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    Clinical Trial Results:
    Constitutional Delay of Growth and Puberty: towards evidence-based treatment

    Summary
    EudraCT number
    2012-002477-59
    Trial protocol
    FI  
    Global end of trial date
    05 Feb 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jan 2020
    First version publication date
    26 Jan 2020
    Other versions
    Summary report(s)
    abstract

    Trial information

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    Trial identification
    Sponsor protocol code
    CDGP1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01797718
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Helsinki University Hospital
    Sponsor organisation address
    Tukholmankatu 8 C, 6. krs LKL tutkijat, Helsinki, Finland, 00029
    Public contact
    Pediatric Endocrinology outpatient clinic, Helsinki Univ. Hospital, Helsinki University Hospital, matti.hero@hus.fi
    Scientific contact
    Pediatric Endocrinology outpatient clinic, Helsinki Univ. Hospital, Helsinki University Hospital, matti.hero@hus.fi
    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
    01 Jan 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Feb 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To study in boys with constitutional delay of puberty, showing the first signs of puberty initiation, whether 6 months treatment with the aromatase inhibitor letrozole promotes the progression puberty more efficiently than the current standard of care, low-dose testosterone therapy. The primary outcomes were changes in testicular volume and hormonal markers of puberty at 6 months after treatment initiation.
    Protection of trial subjects
    The participants were evaluated at pediatric outpatient clinic at 0,3,6, and 12 months visit. Blood samples were taken at each visit. Anesthetic cream were offered before blood sampling to minimize pain. Clinical examination did not cause any pain to the participants.
    Background therapy
    No background therapy were included.
    Evidence for comparator
    Intramuscular low-dose testosterone has been used to induct pubertal development in boys with constitutional delay of growth and puberty (CDGP) for decades. Although treatment with testosterone promotes androgenic signs of puberty, it might initially suppress, rather than activate, the hypothalamic–pituitary–gonadal (HPG) axis and its puberty-promoting effects on gonadotropin secretion and testicular growth emerge later after the treatment. Peroral aromatase inhibitor letrozole which inhibits the conversion of androstenedione to estrone and testosterone to estradiol, which results in the activation of the HPG axis and induce testicular growth. Letrozole has been used before in adolescents, but not in a similar randomized controlled setting. Letrozole appears to be a safe treatment modality at least in short term.
    Actual start date of recruitment
    03 Oct 2013
    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
    Finland: 35
    Worldwide total number of subjects
    35
    EEA total number of subjects
    35
    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)
    35
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The trial was conducted between August 1st, 2013, and January 30th, 2017, at the paediatric endocrinology outpatient clinics of Helsinki University Hospital, Turku University Hospital, Kuopio University Hospital, and Kymenlaakso Central Hospital in Finland. The total population covered was approximately 2 million.

    Pre-assignment
    Screening details
    Eligible boys were > 14 years old ; had presented with delayed puberty, and had a mean testicular volume of at least 2.5 mL but less than 4 mL and serum testosterone concentration of less than 5 nmol/L (or serum testosterone concentration ≥1 nmol/L even if the mean testicular volume was <2.5). Chronic illnesses were screened and excluded.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Letrozole was administered perorally, whereas testosterone was given in intramuscular injections. Thus, no blinding was performed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Letrozole
    Arm description
    Letrozole group received aromatase inhibitor letrozole 2.5mg/day for 6 months.
    Arm type
    Active comparator

    Investigational medicinal product name
    letrozole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg per day for 6 months

    Arm title
    Testosterone
    Arm description
    Testosterone arm received intramuscular low dose testosterone 1mg/kg every 4 weeks for 6 months.
    Arm type
    Active comparator

    Investigational medicinal product name
    Sustanon
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1mg/kg every 4 weeks for 6 months

    Arm title
    follow-up group
    Arm description
    boys with delayed puberty who did not want any treatment but wished to participate in the trial were followed up within the trial protocol but they did not receive any puberty inducting treatment.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Letrozole Testosterone follow-up group
    Started
    15
    15
    5
    Completed
    15
    15
    4
    Not completed
    0
    0
    1
         Lack of efficacy
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Letrozole
    Reporting group description
    Letrozole group received aromatase inhibitor letrozole 2.5mg/day for 6 months.

