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    Clinical Trial Results:
    Long-term follow-up study to monitor the growth and development of pediatric patients previously treated with everolimus in study CRAD001M2301 (EXIST-LT)

    Summary
    EudraCT number
    		 2013-003795-13
    Trial protocol
    		 BE   PL  
    Global end of trial date
    18 Dec 2023

    Results information
    Results version number
    		 v2(current)
    This version publication date
    17 Nov 2024
    First version publication date
    22 Jun 2024
    Other versions
    		 v1
    Version creation reason

    Trial information

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    Trial identification
    Sponsor protocol code
    CRAD001M2305
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02338609
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, novartis.email@novartis.com
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Dec 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Dec 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of the trial were: • To assess percentage of participants who achieved Tanner Stage V at or before age of 16 (females) or 17 (males). • To assess height and body mass index (BMI) standard deviation score by year since baseline. • To assess mean endocrine laboratory values of follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estrogen or testosterone by age.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Dec 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    United States: 11
    Country: Number of subjects enrolled
    Russian Federation: 3
    Worldwide total number of subjects
    15
    EEA total number of subjects
    1
    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)
    15
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 6 investigative sites in 3 countries.

    Pre-assignment
    Screening details
    		 All the pediatric patients enrolled into the current study had been treated with everolimus in the parent study CRAD001M2301.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Everolimus
    Arm description
    		 Participants were treated with everolimus as part of CRAD001M2301. Continued treatment with everolimus is allowed but not required for participation in this study.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Everolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were treated with everolimus as part of CRAD001M2301. Continued treatment with everolimus is allowed but not required for participation in this study.

    Number of subjects in period 1
    		Everolimus
    Started
    15
    Safety Analysis set
    14
    Completed
    13
    Not completed
    2
         Physician decision
    1
         Death
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    		 Participants were treated with everolimus as part of CRAD001M2301. Continued treatment with everolimus is allowed but not required for participation in this study.

    Reporting group values
    		 Everolimus Total
    Number of subjects
    		 15 15
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 15 15
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 6.390 ( 3.5647 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 8 8
        Male
    		 7 7
    Race/Ethnicity, Customized
    Units: Subjects
        Black
    		 1 1
        Caucasian
    		 14 14

    End points

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    End points reporting groups
    Reporting group title
    Everolimus
    Reporting group description
    		 Participants were treated with everolimus as part of CRAD001M2301. Continued treatment with everolimus is allowed but not required for participation in this study.

    Primary: Number of participants who achieved Tanner Stage V at or before age 16 (females) or 17 (males)

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    End point title
    		 Number of participants who achieved Tanner Stage V at or before age 16 (females) or 17 (males) [1]
    End point description
    Tanner Staging, also known as Sexual Maturity Rating (SMR), is an objective classification system that providers use to document and track the development and sequence of secondary sex characteristics of children during puberty. Tanner Stage included two components for boys (testis and pubic hair) and two components for girls (breast development and pubic hair). Tanner Stage V: Males and females: Terminal hair that extends beyond the inguinal crease onto the thigh. Female Breast Development Scale: Areolar mound recedes into single breast contour with areolar hyperpigmentation, papillae development, and nipple protrusion. Male External Genitalia Scale: > 20 ml (or > 4.5 cm long) The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Primary
    End point timeframe
    Annually, up to 14 years from the first visit in parent study CRAD001M2301 (including up to 9 years of follow-up in study CRAD001M2305)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only analyzed descriptively.
    End point values
    		 Everolimus
    Number of subjects analysed
    15
    Units: participants
        Female(n=8)
    4
        Male(n=7)
    6
    No statistical analyses for this end point

    Primary: Number of participants with notably low and notably high height and body mass index (BMI) standard deviation score (SDS)

