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    Clinical Trial Results:
    A multicentre, open-label, repeated-dose, pharmacokinetic study of Propranolol in infants treated for proliferating infantile hemangiomas (IHs) requiring systemic therapy.

    Summary
    EudraCT number
    		 2009-018102-22
    Trial protocol
    		 FR  
    Global end of trial date
    07 Jun 2011

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Feb 2016
    First version publication date
    17 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    V00400SB102
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Pierre Fabre Dermatologie
    Sponsor organisation address
    45, Place Abel Gance, Boulogne, France, 92100
    Public contact
    Medical and/or Clinical Study Manager , Pierre Fabre Dermatologie, contact_essais_cliniques@pierre-fabre.com
    Scientific contact
    Medical and/or Clinical Study Manager , Pierre Fabre Dermatologie, contact_essais_cliniques@pierre-fabre.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000511-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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    29 May 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Jun 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Jun 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The purpose of this study is to characterise the pharmacokinetics of propranolol (administered as an oral solution V0400 SB) at steady-state in infants during a treatment for proliferating infantile hemangiomas requiring systemic therapy.
    Protection of trial subjects
    Clinical (including respiratory rate and vital sign measurements) and paraclinical (lab tests (haematology, biochemistry, glycaemia (pin-prick) and ECG) examinations.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    28 May 2010
    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
    France: 23
    Worldwide total number of subjects
    23
    EEA total number of subjects
    23
    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)
    23
    Children (2-11 years)
    0
    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
    		 Of the 23 patients who were included 10 were stratified to Group 1(infants aged from 35 to 90 days inclusive at inclusion), and 13 to Group 2(infants aged from 91 to 150 days inclusive at inclusion).

    Pre-assignment
    Screening details
    		 Infants 35 to 150 days of age with proliferating infantile hemangioma requiring sytemic therapy were stratified to 2 groups to their age at inclusion.

    Period 1
    Period 1 title
    Propranolol hydrochloride oral solution (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 : 35 to 90 days
    Arm description
    		 Infants aged from 35 to 90 days inclusive at inclusion Repeated doses up to 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Propranolol hydrochloride oral solution
    Investigational medicinal product code
    V0400SB
    Other name
    Hemangiol
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Administration of propranolol oral solution twice daily. Titration procedure : D0: 1 mg/kg/day D7: increase to 2 mg/kg/day D14: increase to 3 mg/kg/day, up to the study end (Week 12).

    Arm title
    		 Group 2 : 91 to 150 days
    Arm description
    		 Infants aged from 91 to 150 days inclusive at inclusion. Repeated doses up to 12 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Propranolol hydrochloride oral solution
    Investigational medicinal product code
    V0400SB
    Other name
    Hemangiol
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Administration of propranolol oral solution twice daily. Titration procedure : D0: 1 mg/kg/day D7: increase to 2 mg/kg/day D14: increase to 3 mg/kg/day, up to the study end (Week 12).

    Number of subjects in period 1
    		Group 1 : 35 to 90 days Group 2 : 91 to 150 days
    Started
    10
    13
    Completed
    10
    12
    Not completed
    0
    1
         Sponsor decision (increase QTcB on day 14-467ms)
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1 : 35 to 90 days
    Reporting group description
    		 Infants aged from 35 to 90 days inclusive at inclusion Repeated doses up to 12 weeks.

    Reporting group title
    Group 2 : 91 to 150 days
    Reporting group description
    		 Infants aged from 91 to 150 days inclusive at inclusion. Repeated doses up to 12 weeks.

    Reporting group values
    		 Group 1 : 35 to 90 days Group 2 : 91 to 150 days Total
    Number of subjects
    		 10 13 23
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 10 13 23
    Age continuous
    Units: days
        arithmetic mean (full range (min-max))
    		 69.7 (50 to 89) 128.2 (91 to 152) -
    Gender categorical
    Units: Subjects
        Female
    		 7 10 17
        Male
    		 3 3 6
    Subject analysis sets

    Subject analysis set title
    Safety/efficacy set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients treated (safety set) with at least one post-baseline efficacy assessment (efficacy set).

    Subject analysis set title
    PK set Group 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients having taken all study medications and not presenting any major deviation (for PK evaluation).

    Subject analysis set title
    Pk set Group 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients having taken all study medications and not presenting any major deviation (for PK evaluation)

    Subject analysis sets values
    		 Safety/efficacy set PK set Group 1 Pk set Group 2
    Number of subjects
    23
    8
    11
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    23
    8
    11
    Age continuous
    Units: days
        arithmetic mean (full range (min-max))
    102.7 (50 to 152)
    69.3 (50 to 89)
    134.5 (113 to 152)
    Gender categorical
    Units: Subjects
        Female
    17
    5
    8
        Male
    6
    3
    3

    End points

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    End points reporting groups
    Reporting group title
    Group 1 : 35 to 90 days
    Reporting group description
    		 Infants aged from 35 to 90 days inclusive at inclusion Repeated doses up to 12 weeks.

    Reporting group title
    Group 2 : 91 to 150 days
    Reporting group description
    		 Infants aged from 91 to 150 days inclusive at inclusion. Repeated doses up to 12 weeks.

    Subject analysis set title
    Safety/efficacy set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    All patients treated (safety set) with at least one post-baseline efficacy assessment (efficacy set).

    Subject analysis set title
    PK set Group 1
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients having taken all study medications and not presenting any major deviation (for PK evaluation).

