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    Clinical Trial Results:
    An Open-label Non-comparative, Multi-centre Study To Assess The Efficacy And Safety Of Bicalutamide When Used In Combination With Anastrozole For The Treatment Of Gonadotropin-independent Precocious Puberty In Boys With Testotoxicosis

    Summary
    EudraCT number
    		 2004-000384-10
    Trial protocol
    		 GB   FR  
    Global end of trial date
    06 Dec 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Jun 2018
    First version publication date
    08 Jun 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    Doc ID-002099254
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 BATT: D6873C00047
    Sponsors
    Sponsor organisation name
    AstraZeneca AB
    Sponsor organisation address
    151 85, Södertälje, Sweden,
    Public contact
    Clinical Trial Transparency, AstraZeneca, ClinicalTrialTransparency@astrazeneca.com
    Scientific contact
    AstraZeneca, AstraZeneca Clinical Study Information Center, 0011 08772409479, information.center@astrazeneca.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000283-PIP01-08
    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
    07 May 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 May 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the efficacy of bicalutamide when used in combination with anastrozole in terms of a reduction in growth rate after 12 months treatment of precocious puberty in boys with testotoxicosis.
    Protection of trial subjects
    A data and safety monitoring board is not necessary for this study but an advisory panel, consisting of the international co-ordinating investigator and the following AstraZeneca personnel: the study physician, clinical kineticist and the product medical director, will determine the requirement of the 2 week anastrozole only period following enrolment of the first 4 subjects into the study. In addition, the starting dose of anastrozole and bicalutamide will be evaluated by the advisory panel after the first 4 subjects have been enrolled. Consequently, the starting dose of either product or both products may be adjusted for subsequent subjects entering the study. This process will be repeated for additional groups of 4 subjects until an appropriate dose regimen is established. Any changes to the starting doses for either drug or elimination of the anastrozole only dosing period recommended by the advisory panel will be communicated in writing to all investigators and should be copied to the IRB/ IECs. The change may then be implemented immediately; no protocol amendments will be issued for such changes. The timing and manner of any review and analysis of data collected after the first 12 months of therapy while subjects are being followed to final adult height will be agreed after discussion between the International Co-ordinating Investigator and AstraZeneca, and the FDA as appropriate, after the analysis at 12 months.
    Background therapy
    		 Bicalutamide in combination with anastrozole
    Evidence for comparator
    		 Non-comparative study
    Actual start date of recruitment
    22 Nov 2004
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 10 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    India: 3
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    United States: 10
    Worldwide total number of subjects
    14
    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)
    14
    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
    		 The first patient was enrolled on 22 November 2004 and the last patient completed the 12 months visit on 7 May 2008. Patients were allocated treatment at 9 centres in 3 countries: India, the UK and the USA. Care for two patients, transferred from one US to a new approved US centre, therefore, patients were treated at 10 centres in total.

    Pre-assignment
    Screening details
    		 Of the 24 patients enrolled, 10 failed eligibility criteria and were classed as screening failures while the remaining 14 patients were allocated treatment.

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

    Arms
    Arm title
    		 All treated
    Arm description
    		 -
    Arm type
    		 Non-comparative

    Investigational medicinal product name
    Bicalutamide in combination with anastrozole
    Investigational medicinal product code
    Other name
    CASODEX and ARMIDEX
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dosing of anastrozole and bicalutamide was tailored for each subject.

    Number of subjects in period 1
    		All treated
    Started
    14
    Completed
    13
    Not completed
    1
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Post-assignment
    Reporting group description
    		 All-treated (AT) population will consist of any subjects who receive at least one dose of study medication and have at least one on-treatment measurement.

    Reporting group values
    		 Post-assignment Total
    Number of subjects
    		 14 14
    Age Categorical
    Units: Subjects
        2 - 11 years
    		 14 14
    Age Continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 3.9 (2 to 9) -
    Gender Categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 14 14
    Subject analysis sets

    Subject analysis set title
    All-treated
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All-treated (AT) population will consist of any subjects who receive at least one dose of study medication and have at least one on-treatment measurement.

    Subject analysis sets values
    		 All-treated
    Number of subjects
    14
    Age Categorical
    Units: Subjects
        2 - 11 years
    14
    Age Continuous
    Units: years
        arithmetic mean (full range (min-max))
    3.9 (2 to 9)
    Gender Categorical
    Units: Subjects
        Female
    0
        Male
    14

    End points

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    End points reporting groups
    Reporting group title
    All treated
    Reporting group description
    		 -

    Subject analysis set title
    All-treated
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All-treated (AT) population will consist of any subjects who receive at least one dose of study medication and have at least one on-treatment measurement.