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    End point title
    		 Number of participants with notably low and notably high height and body mass index (BMI) standard deviation score (SDS) [2]
    End point description
    Height and body weight (with minimal clothing, without shoes) were measured annually. The height standard deviation score (SDS) and BMI SDS were calculated based on height/BMI data collected during the study and published reference height/BMI information (De Onis M, et al. Development of a WHO growth reference for school-aged children and adolescents. Bull World Health Organ. 2007 Sep;85(9):660-7). The number of participants with height and BMI SDS values lower than the 5th percentile (notably low) or higher than the 95th percentile (notably high) are reported. The baseline corresponds to the last available assessment on or before the start of everolimus in the parent study CRAD001M2301. The assessment is performed up to age of 12 years. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Primary
    End point timeframe
    Baseline, annually up to Year 10 of treatment since the start of everolimus in parent study CRAD001M2301 (including a median of 5 years of exposure to everolimus in study CRAD001M2305)
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only analyzed descriptively.
    End point values
    		 Everolimus
    Number of subjects analysed
    15
    Units: participants
        Height SDS-notably low-Baseline (n=15)
    2
        Height SDS-notably low- Year 1 (n=15)
    1
        Height SDS-notably low- Year 2 (n=14)
    2
        Height SDS-notably low- Year 3 (n=15)
    2
        Height SDS-notably low- Year 4 (n=15)
    2
        Height SDS-notably low- Year 5 (n=12)
    2
        Height SDS-notably low- Year 6 (n=12)
    1
        Height SDS-notably low- Year 7 (n=9)
    1
        Height SDS-notably low- Year 8 (n=9)
    0
        Height SDS-notably low- Year 9 (n=8)
    0
        Height SDS-notably low- Year 10 (n=3)
    0
        Height SDS-notably high-Baseline (n=15)
    1
        Height SDS-notably high- Year 1 (n=15)
    0
        Height SDS-notably high- Year 2 (n=14)
    0
        Height SDS-notably high- Year 3 (n=15)
    0
        Height SDS-notably high- Year 4 (n=15)
    1
        Height SDS-notably high-Year 5 (n=12)
    0
        Height SDS-notably high- Year 6 (n=12)
    1
        Height SDS-notably high- Year 7 (n=9)
    1
        Height SDS-notably high- Year 8 (n=9)
    1
        Height SDS-notably high- Year 9 (n=8)
    0
        Height SDS-notably high- Year 10 (n=3)
    0
        BMI SDS-notably low-Baseline (n=15)
    0
        BMI SDS-notably low- Year 1 (n=15)
    0
        BMI SDS-notably low- Year 2 (n=14)
    1
        BMI SDS-notably low- Year 3 (n=15)
    0
        BMI SDS-notably low- Year 4 (n=15)
    0
        BMI SDS-notably low- Year 5 (n=12)
    1
        BMI SDS-notably low- Year 6 (n=12)
    2
        BMI SDS-notably low- Year 7 (n=9)
    0
        BMI SDS-notably low- Year 8 (n=9)
    1
        BMI SDS-notably low- Year 9 (n=8)
    2
        BMI SDS-notably low- Year 10 (n=3)
    1
        BMI SDS-notably high-Baseline (n=15)
    4
        BMI SDS-notably high- Year 1 (n=15)
    1
        BMI SDS-notably high- Year 2 (n=14)
    1
        BMI SDS-notably high- Year 3 (n=15)
    0
        BMI SDS-notably high- Year 4 (n=15)
    1
        BMI SDS-notably high- Year 5 (n=12)
    1
        BMI SDS-notably high- Year 6 (n=12)
    1
        BMI SDS-notably high- Year 7 (n=9)
    2
        BMI SDS-notably high- Year 8 (n=9)
    2
        BMI SDS-notably high- Year 9 (n=8)
    1
        BMI SDS-notably high- Year 10 (n=3)
    1
    No statistical analyses for this end point