    Subject analysis set title
    Pk set Group 2
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Patients having taken all study medications and not presenting any major deviation (for PK evaluation)

    Primary: Propranolol - Maximum plasma concentration (Cmax) -

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    End point title
    		 Propranolol - Maximum plasma concentration (Cmax) - [1]
    End point description
    End point type
    Primary
    End point timeframe
    Steady-state PK parameters after repeated twice daily oral administration of propranolol (3 mg/kg/day) for 2 weeks (Group 1) and for 10 weeks (Group2)(following a 2-week uptitration in both groups). 6 micro-blood samples were collected over 9 hours.
    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: Descriptive analyses were performed based on the study groups.
    End point values
    		 Group 1 : 35 to 90 days Group 2 : 91 to 150 days
    Number of subjects analysed
    8
    11
    Units: ng/mL
        geometric mean (full range (min-max))
    78.5 (47.8 to 119)
    79.2 (21.3 to 448)
    No statistical analyses for this end point

    Primary: Propranolol - Area under the plasma concentration time curve observed between two administrations (AUCτ) -

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    End point title
    		 Propranolol - Area under the plasma concentration time curve observed between two administrations (AUCτ) - [2]
    End point description
    End point type
    Primary
    End point timeframe
    Steady-state PK parameters after repeated twice daily oral administration of propranolol (3 mg/kg/day) for 2 weeks (Group 1) and for 10 weeks (Group2)(following a 2-week uptitration in both groups). 6 micro-blood samples were collected over 9 hours.
    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: Descriptive analyses were performed based on the study groups.
    End point values
    		 Group 1 : 35 to 90 days Group 2 : 91 to 150 days
    Number of subjects analysed
    8
    11
    Units: h.ng/mL
        geometric mean (full range (min-max))
    541 (360 to 804)
    430 (116 to 1193)
    No statistical analyses for this end point

    Primary: Propranolol - Time to reach the maximum plasma concentration (Tmax) -

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    End point title
    		 Propranolol - Time to reach the maximum plasma concentration (Tmax) - [3]
    End point description
    End point type
    Primary
    End point timeframe
    Steady-state PK parameters after repeated twice daily oral administration of propranolol (3 mg/kg/day) for 2 weeks (Group 1) and for 10 weeks (Group2)(following a 2-week uptitration in both groups). 6 micro-blood samples were collected over 9 hours.
    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: Descriptive analyses were performed based on the study groups.
    End point values
    		 Group 1 : 35 to 90 days Group 2 : 91 to 150 days
    Number of subjects analysed
    8
    11
    Units: hour
        median (full range (min-max))
    2 (1 to 9)
    2 (1 to 4)
    No statistical analyses for this end point

    Primary: Propranolol - oral clearance (Cltot/F/kg) -

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    End point title
    		 Propranolol - oral clearance (Cltot/F/kg) - [4]
    End point description
    End point type
    Primary
    End point timeframe
    Steady-state PK parameters after repeated twice daily oral administration of propranolol (3 mg/kg/day) for 2 weeks (Group 1) and for 10 weeks (Group2)(following a 2-week uptitration in both groups). 6 micro-blood samples were collected over 9 hours.
    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: Descriptive analyses were performed based on the study groups.
    End point values
    		 Group 1 : 35 to 90 days Group 2 : 91 to 150 days
    Number of subjects analysed
    8
    11
    Units: L/h/kg
        geometric mean (full range (min-max))
    2.71 (1.84 to 4.05)
    3.27 (1.18 to 12.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Whole Study Period
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Group 1 : 35 to 90 days
    Reporting group description
    		 Infants aged from 35 to 90 days inclusive at inclusion Repeated doses up to 12 weeks.

    Reporting group title
    Group 2 : 91 to 150 days
    Reporting group description
    		 Infants aged from 91 days to 150 inclusive at inclusion. Repeated doses up to 12 weeks.

    Serious adverse events
    		 Group 1 : 35 to 90 days Group 2 : 91 to 150 days
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Vascular disorders
    Pallor
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Crying
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Otitis media acute
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Group 1 : 35 to 90 days Group 2 : 91 to 150 days
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 10 (80.00%)
    12 / 13 (92.31%)
    Vascular disorders
    Peripheral coldness
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 13 (30.77%)
         occurrences all number
    5
    7
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 13 (23.08%)
         occurrences all number
    2
    4
    Psychiatric disorders
    Nightmare
         subjects affected / exposed
    3 / 10 (30.00%)
    4 / 13 (30.77%)
         occurrences all number
    3
    4
    Insomnia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Sleep disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Investigations
    Blood alkaline phosphatase increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Blood potassium increased
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Electrocardiogram QT prolonged
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Arthropod bite
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Nervous system disorders
    Poor quality sleep
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    3 / 10 (30.00%)
    1 / 13 (7.69%)
         occurrences all number
    3
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 10 (20.00%)
    5 / 13 (38.46%)
         occurrences all number
    2
    8
    Toothache
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 13 (23.08%)
         occurrences all number
    0
    3
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 13 (7.69%)
         occurrences all number
    1
    1
    Teething
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    2
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Dry skin
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Eczema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 10 (30.00%)
    3 / 13 (23.08%)
         occurrences all number
    4
    3
    Bronchitis
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 13 (15.38%)
         occurrences all number
    1
    2
    Gastroenteritis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Infected bites
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Oral candidiasis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Rhinitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Tracheitis
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Varicella
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Fungal infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Otitis media acute
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 13 (7.69%)
         occurrences all number
    0
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 13 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 10 (20.00%)
    0 / 13 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Mar 2010
    - Increase of the sample size from 18 to 20 infants (EMA requirement) − Precision on the ECG assessment (added by the Sponsor) − Addition of the quantification of the 4-OH-propranolol (the metabolite of propranolol) in order to complete the PK profile (added by the Sponsor)
    01 Jul 2010
    − Change of the Study Medical Manager − Change of Sponsor representative’s address − Annual update of the Investigator Brochure (addition of new bibliographical references, addition of compassionate use experience with the product)

    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
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    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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