    Primary: Change in growth rate (cm/year) after 12 months treatment

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    End point title
    		 Change in growth rate (cm/year) after 12 months treatment
    End point description
    Change in growth rate after 12 months relative to the growth rate during the ≥6 month pre-study period, based on raw height data (cm/year).
    End point type
    Primary
    End point timeframe
    Assessed after 12 months treatment
    End point values
    		 All treated All-treated
    Number of subjects analysed
    13
    13
    Units: cm/year
    arithmetic mean (standard deviation)
        12 months
    -1.62 ( 5.13 )
    -1.62 ( 5.13 )
    Statistical analysis title
    		 Analysis of change in growth rate (cm/year)
    Statistical analysis description
    A 95% 2-sided confidence interval was calculated for the mean change in growth rate.
    Comparison groups
    All treated v All-treated
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.278
    Method
    		 t-test, 2-sided
    Parameter type
    		 Median difference (final values)
    Point estimate
    -1.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.72
         upper limit
    		 1.48

    Primary: Change in growth rate (SD units) after 12 months treatment

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    End point title
    		 Change in growth rate (SD units) after 12 months treatment
    End point description
    Change in growth rate after 12 months relative to the growth rate during the ≥6 month pre-study period, calculated after adjustment for the chronological age of the patient (expressed as a standard deviation [SD] score).
    End point type
    Primary
    End point timeframe
    Assessed after 12 months treatment
    End point values
    		 All treated All-treated
    Number of subjects analysed
    13
    13
    Units: SD units
    arithmetic mean (standard deviation)
        12 months
    -0.07 ( 1.78 )
    -0.07 ( 1.78 )
    Statistical analysis title
    		 Analysis of change in growth rate (SD units)
    Statistical analysis description
    The primary efficacy parameter, change in growth rate (cm and SD units) after 12 months relative to the baseline growth rate was analysed using a one sample t-test.
    Comparison groups
    All treated v All-treated
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.882
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.15
         upper limit
    		 1

    Secondary: Change in growth rate (cm/year) after 6 months treatment

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    End point title
    		 Change in growth rate (cm/year) after 6 months treatment
    End point description
    Change in growth rate after 6 months of treatment relative to the growth rate during the ≥6 months pre-study period.
    End point type
    Secondary
    End point timeframe
    Assessed after 6 months treatment
    End point values
    		 All treated All-treated
    Number of subjects analysed
    13
    13
    Units: cm/year
    arithmetic mean (standard deviation)
        All treated
    -0.07 ( 5.77 )
    -0.07 ( 5.77 )
    No statistical analyses for this end point

    Secondary: Change in growth rate (SD units) after 6 months treatment

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    End point title
    		 Change in growth rate (SD units) after 6 months treatment
    End point description
    Change in growth rate after 6 months of treatment relative to the growth rate during the ≥6 months pre-study period.
    End point type
    Secondary
    End point timeframe
    Assessed after 6 months treatment
    End point values
    		 All treated All-treated
    Number of subjects analysed
    13
    13
    Units: SD units
    arithmetic mean (standard deviation)
        All treated
    -0.14 ( 1.67 )
    -0.14 ( 1.67 )
    No statistical analyses for this end point

    Secondary: Change in bone age maturation rate (cm/year)

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    End point title
    		 Change in bone age maturation rate (cm/year)
    End point description
    Radiographs were used to assess the bone age at ≥6 months pre-study, baseline, 6 and 12 months. The rate of change in bone age at baseline was calculated from a radiograph taken at least 6 months prior to study enrolment. The change in bone maturation after 6 months of treatment was calculated relative to the rate of change in bone age during the ≥ 6 months pre-study period.
    End point type
    Secondary
    End point timeframe
    Assessed after 6 and 12 months treatment
    End point values
    		 All treated All-treated
    Number of subjects analysed
    6
    6
    Units: cm/year
    arithmetic mean (standard deviation)
        6 months
    -2.03 ( 0.38 )
    -2.03 ( 0.38 )
        12 months
    -2.29 ( 0.51 )
    -2.29 ( 0.51 )
    No statistical analyses for this end point

    Secondary: Change in bone age to chronological age ratio

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    End point title
    		 Change in bone age to chronological age ratio
    End point description
    Change in bone age to chronological age ratio after 6 and 12 months treatment relative to the baseline ratio for all patients.
    End point type
    Secondary
    End point timeframe
    Assessed after 6 and 12 months of treatment
    End point values
    		 All treated All-treated
    Number of subjects analysed
    13
    13
    Units: Ratio
    arithmetic mean (standard deviation)
        6 months
    -0.09 ( 0.14 )
    -0.09 ( 0.14 )
        12 months
    -0.24 ( 0.18 )
    -0.24 ( 0.18 )
    No statistical analyses for this end point