    Primary: Endocrine laboratory values LH and FSH in male participants

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    End point title
    		 Endocrine laboratory values LH and FSH in male participants [3]
    End point description
    Luteinizing hormone (LH) is a glycoprotein hormone that is co-secreted along with follicle-stimulating hormone by the gonadotrophin cells in the adenohypophysis (anterior pituitary). Untreated LH deficiency results in infertility, and if it occurs before puberty, the patient fails to develop puberty and secondary sexual characteristics. Follicle-stimulating hormone (FSH) is a hormone produced by the anterior pituitary in response to gonadotropin-releasing hormone (GnRH) from the hypothalamus. FSH plays a role in sexual development and reproduction in both males and females. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Primary
    End point timeframe
    Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305)
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only analyzed descriptively.
    End point values
    		 Everolimus
    Number of subjects analysed
    7
    Units: IU/L
    arithmetic mean (standard deviation)
        10 years age-LH (n=4)
    1.0 ( 1.47 )
        10 years age-FSH (n=4)
    1.5 ( 1.34 )
        11 years age-LH (n=6)
    1.0 ( 0.77 )
        11 years age-FSH (n=6)
    1.7 ( 1.11 )
        12 years age-LH (n=7)
    1.8 ( 1.22 )
        12 years age-FSH (n=7)
    2.1 ( 0.67 )
        13 years age-LH (n=6)
    2.4 ( 2.26 )
        13 years age-FSH (n=6)
    2.9 ( 1.81 )
        14 years age-LH (n=6)
    2.9 ( 2.18 )
        14 years age-FSH (n=6)
    4.6 ( 4.29 )
        15 years age-LH (n=4)
    2.5 ( 1.07 )
        15 years age-FSH (n=4)
    3.3 ( 0.61 )
        16 years age-LH (n=3)
    3.5 ( 0.32 )
        16 years age-FSH (n=3)
    6.0 ( 3.01 )
    No statistical analyses for this end point

    Primary: Endocrine laboratory values LH and FSH in female participants

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    End point title
    		 Endocrine laboratory values LH and FSH in female participants [4]
    End point description
    Luteinizing hormone (LH) is a glycoprotein hormone that is co-secreted along with follicle-stimulating hormone by the gonadotrophin cells in the adenohypophysis (anterior pituitary). Untreated LH deficiency results in infertility, and if it occurs before puberty, the patient fails to develop puberty and secondary sexual characteristics. Follicle-stimulating hormone (FSH) is a hormone produced by the anterior pituitary in response to gonadotropin-releasing hormone (GnRH) from the hypothalamus. FSH plays a role in sexual development and reproduction in both males and females.The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Primary
    End point timeframe
    Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305)
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only analyzed descriptively.
    End point values
    		 Everolimus
    Number of subjects analysed
    8
    Units: IU/L
    arithmetic mean (standard deviation)
        10 years age-LH (n=2)
    5.1 ( 3.89 )
        10 years age-FSH (n=2)
    3.4 ( 2.68 )
        11 years age-LH (n=7)
    3.2 ( 2.47 )
        11 years age-FSH (n=7)
    3.5 ( 1.61 )
        12 years age-LH (n=7)
    7.8 ( 6.73 )
        12 years age-FSH (n=7)
    5.6 ( 2.43 )
        13 years age-LH (n=5)
    4.4 ( 3.08 )
        13 years age-FSH (n=5)
    5.0 ( 0.80 )
        14 years age-LH (n=6)
    5.3 ( 6.97 )
        14 years age-FSH (n=6)
    2.6 ( 2.05 )
        15 years age-LH (n=4)
    7.5 ( 10.96 )
        15 years age-FSH (n=4)
    2.5 ( 2.28 )
        16 years age-LH (n=4)
    3.7 ( 2.69 )
        16 years age-FSH (n=4)
    2.8 ( 2.05 )
    No statistical analyses for this end point