    Reporting group title
    Testosterone
    Reporting group description
    Testosterone arm received intramuscular low dose testosterone 1mg/kg every 4 weeks for 6 months.

    Reporting group title
    follow-up group
    Reporting group description
    boys with delayed puberty who did not want any treatment but wished to participate in the trial were followed up within the trial protocol but they did not receive any puberty inducting treatment.

    Reporting group values
    Letrozole Testosterone follow-up group Total
    Number of subjects
    15 15 5 35
    Age categorical
    Boys aged over 14 years who presented with constitutional delay of growth and puberty
    Units: Subjects
        Adolescents
    15 15 5 35
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    14.6 ( 0.7 ) 14.8 ( 0.5 ) 14.9 ( 0.4 ) -
    Gender categorical
    Units: Subjects
        Male
    15 15 5 35

    End points

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    End points reporting groups
    Reporting group title
    Letrozole
    Reporting group description
    Letrozole group received aromatase inhibitor letrozole 2.5mg/day for 6 months.

    Reporting group title
    Testosterone
    Reporting group description
    Testosterone arm received intramuscular low dose testosterone 1mg/kg every 4 weeks for 6 months.

    Reporting group title
    follow-up group
    Reporting group description
    boys with delayed puberty who did not want any treatment but wished to participate in the trial were followed up within the trial protocol but they did not receive any puberty inducting treatment.

    Primary: Testicular volume

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    End point title
    Testicular volume [1]
    End point description
    Testicular size was measured with a ruler, and testicular volume (ml) was calculated by using the formula length x width x width x 0.52.
    End point type
    Primary
    End point timeframe
    Change in testicular volume between 0 and 6 months and between 0 and 12 months
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: millilitre(s)
        arithmetic mean (confidence interval 95%)
    7.2 (5.2 to 9.3)
    2.2 (1.4 to 2.9)
    Attachments
    Testicular size increase between groups
    Statistical analysis title
    Mixed-model analysis of testicular volume growth
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Mixed models analysis
    Parameter type
    Hazard ratio (HR)
    Point estimate
    0.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.6
         upper limit
    1.2
    Variability estimate
    Standard deviation

    Primary: Testosterone 3 mo

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    End point title
    Testosterone 3 mo [2]
    End point description
    End point type
    Primary
    End point timeframe
    At 3 months
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specified.
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: nanomole(s)/millilitre
        arithmetic mean (standard deviation)
    21.0 ( 18.6 )
    9.7 ( 6.1 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.033
    Method
    t-test, 2-sided
    Confidence interval

    Primary: Testosterone 6 mo

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    End point title
    Testosterone 6 mo [3]
    End point description
    End point type
    Primary
    End point timeframe
    at 6 months
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: nanomole(s)/millilitre
        arithmetic mean (standard deviation)
    30.2 ( 18.4 )
    5.7 ( 2.7 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    t-test, 2-sided
    Confidence interval

    Primary: testosterone 12mo

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    End point title
    testosterone 12mo [4]
    End point description
    End point type
    Primary
    End point timeframe
    At 12 months
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: nanomole(s)/millilitre
        arithmetic mean (standard deviation)
    10.2 ( 4.3 )
    11.9 ( 3.1 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.22
    Method
    t-test, 2-sided
    Confidence interval

    Primary: LH 3mo

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    End point title
    LH 3mo [5]
    End point description
    End point type
    Primary
    End point timeframe
    At 3 months
    Notes
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: international unit(s)/litre
        arithmetic mean (standard deviation)
    7.1 ( 3.6 )
    0.2 ( 0.2 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    t-test, 2-sided
    Confidence interval

    Primary: LH 6mo

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    End point title
    LH 6mo [6]
    End point description
    End point type
    Primary
    End point timeframe
    At 6 months
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: international unit(s)/millilitre
        arithmetic mean (standard deviation)
    7.6 ( 4.0 )
    2.2 ( 1.4 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001
    Method
    t-test, 2-sided
    Confidence interval

