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    Clinical Trial Results:
    Multi-centre, oral single dose experimental and modelling study to evaluate the pharmacokinetics of deferiprone in patients aged from 1 month to less than 6 years of age affected by transfusion-dependent haemoglobinopathies

    Summary
    EudraCT number
    		 2012-000658-67
    Trial protocol
    		 IT   Outside EU/EEA  
    Global end of trial date
    10 Dec 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Mar 2016
    First version publication date
    23 Mar 2016
    Other versions
    Summary report(s)
    		 DEEP-1 Clinical Study Synopsis v1.8 25MAY15

    Trial information

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    Trial identification
    Sponsor protocol code
    DEEP-1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01740713
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Consorzio per Valutazioni Biologiche e Farmacologiche
    Sponsor organisation address
    via Luigi Porta, 14, Pavia, Italy, 27100
    Public contact
    Clinical Research Unit, Consorzio per Valutazioni Biologiche e Farmacologiche , 0039 0382 25075, mariagraziafelisi@cvbf.net
    Scientific contact
    Clinical Research Unit, Consorzio per Valutazioni Biologiche e Farmacologiche , 0039 0382 25075, mariagraziafelisi@cvbf.net
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001126-PIP01-10
    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
    17 Feb 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2013
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the pharmacokinetics of deferiprone in paediatric patients aged from 1 month to less than 6 years
    Protection of trial subjects
    The study was conducted in accordance with all applicable regulatory requirements: the European Directive 95/46/EC on the protection of individuals with regard to the processing of personal data and on the free movement of such data, and the Convention of Human Rights and Biomedicine and its Additional Protocol on Biomedical Research (2005) and in accordance with "good clinical practice" (GCP), all applicable subject privacy requirements, and, the guiding principles of the 2008 Declaration of Helsinki. The sponsor obtained favourable opinion/approval to conduct the study from the appropriate regulatory agency in accordance with any applicable country-specific regulatory requirements prior to a site initiating the study in that country. Information Document was provided and written consent was obtained from the legal guardian for each subject before participation in the study. Children took part in the information process under the responsibility of parents. and the investigator according to their age and maturity level.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    31 Jan 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
    Italy: 21
    Worldwide total number of subjects
    21
    EEA total number of subjects
    21
    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)
    2
    Children (2-11 years)
    19
    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
    		 Recruitment lasted from January 2013 to November 2013.

    Pre-assignment
    Screening details
    		 A total of 23 children affected by transfusion-dependent haemoglobinopathies were enrolled in this study. Of these 23 children, 2 were screening failures and 3 early terminations.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject
    Blinding implementation details
    This is a single blind PK study, i.e. both the site investigator and internal per sonnel at the University of Leiden are not blinded with regard to the administered dose level. Patients were randomised to 3 dose-levels: Dose level 1: 25 mg/kg/day, equivalent to AUC values | 20-50 mg/L • h Dose level 2: 50 mg/kg/day, equivalent to AUC values | 50.1-125 mg/L • h Dose level 3: 100 mg/kg/day, equivalent to AUC values >125 mg/L • h

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Dose level 1
    Arm description
    		 25 mg/Kg/day
    Arm type
    		 Dose level

    Investigational medicinal product name
    deferiprone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg/Kg/day

    Arm title
    		 Dose level 2
    Arm description
    		 50mg/Kg/day
    Arm type
    		 Dose level

    Investigational medicinal product name
    deferiprone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    50mg/Kg/day

    Arm title
    		 Dose level 3
    Arm description
    		 100 mg/Kg/day
    Arm type
    		 Dose level

    Investigational medicinal product name
    deferiprone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    100 mg/Kg/die

    Number of subjects in period 1
    		Dose level 1 Dose level 2 Dose level 3
    Started
    6
    8
    7
    Completed
    6
    6
    6
    Not completed
    0
    2
    1
         Adverse event, non-fatal
    -
    2
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 21 21
    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)
    		 2 2
        Children (2-11 years)
    		 19 19
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 10 10
    Subject analysis sets

    Subject analysis set title
    PK population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Data from 18 evaluable children (9 males and 9 females) were used for the pharmacokinetic analysis. Patients were randomised to 3 dose levels (8.3, 16.7 and 33.3 mg/kg) with 6 patients assigned to each group. 16 patients were diagnosed with β-thalassaemia major and 2 with thalassodrepanocytosis.

    Subject analysis sets values
    		 PK population
    Number of subjects
    18
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    2
        Children (2-11 years)
    16
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units:
        
    ( )
    Gender categorical
    Units: Subjects
        Female
    9
        Male
    9

    End points

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    End points reporting groups
    Reporting group title
    Dose level 1
    Reporting group description
    		 25 mg/Kg/day

    Reporting group title
    Dose level 2
    Reporting group description
    		 50mg/Kg/day

    Reporting group title
    Dose level 3
    Reporting group description
    		 100 mg/Kg/day

    Subject analysis set title
    PK population
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Data from 18 evaluable children (9 males and 9 females) were used for the pharmacokinetic analysis. Patients were randomised to 3 dose levels (8.3, 16.7 and 33.3 mg/kg) with 6 patients assigned to each group. 16 patients were diagnosed with β-thalassaemia major and 2 with thalassodrepanocytosis.