    Primary: Endocrine laboratory values of testosterone in male participants

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    End point title
    		 Endocrine laboratory values of testosterone in male participants [5]
    End point description
    Testosterone is the primary male hormone responsible for regulating sex differentiation, producing male sex characteristics, spermatogenesis, and fertility. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Primary
    End point timeframe
    Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305)
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only analyzed descriptively.
    End point values
    		 Everolimus
    Number of subjects analysed
    7
    Units: nmol/L
    arithmetic mean (standard deviation)
        10 years age (n=4)
    0.7 ( 1.17 )
        11 years age (n=6)
    2.5 ( 4.60 )
        12 years age (n=7)
    3.8 ( 4.29 )
        13 years age (n=6)
    4.3 ( 4.04 )
        14 years age (n=6)
    7.2 ( 4.34 )
        15 years age (n=4)
    12.9 ( 6.28 )
        16 years age (n=3)
    15.5 ( 3.93 )
    No statistical analyses for this end point

    Primary: Endocrine laboratory values of estrogen in female participants

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    End point title
    		 Endocrine laboratory values of estrogen in female participants [6]
    End point description
    Estrogen is a steroid hormone associated with the female reproductive organs and is responsible for developing female sexual characteristics. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ¨999¨. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Primary
    End point timeframe
    Annually, starting at 10-year age until 16-year age (in both studies CRAD001M2301 and CRAD001M2305)
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: only analyzed descriptively.
    End point values
    		 Everolimus
    Number of subjects analysed
    8
    Units: ng/L
    arithmetic mean (standard deviation)
        10 years age (n=1)
    139.8 ( 999 )
        11 years age (n=4)
    80.5 ( 119.22 )
        12 years age (n=3)
    43.7 ( 41.26 )
        13 years age (n=2)
    50.0 ( 7.07 )
        14 years age (n=2)
    139.0 ( 141.42 )
        15 years age (n=4)
    47.7 ( 48.89 )
        16 years age (n=4)
    149.7 ( 128.21 )
    No statistical analyses for this end point

    Secondary: Number of participants with treatment emergent adverse events (AEs) and serious adverse events (SAEs)

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    End point title
    		 Number of participants with treatment emergent adverse events (AEs) and serious adverse events (SAEs)
    End point description
    Number of participants with treatment emergent AEs (any AE regardless of seriousness), AEs led to study treatment discontinuation, SAEs and SAEs led to study treatment discontinuation.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    14
    Units: participants
        At least one AE
    12
        At least one SAE
    6
        AE leading to discontinuation
    0
        SAE leading to discontinuation
    0
    No statistical analyses for this end point

    Secondary: Participants age at menarche/thelarche (females) or adrenarche (males)

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    End point title
    		 Participants age at menarche/thelarche (females) or adrenarche (males)
    End point description
    Menarche is defined as the first menstrual period in a female.Menarche typically occurs between the ages of 10 and 16, with the average age of onset being 12.4 years. Thelarche is the beginning of adult breast development, marks the onset of puberty in the majority of women and occurs at a mean age of 10 years. Adrenarche refers to the time during puberty when the adrenal glands increase their production and secretion of adrenal androgens. Potential delayed puberty in girls is defined as failure to attain Tanner Stage II by age 13, or absence of menarche by age 15 or within 5 years of attainment of Tanner Stage II. Potential delayed puberty in boys is defined as failure to attain Tanner Stage II by age 14. Due to EudraCT system limitations, data fields in the table cannot contain letters. Therefore, not applicable values are indicated as ¨999¨. The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    Up to approximately 14.4 years from the first dose of everolimus in parent study CRAD001M2301 (including up to 9 years of follow-up in study CRAD001M2305)
    End point values
    		 Everolimus
    Number of subjects analysed
    14 [7]
    Units: years
    median (confidence interval 95%)
        Menarche (n=7)
    12.5 (11.0 to 13.6)
        Thelarche (n=5)
    10.2 (9.1 to 999)
        Adrenarche (n=7)
    11.0 (10.0 to 11.6)
    Notes
    [7] - 999=Not estimable due to insufficient number of participants with events
    No statistical analyses for this end point