    Secondary: Number (%) of patients with height between 5th and 95th percentile

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    End point title
    		 Number (%) of patients with height between 5th and 95th percentile
    End point description
    The number of patients whose height lies between the 5th and 95th percentiles (using the percentile tables on the WHO database) for chronological age at the 12 month assessment.
    End point type
    Secondary
    End point timeframe
    Assessed after 3, 6, 9 and 12 months of treatment
    End point values
    		 All treated All-treated
    Number of subjects analysed
    13
    13
    Units: Count
        3 months
    3
    3
        6 months
    3
    3
        9 months
    3
    3
        12 months
    3
    3
    No statistical analyses for this end point

    Secondary: Change in predicted adult height (PAH)

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    End point title
    		 Change in predicted adult height (PAH)
    End point description
    Radiographs are used to assess the bone age, the change in predicted adult height (PAH) is calculated from the bone age using the Bayley and Pinneau Method. The change in PAH is be calculated by subtracting the PAH at baseline from the PAH at 12 months.
    End point type
    Secondary
    End point timeframe
    Assessed after 12 months treatment
    End point values
    		 All treated All-treated
    Number of subjects analysed
    9
    9
    Units: cm
    arithmetic mean (standard deviation)
        12 months
    6.21 ( 3.93 )
    6.21 ( 3.93 )
    No statistical analyses for this end point

    Secondary: Change in average testicular volume

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    End point title
    		 Change in average testicular volume
    End point description
    Testicular volume of both testes was measured using either ultrasound or an orchidometer. Testicular volume was measured at baseline and at 6 and 12 months. The change in testicular volume from baseline was calculated for the left and right testicle as well as the average across both testes by subtracting the baseline volume from the volumes at 6 and 12 months within each patient.
    End point type
    Secondary
    End point timeframe
    Assessed after 6 and 12 months of treatment
    End point values
    		 All treated All-treated
    Number of subjects analysed
    13
    13
    Units: mL
    arithmetic mean (standard deviation)
        6 months
    1.46 ( 2.29 )
    1.46 ( 2.29 )
        12 months
    2.69 ( 2.51 )
    2.69 ( 2.51 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Safety data was collected and summarised for patients receiving bicalutamide in combination with anastrozole for 12 months.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    All treated
    Reporting group description
    		 All-treated (AT) population consists of any subjects who receive at least one dose of study medication and have at least one on-treatment measurement.

    Serious adverse events
    		 All treated
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 All treated
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    13 / 14 (92.86%)
    General disorders and administration site conditions
    PYREXIA
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    ASTHENIA
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    FATIGUE
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Immune system disorders
    SEASONAL ALLERGY
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Reproductive system and breast disorders
    GYNAECOMASTIA
         subjects affected / exposed
    7 / 14 (50.00%)
         occurrences all number
    7
    BREAST TENDERNESS
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    1
    BREAST PAIN
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    COUGH
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    STRIDOR
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Psychiatric disorders
    CRYING
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Investigations
    ALANINE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    FALL
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    SUNBURN
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    SKIN LACERATION
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Nervous system disorders
    HEADACHE
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3
    Blood and lymphatic system disorders
    EOSINOPHILIA
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    LYMPHADENOPATHY
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    MICROCYTOSIS
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Eye disorders
    CONJUNCTIVITIS
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    Gastrointestinal disorders
    VOMITING
         subjects affected / exposed
    5 / 14 (35.71%)
         occurrences all number
    5
    ABDOMINAL PAIN
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    NAUSEA
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    DIARRHOEA
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    ACNE
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    CAFE AU LAIT SPOTS
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    SKIN HYPERPIGMENTATION
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Endocrine disorders
    PRECOCIOUS PUBERTY
         subjects affected / exposed
    6 / 14 (42.86%)
         occurrences all number
    6
    Musculoskeletal and connective tissue disorders
    MUSCULOSKELETAL CHEST PAIN
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Infections and infestations
    CROUP INFECTIOUS
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    GASTROENTERITIS
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    NASOPHARYNGITIS
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    TONSILLITIS
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    2 / 14 (14.29%)
         occurrences all number
    2
    EAR INFECTION
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    FURUNCLE
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    LABYRINTHITIS
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    LOWER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    OTITIS EXTERNA
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    PYODERMA
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    RESPIRATORY TRACT INFECTION VIRAL
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    RHINITIS
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    SINUSITIS
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    STAPHYLOCOCCAL ABSCESS
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    VARICELLA
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    VIRAL INFECTION
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    DECREASED APPETITE
         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 Mar 2005
    Amendment Number 1
    26 Jul 2005
    Amendment Number 2
    07 May 2009
    Amendment Number 3
    04 Oct 2016
    Amendment Number 4

    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
    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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