    Primary: LH 12 mo

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    End point title
    LH 12 mo [7]
    End point description
    End point type
    Primary
    End point timeframe
    At 12 months
    Notes
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: international unit(s)/litre
        arithmetic mean (standard deviation)
    2.9 ( 1.3 )
    3.3 ( 1.1 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.45
    Method
    t-test, 2-sided
    Confidence interval

    Primary: Inhibin B 3 mo

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    End point title
    Inhibin B 3 mo [8]
    End point description
    End point type
    Primary
    End point timeframe
    At 3 months
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: nanogram(s)
        arithmetic mean (standard deviation)
    198 ( 62 )
    112 ( 65 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.001
    Method
    t-test, 2-sided
    Confidence interval

    Primary: Inhibin B 6 mo

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    End point title
    Inhibin B 6 mo [9]
    End point description
    End point type
    Primary
    End point timeframe
    At 6 months
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: nanogram(s)
        arithmetic mean (standard deviation)
    211 ( 57 )
    166 ( 96 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.13
    Method
    t-test, 2-sided
    Confidence interval

    Primary: Inhibin B 12 mo

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    End point title
    Inhibin B 12 mo [10]
    End point description
    End point type
    Primary
    End point timeframe
    At 12 months
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: nanogram(s)
        arithmetic mean (standard deviation)
    223 ( 73 )
    212 ( 96 )
    Statistical analysis title
    Comparison
    Comparison groups
    Testosterone v Letrozole
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.73
    Method
    t-test, 2-sided
    Confidence interval

    Primary: Growth velocity 0-6mo

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    End point title
    Growth velocity 0-6mo [11]
    End point description
    End point type
    Primary
    End point timeframe
    Between 0 and 6months
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: millimeter(s)
        arithmetic mean (standard deviation)
    6.3 ( 2.4 )
    8.2 ( 2.1 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.032
    Method
    t-test, 2-sided
    Confidence interval

    Primary: Growth velocity 0-12mo

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    End point title
    Growth velocity 0-12mo [12]
    End point description
    End point type
    Primary
    End point timeframe
    Between 0 and 12 months
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: millimeter(s)
        arithmetic mean (standard deviation)
    7.0 ( 2.2 )
    7.9 ( 1.5 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.17
    Method
    t-test, 2-sided
    Confidence interval

    Primary: Genital Stage 6 mo

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    End point title
    Genital Stage 6 mo [13]
    End point description
    End point type
    Primary
    End point timeframe
    At 6 months
    Notes
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: number
        G1
    0
    0
        G2
    7
    4
        G3
    6
    10
        G4
    2
    1
        G5
    0
    0
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.2
    Method
    Fisher exact
    Confidence interval

    Primary: Pubic hair stage 6 mo

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    End point title
    Pubic hair stage 6 mo [14]
    End point description
    End point type
    Primary
    End point timeframe
    Between 0 and 12 months
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: number
        P1
    3
    0
        P2
    5
    5
        P3
    6
    9
        P4
    1
    1
        P5
    0
    0
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.3
    Method
    Fisher exact
    Confidence interval

    Primary: Genital stage 12 mo

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    End point title
    Genital stage 12 mo [15]
    End point description
    End point type
    Primary
    End point timeframe
    At 12 months
    Notes
    [15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: number
        G1
    0
    0
        G2
    2
    0
        G3
    6
    8
        G4
    7
    7
        G5
    0
    0
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.4
    Method
    Fisher exact
    Confidence interval

    Primary: GnRH stimulated LH 0 mo

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    End point title
    GnRH stimulated LH 0 mo [16]
    End point description
    End point type
    Primary
    End point timeframe
    At 0 months
    Notes
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: international unit(s)/litre
        arithmetic mean (standard deviation)
    14.6 ( 5.3 )
    15.1 ( 6.7 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.5
    Method
    t-test, 2-sided
    Confidence interval