    Secondary: Participants age at Tanner Stage II, III, IV, V

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    End point title
    		 Participants age at Tanner Stage II, III, IV, V
    End point description
    Tanner Staging is a classification system that providers use to document and track the development of secondary sex characteristics during puberty. Pubic Hair Scale II-Downy hair III-Scant terminal hair IV-Terminal hair that fills the triangle overlying the pubic region V-Terminal hair that extends beyond the inguinal crease onto the thigh Female Breast Development Scale II-Breast bud palpable under the areola-1stpubertal sign in females III-Breast tissue palpable outside areola;no areolar development IV-Areola elevated above the contour of the breast, forming a “double scoop” appearance V-Areolar mound recedes into single breast contour with areolar hyperpigmentation, papillae development, and nipple protrusion Male External Genitalia Scale II-2.5 to3.3cm long,1st pubertal sign in males III-3.4 to4.0cm long IV-4.1 to4.5cm long V-or>4.5cm long The Number of Subjects Analyzed differs as stated on the category column, in case of difference from Number of subjects that started the Arm.
    End point type
    Secondary
    End point timeframe
    Up to approximately 14.4 years from the first dose of everolimus in parent study CRAD001M2301 (including up to 9 years of follow-up in study CRAD001M2305)
    End point values
    		 Everolimus
    Number of subjects analysed
    15 [8]
    Units: years
    median (confidence interval 95%)
        Tanner stage II-pubic hair-male (n=6)
    11.8 (10.2 to 999)
        Tanner stage II-genitalia (n=6)
    11.9 (10.4 to 999)
        Tanner stage III-pubic hair-male (n=6)
    13.3 (11.3 to 999)
        Tanner stage III-genitalia (n=6)
    12.6 (11.3 to 14.2)
        Tanner stage IV-pubic hair-male (n=6)
    14.2 (11.3 to 999)
        Tanner stage IV-genitalia (n=6)
    14.2 (11.3 to 999)
        Tanner stage V-pubic hair-male (n=5)
    16.4 (15.3 to 999)
        Tanner stage V-genitalia (n=6)
    16.4 (12.7 to 999)
        Tanner stage II-pubic hair-female (n=8)
    10.4 (7.3 to 11.8)
        Tanner stage II-Breast (n=7)
    11.5 (9.9 to 11.8)
        Tanner stage III-pubic hair-female (n=8)
    12.2 (10.4 to 12.8)
        Tanner stage III-Breast (n=7)
    12.5 (10.4 to 14.6)
        Tanner stage IV-pubic hair-female (n=6)
    13.4 (11.6 to 14.5)
        Tanner stage IV-Breast (n=7)
    13.8 (12.7 to 14.6)
        Tanner stage V-pubic hair-female (n=4)
    16.0 (13.8 to 999)
        Tanner stage V-Breast (n=2)
    999 (13.8 to 999)
    Notes
    [8] - 999=Not estimable due to insufficient number of participants with events
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants Achieved Basic Developmental Milestones and the Age at which Participants Achieved the Basic Developmental Milestones

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    End point title
    		 TAND checklist - Number of Participants Achieved Basic Developmental Milestones and the Age at which Participants Achieved the Basic Developmental Milestones
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. This outcome measure assesses the TAND checklist part about basic development skills. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15 [9]
    Units: age (months)
    arithmetic mean (standard error)
        First smile-BS
    2.9 ( 1.85 )
        First smile-OA
    2.9 ( 1.85 )
        Sat without support-BS
    7.5 ( 3.68 )
        Sat without support-OA
    7.5 ( 3.68 )
        Walked without holding on-BS
    16.5 ( 8.23 )
        Walked without holding on-OA
    16.5 ( 8.23 )
        First used words other than “mama” or “dada”-BS
    29.5 ( 24.81 )
        First used words other than “mama” or “dada”-OA
    29.5 ( 24.81 )
        First used two words/short phrases-BS
    33.2 ( 16.66 )
        First used two words/short phrases-OA
    34.3 ( 19.77 )
        Toilet trained during the day-BS
    46.2 ( 31.22 )
        Toilet trained during the day-OA
    51.5 ( 35.89 )
        Toilet trained at night-BS
    52.5 ( 35.60 )
        Toilet trained at night-OA
    60.1 ( 43.23 )
    Notes
    [9] - BS=baseline OA=overall
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants with Behavioral Disorders

