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    Clinical Trial Results:
    Relative bioavailability and comparative pharmacokinetics of 13-CRA oral liquid and extracted capsule formulations: a randomised, open label, multi-dose, cross-over clinical trial in patients requiring treatment cycles of 13-CRA.

    Summary
    EudraCT number
    		 2016-005104-25
    Trial protocol
    		 GB  
    Global end of trial date
    13 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Dec 2020
    First version publication date
    30 Dec 2020
    Other versions
    Summary report(s)
    		 Medical Journal Manuscript
    Supplement file 1
    Supplement file 2

    Trial information

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    Trial identification
    Sponsor protocol code
    INV500
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03291080
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Nova Labs Ltd
    Sponsor organisation address
    Gloucester Crescent, Leicester, United Kingdom, LE184YL
    Public contact
    Project Manager / Head of Clinical , Nova BioPharma Limited, 44 0116 2230100, hussain.mulla@novalabs.co.uk
    Scientific contact
    Project Manager / Head of Clinical , Nova BioPharma Limited, 44 0116 2230100, hussain.mulla@novalabs.co.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
    31 Jan 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine how 13-CRA is absorbed into the body, to what extent, and how it is handled in the body, when it is administered using the new liquid formulation and the current 'extract from capsule' method.
    Protection of trial subjects
    This was a low intervention study requiring only blood samples for measurement of pharmacokinetics.
    Background therapy
    		 Neuroblastoma treatment protocols involve multiple chemotherapy agents. IN the maintenance phase, 13-CRA is administered with immunotherapy (anti-GD2 monoclonal antobodies) e.g. Dinutuximab
    Evidence for comparator
    		 This was a relative bioavialbility and PK study to evaluate a new liquid formulation of oral 13-CRA. The appropriate comparator was 13-CRA capsule (isotretinoin) which is approved in the community.
    Actual start date of recruitment
    01 Jan 2018
    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: 20
    Worldwide total number of subjects
    20
    EEA total number of subjects
    20
    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)
    18
    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
    		 All children recruited in UK hospitals. Date of first consent: 07 June 2018 Date of firs enrolment: 09 July 2018 Date of last completed: 13 Sept 2019

    Pre-assignment
    Screening details
    		 When the patient attended the hospital clinic for initiation fo 13-CRA treatment, the parents/legal guardians of the patient was approached to discuss the possibility of the child's entry into the trial.

    Pre-assignment period milestones
    Number of subjects started
    		 20
    Number of subjects completed
    		 20

    Period 1
    Period 1 title
    Cycle 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Test oral liquid
    Arm description
    		 Dosing with oral liquid 13-CRA
    Arm type
    		 Experimental

    Investigational medicinal product name
    13-cis-retinoic acid
    Investigational medicinal product code
    Other name
    isotretinoin
    Pharmaceutical forms
    Oral liquid
    Routes of administration
    Oral use
    Dosage and administration details
    160mg/m2/ per day in two divided doses (morning and evening)

    Number of subjects in period 1
    		Test oral liquid
    Started
    20
    Completed
    20
    Period 2
    Period 2 title
    Cycle 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Oral 13-CRA capsule
    Arm description
    		 Reference 13-CRA capsule
    Arm type
    		 Active comparator

    Investigational medicinal product name
    13-cis retinoic acid
    Investigational medicinal product code
    Other name
    isotretinoin
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    160mg/m2/day in two divided doses (morning and evening)

    Number of subjects in period 2
    		Oral 13-CRA capsule
    Started
    20
    Completed
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Test oral liquid
    Reporting group description
    		 Dosing with oral liquid 13-CRA

    Reporting group values
    		 Test oral liquid Total
    Number of subjects
    		 20 20
    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)
    		 18 18
        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
    		 5 5
        Male
    		 15 15

    End points

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    End points reporting groups
    Reporting group title
    Test oral liquid
    Reporting group description
    		 Dosing with oral liquid 13-CRA
    Reporting group title
    Oral 13-CRA capsule
    Reporting group description
    		 Reference 13-CRA capsule

    Primary: Pharmacokinetics

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    End point title
    		 Pharmacokinetics
    End point description
    End point type
    Primary
    End point timeframe
    PK parameters estimated at the end of the study once all patients had completed treatment.
    End point values
    		 Test oral liquid Oral 13-CRA capsule
    Number of subjects analysed
    20
    20 [1]
    Units: Relative bioavailability
        geometric mean (confidence interval 95%)
    65 (54 to 77)
    0 (0 to 0)
    Notes
    [1] - cross-over pooled analysis
    Statistical analysis title
    		 Mean difference in AUC
    Statistical analysis description
    Difference in the mean AUC between the formulations (oral liquid and capsule)
    Comparison groups
    Test oral liquid v Oral 13-CRA capsule
    Number of subjects included in analysis
    40
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 < 0.01
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3933
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2020
         upper limit
    		 5846

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AE was collected in the clinic, for the 14 days that the patient received the medication at home, for 14 (+7) days between dosing cycles and for the 14 days from the time of the last dose after cycle 2.
    Adverse event reporting additional description
    Trial site personnel reported any AE, whether observed by the research staff or reported by the patient or recorded in the diary card. Oropharyngeal tolerability was assessed at baseline and following dosing until the patient completed the trial. Any local clinically relevant changes were recorded as adverse events.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.1
    Reporting groups
    Reporting group title
    All subjects
    Reporting group description
    		 -

    Serious adverse events
    		 All subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 20 (5.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Haematemesis
         subjects affected / exposed
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 All subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 20 (90.00%)
    Gastrointestinal disorders
    Chapped lips
         subjects affected / exposed
    18 / 20 (90.00%)
         occurrences all number
    85

    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
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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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