scan if the patient discontinued for reasons other than progression and enough time had passed since their most recent scan; Added instructions for the permitted local laboratory collections for the 6 week visit for patients in the United States for whom travel to the clinic was difficult; Changed the requirement of a confirmatory scan from “at least 4 weeks” after the first assessment of response to “approximately 12” (and no sooner than 8 weeks) after the first assessment of response; Changed the confirmation of skin lesion response from “at least 4 weeks” after the first response assessment to “approximately 12 weeks” (and no sooner than 8 weeks) after the first response assessment; Added the following exclusion criteria: Patients with angiomyolipoma which, in the opinion of the Investigator, requires surgery at the time of randomization; Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks or compromise compliance with the protocol; Modified the exclusion criterion on impaired lung function to define separate thresholds for patients with and without LAM;
    29 Mar 2010
    Amendment 1 (continued): Replaced PFTs at BL and at every trial visit with PFTs at BL for all LAM patients, and PFTs to be performed 1) as clinically indicated in patients without LAM and 2) at 6, 12, 18 and 24 weeks and every 12 weeks thereafter, for patients with LAM. Removed the requirement for chest CT at BL for patients who are unable to perform PFTs; Modified the definition of angiomyolipoma progression to not only an increase from nadir of 25% or more in angiomyolipoma volume, but also to a value greater than BL angiomyolipoma volume; of 20% or more in the volume of either kidney to a value greater than BL, where nadir was the lowest kidney volume obtained for the patient, separately for each kidney, previously in the trial (including BL); Modified the definition of SEGA progression to be not only an increase from nadir of 25% or more in SEGA volume, but also to a value greater than BL SEGA volume; Increased from 3 to 6 weeks the amount of time off study drug (e.g. for an AE or surgery) which was permitted before a patient was discontinued from the trial; Increased the screening period from 14 to 21 days; permitted screening blood tests carried out within 14 days of Treatment Day 1 to be used for BL values; Required a urine pregnancy screen at Treatment Day 1 and added follow-up urine pregnancy tests to be conducted every 12 weeks after the start of study drug; Added LH, FSH, and testosterone levels in all patients and estradiol levels in all female patients at Screening and every 24 weeks after the start of study drug.
    22 Aug 2012
    Amendment 3 contained administrative changes to the Visit Evaluation Schedules as well as editorial changes and clarifications: 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; Revised visit schedule and assessment for urine pregnancy, serum pregnancy, and endocrine testing; Revised Additional menstrual history and pregnancy history information collected. Will conduct monthly monitoring of menstrual status; Added completion of hormone evaluations when amenorrhea is seen between scheduled visits; Reproductive history and endocrine testing section added. Additional medical information on reproductive history will be collected. Endocrine testing information added; Additional safety language for pregnancies added; Information on documentation of at home pregnancy testing and documentation of menstrual status monitoring added.
    15 Jan 2013
    Amendment 4 was issued when the enrollment was complete and approximately 100 active patients were being followed in the extension phase of the study. The following paragraph was deleted from the protocol: This amendment is required for patient safety (i.e. necessary to eliminate immediate hazards to the trial subjects ICH Good Clinical Practice 3.3.8). Therefore it will be implemented prior to IRB/IEC approval, but will be sent for approval as well. The following paragraph was added: The changes described in this amended protocol require IRB/IEC 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.
    24 Oct 2013
    Amendment 5 was issued when the enrollment had been completed and approximately 98 patients had been treated with everolimus in the extension phase of the study. The protocol was amended to add a non-interventional follow-up phase, fulfilling a commitment made to European Medicines Agency, in order to better characterize tumor behavior after discontinuation of everolimus; Administrative change to corrected typo in rationale section for Amendment 4 which previously cited the wrong amendment number; Updated Exploratory objectives to include assessment of tumor characteristics after stopping everolimus treatment; Clarified collection window for concomitant medications/non-drug therapies taken after discontinuing study treatment; Added non-interventional follow-up phase to the study design; Added end of protocol section; Added new study design schema for non-interventional follow-up phase; Added non-interventional follow-up phase inclusion criteria; Added non-interventional follow-up phase exclusion criteria; Clarified that placebo was only used during the blinded phase; Table updated with newest list of cytochrome P450 (CYP)3A4 inhibitors/inducer; Table updated with newest list of PGP inhibitors/inducers; Added new section that describes non-interventional follow-up phase; added new table, revised old tables, updated text to include references to the new table; Added text to clarify when to perform final study treatment-related serum pregnancy testing; New text added to clarify radiological evaluation of non-interventional follow-up phase; New text to clarify the safety data collection in the non-interventional follow-up phase; New text added to clarify the adverse event reporting in non-interventional follow-up phase; Added text to clarify when to perform final study treatment-related serum pregnancy testing; Administrative change to correct data collection as this is a pCRF study and to add methodology for radiological imaging;
    24 Oct 2013
    Amendment 5 (continued): Added evaluation after everolimus discontinuation; Administrative changes were made, as needed.

    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, results of crossover studies and data using 999 as data points are not accurately represented in this record. Please go to https://www.novctrd.com/CtrdWeb/home.nov for complete trial results
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