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    End point title
    		 TAND checklist - Number of Participants with Behavioral Disorders
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. Behavioral level- This level refers to any observed behaviors that may cause concern to the individual. Behavioral presentations include anxiety, depressed mood, aggressive behaviors, temper tantrums, attention-related behaviors (such as difficulty concentrating, hyperactivity, impulsivity), social, and communication-related behaviors (such as speech and language delays, poor eye contact, difficulties in relationships with peers, repetitive behaviors), self-injurious behaviors, and eating or sleep difficulties. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15 [10]
    Units: participants
        Anxiety-BS
    12
        Anxiety-OA
    13
        Depressed mood-BS
    6
        Depressed mood-OA
    8
        Extreme shyness-BS
    5
        Extreme shyness-OA
    7
        Mood swings-BS
    10
        Mood swings-OA
    12
        Aggressive outbursts-BS
    7
        Aggressive outbursts-OA
    11
        Temper Tantrums-BS
    9
        Temper Tantrums-OA
    12
        Self-injury-hitting, biting, scratching self-BS
    3
        Self-injury-hitting, biting, scratching self-OA
    5
        Absent/delayed onset of language to communicate-BS
    11
        Absent/delayed onset of language to communicate-OA
    12
        Repeating words or phrases over and over again-BS
    9
        Repeating words or phrases over and over again-OA
    12
        Poor eye contact-BS
    6
        Poor eye contact-OA
    8
        Difficulty getting on with people similar age-BS
    9
        Difficulty getting on with people similar age-OA
    10
        Repetitive behaviours-BS
    9
        Repetitive behaviours-OA
    11
        Very rigid/inflexible-how to do things-BS
    8
        Very rigid/inflexible-how to do things-OA
    11
        Overactivity/hyperactivity-constantly on the go-BS
    8
        Overactivity/hyperactivity-constantly on the go-OA
    9
        Difficulty paying attention or concentrating-BS
    13
        Difficulty paying attention or concentrating-OA
    15
        Restlessness or fidgetiness-wriggling/squirming-BS
    13
        Restlessness or fidgetiness-wriggling/squirming-OA
    14
        Impulsivity - butting in, not waiting turn-BS
    10
        Impulsivity - butting in, not waiting turn-OA
    12
        Eat difficulties-too much/too little/unusual-BS
    5
        Eat difficulties-too much/too little/unusual-OA
    8
        Sleep difficulties-with falling asleep/waking-BS
    6
        Sleep difficulties-with falling asleep/waking-OA
    8
    Notes
    [10] - BS=baseline OA=overall
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants with Psychiatric disorders

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    End point title
    		 TAND checklist - Number of Participants with Psychiatric disorders
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. For psychiatric disorders some behaviors of concern are examined and evaluated in the context of the individual's overall developmental level and in terms of their biological, psychological, and social profile. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15 [11]
    Units: participants
        Autism Spectrum Disorder(ASD)-autism/Asperger’s-BS
    4
        Autism Spectrum Disorder(ASD)-autism/Asperger’s-OA
    7
        Attention Deficit Hyperactivity Disorder (ADHD)-BS
    5
        Attention Deficit Hyperactivity Disorder (ADHD)-OA
    9
        Anxiety Disorder-panic/phobia/separation AD-BS
    4
        Anxiety Disorder-panic/phobia/ separation AD-OA
    7
        Depressive Disorder-BS
    0
        Depressive Disorder-OA
    0
        Obsessive Compulsive Disorder-BS
    2
        Obsessive Compulsive Disorder-OA
    2
        Psychotic Disorder, including schizophrenia-BS
    0
        Psychotic Disorder, including schizophrenia-OA
    0
    Notes
    [11] - BS=baseline OA=overall AD=Anxiety Disorder
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants with Scholastic issues

