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    Clinical Trial Results:
    A Phase I Pharmacokinetic Profiling Study in Patients Receiving Trientine Dihydrochloride for the Treatment of Wilson’s Disease

    Summary
    EudraCT number
    		 2012-004445-32
    Trial protocol
    		 DE  
    Global end of trial date
    06 Mar 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    18 Feb 2016
    First version publication date
    18 Feb 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TR-001PK
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Univar BV
    Sponsor organisation address
    Bramley Road, Milton Keynes, United Kingdom, MK1 1PT
    Public contact
    Trientine Enquiries, Univar BV, +44 0845202 6401, Trientine@univareurope.com
    Scientific contact
    Trientine Enquiries, Univar BV, +44 0845202 6401, Trientine@univareurope.com
    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
    06 Mar 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    06 Mar 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    06 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacokinetics of a single dose of trientine in children ≥6 years and adult patients with Wilson’s disease by pharmacokinetic (PK) analysis.
    Protection of trial subjects
    Participation in the study was voluntary and subject to the required patient information and consent procedures. The PIS clearly explained the trial procedures if he/she was to take part. All trial participants were existing Wilson Disease patients, who were used to the need for blood draws as part of their care. IP administered on Day 1 was the patients' usual prescribed dose. All patients received close care and monitoring for the duration of the study and beyond in line with their routine treatment plan.
    Background therapy
    		 Background therapy not applicable.
    Evidence for comparator
    		 Comparator(s) not applicable.
    Actual start date of recruitment
    04 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
    Germany: 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)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    4
    Adults (18-64 years)
    16
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Pre-screening processes were in place for all patients who did and did not visit the site regularly for the PI to select eligible patients who were to be invited to participate in the study.

    Pre-assignment
    Screening details
    		 Principle screening criteria were patients with confirmed Wilson disease (Leipzig score>3), aged ≥ 6 years, whose current treatment was trientine dihydrochloride.

    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
    		 Trientine dihydrochloride 300mg
    Arm description
    		 -
    Arm type
    		 Profiling arm

    Investigational medicinal product name
    Trientine dihydrochloride 300mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Patients took their usual prescribed dose (1 dose to be taken on the morning of the study visit).

    Number of subjects in period 1
    		Trientine dihydrochloride 300mg
    Started
    20
    Completed
    20

    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
    		 20 20
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 4 4
        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)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adults (18-64 years)
    		 16 16
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 11 11
        Male
    		 9 9

    End points

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    End points reporting groups
    Reporting group title
    Trientine dihydrochloride 300mg
    Reporting group description
    		 -

    Primary: Maximum plasma drug concentration level (Cmax) and normalised for dose (Cmax/D)

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    End point title
    		 Maximum plasma drug concentration level (Cmax) and normalised for dose (Cmax/D) [1]
    End point description
    The maximum plasma concentration (Cmax) for each subject was derived directly from their plasma concentration-time profiles. Dose-normalised parameters were generated by dividing the Cmax and the area under the plasma concentration time curve from zero to the last quantifiable concentration in the profile (AUC 0-t) by the nominal dose of trientine dihydrochloride received by the subject.
    End point type
    Primary
    End point timeframe
    Sampling pre-dose (30 mins before drug intake), then at 30 mins, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 h post dose
    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: The object of the study was to determine Pharmacokinetic variables
    End point values
    		 Trientine dihydrochloride 300mg
    Number of subjects analysed
    20
    Units: ng/mL
    arithmetic mean (standard deviation)
        Cmax
    1274.9 ± 707.27
        Cmax/D
    1.937 ± 1.0801
    No statistical analyses for this end point

    Primary: Time to maximum plasma concentration (Tmax) and terminal elimination half-life (t½)

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    End point title
    		 Time to maximum plasma concentration (Tmax) and terminal elimination half-life (t½) [2]
    End point description
    The time to maximum plasma drug concentration was derived directly from the patient's plasma concentration-time profile. The t½ is calculated from the equation t½ = 0.693/ λz (λz = terminal elimination rate constant).
    End point type
    Primary
    End point timeframe
    Sampling pre-dose (30 mins before drug intake), then 30 mins, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 h post dose
    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: The object of the study was to determine Pharmacokinetic variables
    End point values
    		 Trientine dihydrochloride 300mg
    Number of subjects analysed
    20 [3]
    Units: hours
    arithmetic mean (standard deviation)
        Tmax
    1.738 ± 1.06
        t½
    3.772 ± 1.2775
    Notes
    [3] - Available observations for Tmax = 20 Available observations for t½ = 14
    No statistical analyses for this end point

    Primary: Area under the plasma concentration-time curve from zero to the last quantifiable concentration (AUC0-t); Area under the plasma concentration-time curve from zero to infinite time (AUC0-inf); AUC0-t normalised for dose (AUC0-t/D)

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    End point title
    		 Area under the plasma concentration-time curve from zero to the last quantifiable concentration (AUC0-t); Area under the plasma concentration-time curve from zero to infinite time (AUC0-inf); AUC0-t normalised for dose (AUC0-t/D) [4]
    End point description
    AUC0-t was calculated by the linear trapezoidal rule between increasing concentrations and the logarithmic trapezoidal rule between decreasing concentrations. A minimum of 3 quantifiable time points in the plasma concentration-time profile were required for generation of the AUC0-t. AUC0-inf was calculated using the formula AUC0-t + Ct/λz , with C being the last quantifiable plasma concentration in the profile. AUC0-t/D was calculated by dividing the AUC0-t by the nominal dose of trientine dihydrochloride received by the subject.
    End point type
    Primary
    End point timeframe
    Sampling pre-dose (30 mins before drug intake), then at 30 mins, 1, 1.5, 2, 3, 4, 5, 6, 8, 12 h post dose.
    Notes
    [4] - 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: The object of the study was to determine Pharmacokinetic variables
    End point values
    		 Trientine dihydrochloride 300mg
    Number of subjects analysed
    20 [5]
    Units: ng/mL.h
    arithmetic mean (standard deviation)
        AUC0-t
    5075.5 ± 3633.56
        AUC0-inf
    5942.1 ± 4054.45
        AUC0-t/D
    7.624 ± 4.7302
    Notes
    [5] - Observations for AUC0-t = 20 Observations for AUC0-inf = 14 Observations for AUC0-t/D = 20
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Overall trial period
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16
    Frequency threshold for reporting non-serious adverse events: 0%
    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: Due to the nature and duration of this study, no adverse events (serious or otherwise) 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
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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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