    Primary: CL/F

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    End point title
    		 CL/F [1]
    End point description
    End point type
    Primary
    End point timeframe
    Blood samples, for quantification of DFP in plasma, were collected at the pre-defined sampling times.
    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: THis is a modelling study. Concentrations was analysed with Nonlinear mixed effects modelling in NONMEM, version 7.2.0
    End point values
    		 PK population
    Number of subjects analysed
    18
    Units: litre/h
        number (not applicable)
    8.3
    No statistical analyses for this end point

    Primary: V/F

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    End point title
    		 V/F [2]
    End point description
    End point type
    Primary
    End point timeframe
    Blood samples, for quantification of DFP in plasma, were collected at the pre-defined sampling times.
    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: This is a modelling study. Concentrations was analysed with Nonlinear mixed effects modelling in NONMEM, version 7.2.0
    End point values
    		 PK population
    Number of subjects analysed
    18
    Units: litre(s)
        number (not applicable)
    18.7
    No statistical analyses for this end point

    Primary: Ka

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    End point title
    		 Ka [3]
    End point description
    End point type
    Primary
    End point timeframe
    Blood samples, for quantification of DFP in plasma, were collected at the pre-defined sampling times.
    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: This is a modelling study. Concentrations was analysed with Nonlinear mixed effects modelling in NONMEM, version 7.2.0
    End point values
    		 PK population
    Number of subjects analysed
    18
    Units: h*-1
        number (not applicable)
    9.13
    No statistical analyses for this end point

    Secondary: AUC_0-8

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    End point title
    		 AUC_0-8
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples, for quantification of DFP in plasma, were collected at the pre-defined sampling times.
    End point values
    		 Dose level 1 Dose level 2 Dose level 3
    Number of subjects analysed
    6
    6
    6
    Units: micromole(s)/litre*hour
        median (inter-quartile range (Q1-Q3))
    116.7 (90.6 to 129)
    210 (173.1 to 266.6)
    428.8 (291.4 to 547.8)
    No statistical analyses for this end point

    Secondary: Cmax

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    End point title
    		 Cmax
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples, for quantification of DFP in plasma, were collected at the pre-defined sampling times.
    End point values
    		 Dose level 1 Dose level 2 Dose level 3
    Number of subjects analysed
    6
    6
    6
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    61.7 (45.1 to 80.7)
    119.8 (106 to 154)
    229.5 (179.7 to 278.1)
    No statistical analyses for this end point

    Secondary: Tmax

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    End point title
    		 Tmax
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples, for quantification of DFP in plasma, were collected at the pre-defiend sampling times.
    End point values
    		 Dose level 1 Dose level 2 Dose level 3
    Number of subjects analysed
    6
    6
    6
    Units: hour
        median (inter-quartile range (Q1-Q3))
    0.33 (0.19 to 0.92)
    0.33 (0.21 to 0.63)
    0.37 (0.27 to 0.42)
    No statistical analyses for this end point

    Secondary: Css

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    End point title
    		 Css
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples, for quantification of DFP in plasma, were collected at the pre-defiend sampling times.
    End point values
    		 Dose level 1 Dose level 2 Dose level 3
    Number of subjects analysed
    6
    6
    6
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    2.1 (1.6 to 2.3)
    3.7 (3.1 to 4.9)
    7.7 (5.1 to 10)
    No statistical analyses for this end point

    Secondary: Cmin

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    End point title
    		 Cmin
    End point description
    End point type
    Secondary
    End point timeframe
    Blood samples, for quantification of DFP in plasma, were collected at the pre-defiend sampling times.
    End point values
    		 Dose level 1 Dose level 2 Dose level 3
    Number of subjects analysed
    6
    6
    6
    Units: micromole(s)/litre
        median (inter-quartile range (Q1-Q3))
    1.5 (0.92 to 2.6)
    1.9 (0.79 to 5.5)
    6.8 (3.1 to 13.9)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All the medical occurrences that started after the administration of the drug under investigation have been recorded as AEs till the follow-up visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Safety population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 21 (14.29%)
    Pregnancy, puerperium and perinatal conditions
    Infantile spitting up
         subjects affected / exposed
    2 / 21 (9.52%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 21 (4.76%)
         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
    26 Sep 2012
    A substantial amendment (Amendment 1) for the notification of the change of sponsor’s responsibility from Universiteit Leiden to Consorzio per Valutazioni Biologiche e Farmacologiche (CVBF) was approved on 26/09/2012.
    29 Oct 2013
    A last amendment (Amendment 2) was notified and accepted on 29/10/2013 to include an additional clinical site (Clinica Pediatrica Università – ASL 1, D.H: per Talassemia, Sassari, Italy).

    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
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