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    Clinical Trial Results:
    Plasma kinetics for tablet and liquid formulations of 6-mercaptopurine in childhood acute lympholastic leukemia

    Summary
    EudraCT number
    		 2013-001236-21
    Trial protocol
    		 DK  
    Global end of trial date
    27 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Jan 2021
    First version publication date
    01 Jan 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2008-003235-20
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01906671
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Rigshospitalet
    Sponsor organisation address
    Blegdamsvej 9, Copenhagen, Denmark, 2100
    Public contact
    Clinical Trial information, Kjeld Schmiegelow, +45 35451357, Kjeld.Schmiegelow@regionh.dk
    Scientific contact
    Clinical Trial information, Kjeld Schmiegelow, +45 35451357, Kjeld.Schmiegelow@regionh.dk
    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
    28 Apr 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial in to investigate whether previous findings, from a trial conducted on healthy adults regarding plasma kinetics and bioavailability of tablet (Puri-Nethol) and oral liquid formulation (Xaluprine) of 6-mercaptopurine, is similar in the target population, children with ALL.
    Protection of trial subjects
    Patients were examined in a well known and safe environment, and ingested 6-mercaptopurine, which is part of their normal treatment for acute lymphoblastic leukemia
    Background therapy
    		 Children diagnosed with acute lymphoblastic leukemia are treated according to the Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol, where 6-mercaptopurine comprises one of two cornerstones of maintenance therapy. In this trial we aimed to compare pharmacokinetics of tablet and liquid formulations of 6-mercaptopurine, which is thus a normal part of these childrens' treatment.
    Evidence for comparator
    		 A comparative pharmacokinetic study in healthy adults demonstrated bioequivalence between tablet and liquid formulation of 6-mercaptopurine, we aimed to explore this in the target population, children with acute lymphoblastic leukemia
    Actual start date of recruitment
    24 Jun 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
    Denmark: 17
    Worldwide total number of subjects
    17
    EEA total number of subjects
    17
    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)
    16
    Adolescents (12-17 years)
    1
    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
    		 Clinical examination, and receiving maintenance therapy according to Nordic Society of Pediatric Hematology and Oncology (NOPHO) ALL2008 protocol

    Pre-assignment
    Screening details
    		 Clinical examination Receiving maintenance therapy according to the NOPHO ALL2008 protocol

    Period 1
    Period 1 title
    Purinethol
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Purinethol (tablet version of 6-mercaptopurine)
    Arm description
    		 -
    Arm type
    		 Regular treatment

    Investigational medicinal product name
    6-mercaptopurine
    Investigational medicinal product code
    Other name
    Puri-nethol
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    According to the child's therapeutic 6-mercaptopurine dose

    Number of subjects in period 1
    		Purinethol (tablet version of 6-mercaptopurine)
    Started
    17
    Completed
    16
    Not completed
    1
         Consent withdrawn by subject
    1
    Period 2
    Period 2 title
    Xaluprine
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Xaluprine (liquid formulation of 6-mercaptopurine)
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    6-mercaptupurine
    Investigational medicinal product code
    Other name
    Xaluprine
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    According to the child's therapeutic 6-mercaptopurine dose

    Number of subjects in period 2
    		Xaluprine (liquid formulation of 6-mercaptopurine)
    Started
    16
    Completed
    16

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Purinethol
    Reporting group description
    		 -

    Reporting group values
    		 Purinethol Total
    Number of subjects
    		 17 17
    Age categorical
    Units: Subjects
        Children (2-11 years)
    		 16 16
        Adolescents (12-17 years)
    		 1 1
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 9 9
    Diagnosis of acute lymphoblastoc leukemia
    Units: Subjects
        ALL
    		 17 17
    Subject analysis sets

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis of all pharmacokinetic parameters

    Subject analysis sets values
    		 Full analysis
    Number of subjects
    16
    Age categorical
    Units: Subjects
        Children (2-11 years)
    15
        Adolescents (12-17 years)
    1
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        Female
    8
        Male
    8
    Diagnosis of acute lymphoblastoc leukemia
    Units: Subjects
        ALL
    16

    End points

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    End points reporting groups
    Reporting group title
    Purinethol (tablet version of 6-mercaptopurine)
    Reporting group description
    		 -
    Reporting group title
    Xaluprine (liquid formulation of 6-mercaptopurine)
    Reporting group description
    		 -

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Full analysis of all pharmacokinetic parameters

    Primary: Pharmacokinetic parameters, AUC, Cmax, Tmax, t½

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    End point title
    		 Pharmacokinetic parameters, AUC, Cmax, Tmax, t½
    End point description
    End point type
    Primary
    End point timeframe
    On blood samples taken on study days.
    End point values
    		 Purinethol (tablet version of 6-mercaptopurine) Xaluprine (liquid formulation of 6-mercaptopurine) Full analysis
    Number of subjects analysed
    16
    16
    16
    Units: nmol/L
        number (not applicable)
    16
    16
    16
    Statistical analysis title
    		 Paired t-tests
    Comparison groups
    Xaluprine (liquid formulation of 6-mercaptopurine) v Purinethol (tablet version of 6-mercaptopurine)
    Number of subjects included in analysis
    32
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority
    P-value
    		 < 0.05
    Method
    		 t-test, 1-sided
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         sides
    2-sided
         lower limit
    		 0.8
         upper limit
    		 1.25
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Upon leaving the trial unit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Frequency threshold for reporting non-serious adverse events: 0.01%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: As this was a small study, with only 17 participants and a short timeframe, no non-serious adverse events were reported.

    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/32519032
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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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