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    End point title
    		 TAND checklist - Number of Participants with Scholastic issues
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At academic level, it is described the specific learning disorders associated with school performance, such as reading, writing, mathematics, and spelling. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15
    Units: participants
        Reading-baseline
    12
        Reading-overall
    14
        Writing-baseline
    12
        Writing-overall
    14
        Spelling-baseline
    12
        Spelling-overall
    14
        Mathematics-baseline
    12
        Mathematics-overall
    14
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants with Difficulty in Specific Brain Skills

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    End point title
    		 TAND checklist - Number of Participants with Difficulty in Specific Brain Skills
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. Neuropsychological evaluations are used to describe the strengths and weaknesses of brain referenced systems used for learning, thinking, and behavior regulation. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15
    Units: participants
        Memory-baseline
    7
        Memory-overall
    12
        Attention-baseline
    12
        Attention-overall
    14
        Dual-tasking/ Multi-tasking-baseline
    12
        Dual-tasking/ Multi-tasking-overall
    14
        Visuo-spatial tasks-baseline
    8
        Visuo-spatial tasks-overall
    13
        Executive skills-baseline
    10
        Executive skills-overall
    15
        Getting disoriented-baseline
    7
        Getting disoriented-overall
    12
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants with Psychological issues

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    End point title
    		 TAND checklist - Number of Participants with Psychological issues
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At psychosocial level it is considered important determinants of quality of life, such as self-esteem, family functioning, parental stress, and relationship difficulties. All these are markers of resilience and burden of care, and all the psychosocial factors may be amenable to intervention and support. Baseline is defined as the first available assessment on or after the enrollment date of the CRAD001M2305 study. Overall consists of all responses including baseline.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15 [12]
    Units: participants
        Low self-esteem-baseline
    2
        Low self-esteem-overall
    6
        VHLS in families, for instance between siblings-BS
    6
        VHLS in families, for instance between siblings-OA
    8
        VHLS between parents leading to significant RD-BS
    5
        VHLS between parents leading to significant RD-OA
    7
    Notes
    [12] - BS=baseline OA=overall VHLS=very high level of stress RD=relationship difficulties
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants with Varied Levels of Language skills

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    End point title
    		 TAND checklist - Number of Participants with Varied Levels of Language skills
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. Neuropsychological evaluations are used to describe the strengths and weaknesses of brain referenced systems used for learning, thinking, and behavior regulation. These include language skills (including non-verbal, simple language, fluence of language). All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15
    Units: participants
        Non-verbal
    2
        Simple language
    6
        Fluent
    4
        Missing
    3
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants with Different Levels of Physical Dependency

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    End point title
    		 TAND checklist - Number of Participants with Different Levels of Physical Dependency
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. This outcome measure assesses the TAND checklist part about physical dependency. All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15
    Units: participants
        Dependent on others
    4
        Some self-care skills
    7
        Independent
    1
        Missing
    3
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants with Different Levels of Mobility

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    End point title
    		 TAND checklist - Number of Participants with Different Levels of Mobility
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. This outcome measure assesses the TAND checklist part about mobility. All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15
    Units: participants
        Wheelchair
    1
        Needs significant support
    1
        Some difficulty
    0
        Completely mobile
    10
        Missing
    3
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants with Different Levels of Intelligence Quotient

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    End point title
    		 TAND checklist - Number of Participants with Different Levels of Intelligence Quotient
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At intellectual level, it is described the intellectual developmental abilities of an individual in comparison with others of the same chronological age. All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15
    Units: participants
        Normal Intellectual Ability (IQ > 80)
    2
        Borderline Intellectual Ability (IQ 70-80)
    2
        Mild Intellectual Disability (IQ 50-69)
    1
        Moderate Intellectual Disability (IQ 35-49)
    5
        Severe Intellectual Disability (IQ 21-34)
    0
        Profound Intellectual Disability (IQ <20)
    1
        Missing
    4
    No statistical analyses for this end point

    Secondary: TAND checklist - Number of Participants with Different Levels of Intellectual Ability

