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    Clinical Trial Results:
    Pilot study to investigate the feasibility of 13-cis-Retinoic acid pharmacokinetic monitoring in high-risk neuroblastoma

    Summary
    EudraCT number
    		 2008-003606-33
    Trial protocol
    		 GB  
    Global end of trial date
    19 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2019
    First version publication date
    29 Mar 2019
    Other versions
    Summary report(s)
    		 Adaptive dosing approaches to the individualization of 13-cis-retinoic acid (isotretinoin) treatment for children with high-risk neuroblastoma

    Trial information

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    Trial identification
    Sponsor protocol code
    PK 2008 03
    Additional study identifiers
    ISRCTN number
    		 ISRCTN37126758
    US NCT number
    		 NCT00939965
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Newcastle Upon Tyne Hospitals NHS Foundation Trust
    Sponsor organisation address
    Level 1, Regent Point, Regent Farm Road, Newcastle upon Tyne, United Kingdom, NE3 3HD
    Public contact
    Prof. Gareth J Veal, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, 44 01912084332, g.j.veal@newcastle.ac.uk
    Scientific contact
    Prof. Gareth J Veal, Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, NE2 4HH, 44 01912084332, g.j.veal@newcastle.ac.uk
    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 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study is designed as a pilot study to: •Investigate the feasibility of implementing 13-cis-Retinoic acid dose modification following course 1 of treatment, based on targeted 13-cis-Retinoic acid plasma concentrations and observed toxicity. • Minimize the large inter-patient variation in plasma concentrations of 13-cis-Retinoic acid observed following standard treatment for high-risk neuroblastoma. This will ensure that patients are not exposed to potentially sub-optimal plasma concentrations of 13-cis-RA during long-term treatment, particularly for those children who are not able to swallow 13-cis-RA capsules. • Obtain preliminary data investigating the potential impact of 13-cis-RA therapeutic monitoring on clinical response and toxicity in children with high-risk neuroblastoma
    Protection of trial subjects
    Patients receiving the IMP were doing so as part of their standard clinical treatment. Blood volumes for samples taken as part of this trial were kept to a minimum and were taken from the patients central line to minimise pain and distress. Where possible PK samples were taken at the same time as clinical samples to keep discard volumes to a minimum. Participants received age specific participant information sheets so they understood what taking part in the trial involved.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jul 2009
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 75
    Worldwide total number of subjects
    75
    EEA total number of subjects
    75
    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)
    9
    Children (2-11 years)
    65
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period 17/07/2009 to 05/03/2012 UK wide (NHS Sites only).

    Pre-assignment
    Screening details
    		 Patients screened by their treating clinician/research nurses as they reach their 13-cis-retinoic acid treatment period (standard care) against the inclusion criteria stated in the protocol. Patients only excluded during screening if they fail to meet the study inclusion criteria.

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

    Arms
    Arm title
    		 Overall trial
    Arm description
    		 Overall trial
    Arm type
    		 Experimental

    Investigational medicinal product name
    Roaccutane
    Investigational medicinal product code
    Other name
    13-cis-retinoic acid, Isotretinoin
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Maximum dose 240mg/m2/day. Start dose 160mg/m2/day given over 2 divided doses for 14 days followed by 14 days drug free (1 cycle), typically 6 cycles of treatment. Dose adjustments were carried out on cycle 2 with dose increases of 25% and 50% in patients with peak plasma concentrations of <2.0µM and <1.0µM respectively. Children less than 12kg received a reduced starting dose of 5.33mg/kg/day.

    Number of subjects in period 1
    		Overall trial
    Started
    75
    Completed
    75

    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
    		 75 75
    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)
    		 9 9
        Children (2-11 years)
    		 65 65
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 1 1
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 26 26
        Male
    		 49 49

    End points

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    End points reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 Overall trial

    Primary: Quantification of Roaccutane plasma levels

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    End point title
    		 Quantification of Roaccutane plasma levels [1]
    End point description
    End point type
    Primary
    End point timeframe
    Drug levels measured on multiple courses of treatment for each patient until target level reached
    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: End point was determined by a defined cut off point which patients fell either above or below. No statistical analysis directly related to the primary endpoint required.
    End point values
    		 Overall trial
    Number of subjects analysed
    75 [2]
    Units: µM
        number (not applicable)
    75
    Notes
    [2] - Values obtained for all patients
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Per patient - from start of recruitment to 1 month after final cycle of treatment for which PK monitoring is carried out.
    Adverse event reporting additional description
    Only adverse events directly related to PK sampling were collected for this trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 NCI CTC
    Dictionary version
    4
    Frequency threshold for reporting non-serious adverse events: 5%
    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: There were no reported non serious adverse events recorded. Only adverse events related to PK sampling from the central line are required to be reported. All other AE's are reported via the main clinical trial the patient is being treated on.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Oct 2009
    Change of sponsor from University Hospitals of Leicester NHS Trust to Newcastle upon Tyne Hospitals NHS Foundation Trust. Change in study sponsor accompanied by change in study management to the Northern Institute for Cancer Research, Newcastle University from the CCLG Data Centre in Leicester. Protocol changes relate to change of sponsor and study management only (New protocol version 2.0).
    29 Jun 2010
    Change of Principal Investigator at Birmingham Children's Hospital. No changes to protocol.
    26 Jul 2010
    Change of Principal Investigator at Nottingham University Hospitals. No changes to protocol.
    15 Aug 2011
    Addition of a new site, the Royal Hospital for Sick Children, Edinburgh and new Principal Investigator. No changes to protocol.
    15 Mar 2012
    Change of Principal Investigator at Southampton University Hospital NHS Foundation Trust. No changes to protocol.

    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/23087409
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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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