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    Clinical Trial Results:
    Pilot dose conversion study of extended release tacrolimus, Envarsus from standard twice daily tacrolimus in paediatric renal transplant recipients.

    Summary
    EudraCT number
    		 2018-003595-13
    Trial protocol
    		 GB  
    Global end of trial date
    31 Jan 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    08 Feb 2024
    First version publication date
    08 Feb 2024
    Other versions
    Summary report(s)
    		 Abstract

    Trial information

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    Trial identification
    Sponsor protocol code
    17CS079
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Nottingham University Hospitals NHS Trust
    Sponsor organisation address
    Derby Road, Nottingham, United Kingdom, NG7 2UH
    Public contact
    Dr Jon Jin Kim, Nottingham University Hospitals NHS Trust, jonjin.kim@nuh.nhs.uk
    Scientific contact
    Dr Jon Jin Kim, Nottingham University Hospitals NHS Trust, jonjin.kim@nuh.nhs.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
    20 Oct 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This pilot study aims to provide dosing guidelines for the conversion of twice daily preparations of tacrolimus to Envarsus. To do this, we will compare pharmacokinetics of Envarsus to standard twice daily tacrolimus. The following values will be obtained: 1) Maximum concentration (Cmax) 2) Time to maximum concentration (Tmax) 3) 24 hour area under the curve (AUC)
    Protection of trial subjects
    Participants complied with the study protocol. Serious adverse events were reported and assessed according to stipulated time frames. Study was monitored by the data monitoring committee.
    Background therapy
    		 Patients continued all other concomittent medication including other immunosuppression as directed by the medical care team.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Jan 2020
    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: 5
    Worldwide total number of subjects
    5
    EEA total number of subjects
    0
    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)
    0
    Adolescents (12-17 years)
    5
    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
    		 13 patients were screened and 7 patients consented. 2 patients did not proceed to the trial: 1 patient passed the age of 18 when the trial was paused during COVID-19 pandemic. 1 patient (under 11 years of age) developed unstable kidney function before any trial procedures (other than consenting) and did not start the study.

    Pre-assignment
    Screening details
    		 13 patients were screened by the direct care medical team based on review of hospital records.

    Period 1
    Period 1 title
    Twice daily tacrolimus
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Twice daily tacrolimus
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tacrolimus (immediate release)
    Investigational medicinal product code
    Other name
    Adoport
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Baseline dose based on current management by direct care team.

    Number of subjects in period 1
    		Twice daily tacrolimus
    Started
    5
    Completed
    5
    Period 2
    Period 2 title
    Extended release tacrolimus
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Extended release tacrolimus
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tacrolimus, prolonged release
    Investigational medicinal product code
    L04AD02
    Other name
    Envarsus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants switched from twice daily tacrolimus to prolonged release tacrolimus based on the total daily dose ratio of 1:0.7 respectively.

    Number of subjects in period 2
    		Extended release tacrolimus
    Started
    5
    Completed
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Twice daily tacrolimus
    Reporting group description
    		 -

    Reporting group values
    		 Twice daily tacrolimus Total
    Number of subjects
    		 5 5
    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)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Age at study entry
    Units: years
        median (full range (min-max))
    		 15 (11 to 17) -
    Gender categorical
    Units: Subjects
        Female
    		 4 4
        Male
    		 1 1
    Time post-transplant
    Units: Years
        median (full range (min-max))
    		 5 (1 to 11) -

    End points

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    End points reporting groups
    Reporting group title
    Twice daily tacrolimus
    Reporting group description
    		 -
    Reporting group title
    Extended release tacrolimus
    Reporting group description
    		 -

    Primary: Maximum concentration (Cmax)

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    End point title
    		 Maximum concentration (Cmax) [1]
    End point description
    End point type
    Primary
    End point timeframe
    Pharmacokinetic study was performed at baseline on twice daily tacrolimus and after stable drug levels on extended release tacrolimus.
    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: No statistical comparisons were performed (as stated in the protocol) as this was a pilot study.
    End point values
    		 Twice daily tacrolimus Extended release tacrolimus
    Number of subjects analysed
    5
    5
    Units: ng/ml
        geometric mean (geometric coefficient of variation)
    14.4 ± 46.9
    9.9 ± 49.3
    No statistical analyses for this end point

    Primary: Time to maximum concentration (Tmax)

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    End point title
    		 Time to maximum concentration (Tmax) [2]
    End point description
    End point type
    Primary
    End point timeframe
    As previous
    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: No statistical comparisons were performed (as stated in the protocol) as this was a pilot study.
    End point values
    		 Twice daily tacrolimus Extended release tacrolimus
    Number of subjects analysed
    5
    5
    Units: ng/ml
        median (full range (min-max))
    1 (1 to 4)
    5 (3 to 8)
    No statistical analyses for this end point

    Primary: Area under the curve (24 hour)

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    End point title
    		 Area under the curve (24 hour) [3]
    End point description
    End point type
    Primary
    End point timeframe
    As previous
    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: No statistical comparisons were performed (as stated in the protocol) as this was a pilot study.
    End point values
    		 Twice daily tacrolimus Extended release tacrolimus
    Number of subjects analysed
    5
    5
    Units: ng/ml
        geometric mean (geometric coefficient of variation)
    164 ± 27.8
    141 ± 46.5
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Patients were followed up for 6 months after conversion.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    Post conversion to prolonged release formulation
    Reporting group description
    		 -

    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: No non-serious adverse reports (new or worsening of symptoms) were reported by subjects. There were no episodes of rejection or worsening of kidney function, though these were prespecified in the protocol as not included in the adverse event reporting as they ar part of the secondary study outcomes.
    Serious adverse events
    		 Post conversion to prolonged release formulation
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 5 (20.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Renal and urinary disorders
    Paraphimosis
    Additional description: Self-admission to hospital for episode of para-phimosis.
         subjects affected / exposed
    1 / 5 (20.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Post conversion to prolonged release formulation
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)

    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? Yes
    Date
    Interruption
    Restart date
    23 Mar 2020
    Study was paused due to COVID-19.
    09 Sep 2020

    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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