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    End point title
    		 TAND checklist - Number of Participants with Different Levels of Intellectual Ability
    End point description
    Tuberous Sclerosis Complex (TSC) is associated with a range of neuropsychiatric disorders which refers to as TAND (TSC–Associated–Neuropsychiatric–Disorders). A specific TAND Checklist has been developed to assess Behavioral, Psychiatric, Intellectual, Academic, Neuropsychological and Psychosocial areas. At intellectual level, it is described the intellectual developmental abilities of an individual to identify their overall functional and adaptive behaviors in comparison with others of the same chronological age. This level is the combination of formal measures of intellectual ability (such as IQ-type tests) and evaluation of adaptive behaviors (such as self-care, daily living skills, communication, and social abilities in daily life). All the responses are categorical in nature from the TAND Checklist. The frequency of (baseline and) worst-post baseline is summarized.
    End point type
    Secondary
    End point timeframe
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    End point values
    		 Everolimus
    Number of subjects analysed
    15
    Units: participants
        Normal Intellectual Ability
    1
        Mild-Moderate Intellectual Disability
    8
        Severe - Profound Intellectual Disability
    3
        Missing
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From enrollment in study CRAD001M2305 until end of study, up to approximately 9 years.
    Adverse event reporting additional description
    Adverse events are assessed in the Safety Set. The Safety Set included all pediatric patients enrolled who had at least one-post baseline safety assessment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    CRAD001M2305
    Reporting group description
    		 CRAD001M2305

    Serious adverse events
    		 CRAD001M2305
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 14 (42.86%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Astrocytoma, low grade
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Near drowning
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Post procedural complication
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Status epilepticus
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Seizure
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Drowning
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences causally related to treatment / all
    2 / 3
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Arthritis infective
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 CRAD001M2305
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 14 (85.71%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Astrocytoma, low grade
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    General disorders and administration site conditions
    Gait disturbance
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Microsomia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    6 / 14 (42.86%)
         occurrences all number
    11
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Reproductive system and breast disorders
    Heavy menstrual bleeding
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Ovarian cyst
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Central sleep apnoea syndrome
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cough
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    Oropharyngeal pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Sleep apnoea syndrome
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Upper respiratory tract congestion
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Anxiety
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    4
    Attention deficit hyperactivity disorder
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Euphoric mood
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Insomnia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Investigations
    Cardiac murmur
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cutibacterium test positive
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    SARS-CoV-2 test negative
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Contusion
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Limb injury
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Procedural pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Right ventricular dilatation
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Head discomfort
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Headache
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Seizure
         subjects affected / exposed
    4 / 14 (28.57%)
         occurrences all number
    7
    Vasogenic cerebral oedema
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Hypofibrinogenaemia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Iron deficiency anaemia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Lymphadenopathy
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Hypoacusis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Eye disorders
    Periorbital swelling
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gastrointestinal disorders
    Mouth ulceration
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Abdominal pain upper
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    3
    Constipation
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    4
    Flatulence
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gingival hypertrophy
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Nausea
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Oral pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Stomatitis
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Vomiting
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Acne
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Blister
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Neck pain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Pain in extremity
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Tendonitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Cellulitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Clostridium difficile infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Conjunctivitis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Croup infectious
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Ear infection
         subjects affected / exposed
    4 / 14 (28.57%)
         occurrences all number
    5
    Fungal skin infection
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gastroenteritis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Infectious mononucleosis
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    4 / 14 (28.57%)
         occurrences all number
    5
    Otitis media
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Pharyngitis streptococcal
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Pneumonia
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    5
    Sinusitis
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    6
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Hyperlipidaemia
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    2
    Vitamin D deficiency
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Abnormal weight gain
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Aug 2014
    This protocol was amended in order to address comments received from the reviewers at the Committee for Medicinal Products for Human Use (CHMP). In light of these comments from the Health Authority, the protocol was amended to clarify operational activities that were planned for each visit.

    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.
    It was anticipated that max. of 50 patients who have participated in Study M2301 would be eligible to enter Study M2305. However, only 15 patients were enrolled into this study, due to delays in study start-up at country level.
    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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