    Primary: GnRH stimulated LH 12 mo

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    End point title
    GnRH stimulated LH 12 mo [17]
    End point description
    End point type
    Primary
    End point timeframe
    At 12 months
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: international unit(s)/litre
        arithmetic mean (standard deviation)
    19.6 ( 7.1 )
    20.1 ( 9.2 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.34
    Method
    t-test, 2-sided
    Confidence interval

    Primary: Pubic hair stage 12 mo

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    End point title
    Pubic hair stage 12 mo [18]
    End point description
    End point type
    Primary
    End point timeframe
    At 12 months
    Notes
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    15
    Units: number
        P1
    1
    0
        P2
    3
    0
        P3
    7
    7
        P4
    4
    8
        P5
    0
    0
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.4
    Method
    Fisher exact
    Confidence interval

    Secondary: Change in lumbar spine BMD 0-6mo

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    End point title
    Change in lumbar spine BMD 0-6mo [19]
    End point description
    End point type
    Secondary
    End point timeframe
    Between 0 and 6 months
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    14
    Units: gram(s)/cubic meter
        arithmetic mean (standard deviation)
    0.004 ( 0.02 )
    0.029 ( 0.03 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.011
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Change in lumbar spine BMD 0-12

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    End point title
    Change in lumbar spine BMD 0-12 [20]
    End point description
    End point type
    Secondary
    End point timeframe
    Between 0 and 12 months
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    14
    Units: gram(s)/cubic meter
        arithmetic mean (standard deviation)
    0.04 ( 0.05 )
    0.08 ( 0.05 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.038
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Change in BMAD 0-6 mo

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    End point title
    Change in BMAD 0-6 mo [21]
    End point description
    Bone mineral apparent density (g/m3).
    End point type
    Secondary
    End point timeframe
    Between 0 and 6 months.
    Notes
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    14
    Units: gram(s)/cubic meter
        arithmetic mean (standard deviation)
    -0.002 ( 0.006 )
    -0.0006 ( 0.008 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.55
    Method
    t-test, 2-sided
    Confidence interval

    Secondary: Change in BMAD 0-12mo

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    End point title
    Change in BMAD 0-12mo [22]
    End point description
    Bone mineral apparent density g/m3
    End point type
    Secondary
    End point timeframe
    Change between 0 and 12 months
    Notes
    [22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Only treatment groups were compared, and follow-up group was used as background data. This decision was pre-specifie
    End point values
    Letrozole Testosterone
    Number of subjects analysed
    15
    14
    Units: gram(s)/cubic meter
        arithmetic mean (standard deviation)
    -0.003 ( 0.01 )
    0.004 ( 0.01 )
    Statistical analysis title
    Comparison
    Comparison groups
    Letrozole v Testosterone
    Number of subjects included in analysis
    29
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    = 0.093
    Method
    t-test, 2-sided
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were assessed at 0, 3, 6 and 12 months visits
    Adverse event reporting additional description
    Adverse events were asked from the participants and their parents. Additionally, a structured adverse event questionnaire was used, which included all major symptoms of major organ systems.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    NA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    Letrozole
    Reporting group description
    -

    Reporting group title
    Testosterone
    Reporting group description
    -

    Serious adverse events
    Letrozole Testosterone
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 15 (0.00%)
    0 / 15 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Letrozole Testosterone
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 15 (33.33%)
    6 / 15 (40.00%)
    Nervous system disorders
    Migraine
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 15 (13.33%)
    1 / 15 (6.67%)
         occurrences all number
    2
    1
    Nausea
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Hepatobiliary disorders
    Enzyme abnormality
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Aggression
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 15 (20.00%)
    3 / 15 (20.00%)
         occurrences all number
    3
    3
    Fracture
         subjects affected / exposed
    1 / 15 (6.67%)
    1 / 15 (6.67%)
         occurrences all number
    1
    1
    Infections and infestations
    Myocarditis
         subjects affected / exposed
    1 / 15 (6.67%)
    0 / 15 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30612946
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    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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