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    Clinical Trial Results:
    A Multi Center, Prospective, Observational, Open-label, Pharmacokinetic Study of Tacrolimus in Heart and Lung Transplantation Patients during the First Days after Transplantation

    Summary
    EudraCT number
    		 2012-001909-24
    Trial protocol
    		 NL  
    Global end of trial date
    15 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    11 Aug 2021
    First version publication date
    11 Aug 2021
    Other versions
    Summary report(s)
    		 A Multi Center, Prospective, Observational, Open-label, Pharmacokinetic Study of Tacrolimus in Heart and Lung Transplantation Patients during the First Days after Transplantation
    analysis unbound tacrolimus concentrations
    NONMEM model unbound tacrolimus concentrations
    European Journal of Drug Metabolism and Pharmacokinetics (2020) 45:123–134

    Trial information

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    Trial identification
    Sponsor protocol code
    Spartacus/007
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 National Trial registration: NTR3912
    Sponsors
    Sponsor organisation name
    University Medical Center Utrecht
    Sponsor organisation address
    Heidelberglaan 100, Utrecht, Netherlands, 3584 CX
    Public contact
    Dutch Poisons Information Center, University Medical Center Utrecht, 0031 8875585611, m.a.sikma@umcutrecht.nl
    Scientific contact
    Dutch Poisons Information Center, University Medical Center Utrecht, 0031 8875585611, m.a.sikma@umcutrecht.nl
    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
    15 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Sep 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To show that the variability of whole blood trough and unbound plasma tacrolimus concentrations during the first 6 days post transplantation is larger than the variability of tacrolimus concentrations in stable clinical situation.
    Protection of trial subjects
    This study was an observational study.
    Background therapy
    		 Tacrolimus is an immunosuppressant used in solid organ transplantation for prevention of rejection.
    Evidence for comparator
    		 No comparator.
    Actual start date of recruitment
    06 May 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
    Netherlands: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    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)
    0
    Adults (18-64 years)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Thirty transplantation patients are studied. Ten heart transplant recipients and 20 lung transplant recipients, of which 10 cystic fibrosis patients, are analyzed as planned.

    Pre-assignment
    Screening details
    		 Each heart and lung transplantation patient fulfilling all of the inclusion criteria and none of the exclusion criteria are included after the nature and purpose of the investigation is explained to them, and they all have signed a study specific informed consent form.

    Pre-assignment period milestones
    Number of subjects started
    		 30
    Intermediate milestone: Number of subjects
    inclusion: 30
    Number of subjects completed
    		 30

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

    Arms
    Arm title
    		 baseline characteristics
    Arm description
    		 baseline characteristics
    Arm type
    		 observation

    Investigational medicinal product name
    tacrolimus
    Investigational medicinal product code
    L04AD02
    Other name
    prograft
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    The tacrolimus dose is adjusted by the attending physicians according to the trough tacrolimus blood concentration measured the previous day at 6 am.

    Number of subjects in period 1
    		baseline characteristics
    Started
    30
    Completed
    30
    Period 2
    Period 2 title
    end data
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 end data
    Arm description
    		 Observation of tacrolimus blood concentrations
    Arm type
    		 observation

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		end data
    Started
    30
    Completed
    30

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    baseline characteristics
    Reporting group description
    		 Mean age 43 (IQR 34;60), Male 15 (50%), bodyweight 73.5 kg (IQR 61;86), heart transplants 10 (ischemic cardiomyopathy 5, non-ischemic cardiomyopathy 5), lung transplants 20 (Cystic fibrosis 10 , COPD 4, ILD 6, Double lung transplantation 18), mean SOFA score 7 (IQR 4;12), SIRS at least once between days 1 and 6 30 (100%), SIRS duration (days) 4.5 (3;6), Gut dysmotility frequency 29 (96.7%), percentage Ileus at least once between days 1 and 6 27 (90%), Ileus duration 2 days (IQR 2; 3), Diarrhea at least once between days 1 and 6 18 (60%), Diarrhea duration 1 day (IQR 0;2), Postoperative ECMO frequency 8 (27%), Postoperative ECMO duration (days) 4 (2;6). Tacrolimus, Tacrolimus C12 h (ng/ml) (min–max) 9.5 (0.5–38.7), Cmax (ng/ml) 18.5 (2.1–74.7), Tmax (h) 1.6 (0.4–8.0), AUC (ng·h/mL) 151.2 (31.2–2525), T1/2 (h) 9.4 (6.0–31.4)

    Reporting group values
    		 baseline characteristics Total
    Number of subjects
    		 30 30
    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)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 30 30
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Data are collected at study entry
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 43.7 (34.3 to 59.1) -
    Gender categorical
    Units: Subjects
        male
    		 15 15
        female
    		 15 15
        not recorded
    		 0 0
    gender
    Units: Subjects
        male
    		 15 15
        female
    		 15 15
    Subject analysis sets

    Subject analysis set title
    transplantation patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    10 heart and 20 lung transplantation patients

    Subject analysis sets values
    		 transplantation patients
    Number of subjects
    30
    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)
    30
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Data are collected at study entry
    Units: years
        median (inter-quartile range (Q1-Q3))
    Gender categorical
    Units: Subjects
        male
    15
        female
    15
        not recorded
    gender
    Units: Subjects
        male
    15
        female
    15

    End points

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    End points reporting groups
    Reporting group title
    baseline characteristics
    Reporting group description
    		 baseline characteristics
    Reporting group title
    end data
    Reporting group description
    		 Observation of tacrolimus blood concentrations

    Subject analysis set title
    transplantation patients
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    10 heart and 20 lung transplantation patients

    Primary: variability of tacrolimus blood concentrations

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    End point title
    		 variability of tacrolimus blood concentrations
    End point description
    End point type
    Primary
    End point timeframe
    First 6 days after heart and lung transplantation
    End point values
    		 baseline characteristics end data transplantation patients
    Number of subjects analysed
    30
    30
    30
    Units: ng/ml
        median (inter-quartile range (Q1-Q3))
    9.5 (0.5 to 38.7)
    9.5 (0.5 to 38.7)
    9.5 (0.5 to 38.7)
    Attachments
    		 Untitled (Filename: Table 1.docx)
    Statistical analysis title
    		 Population pharmacokinetic modelling
    Statistical analysis description
    nonlinear mixed effects modelling software tool NONMEM (version 7.3.0) A two-compartment linear model with first-order oral absorption was used
    Comparison groups
    baseline characteristics v end data v transplantation patients
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    Method
    		 Mixed models analysis
    Parameter type
    		 variability %
    Point estimate
    0.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.05
         upper limit
    		 97.5
    Variability estimate
    Standard error of the mean
    Notes
    [1] - nonlinear mixed effects modelling software tool NONMEM (version 7.3.0) A two-compartment linear model with first-order oral absorption The modelling process was performed using the stochastic approximation expectation maximisation (SAEM) estimation method with interaction. The likelihood was subsequently established using the Monte Carlo importance sampling EM assisted by mode a posteriori (IMPMAP) estimation method. Parameter precision was estimated using the SIR (sampling importance res

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Once per 6 months
    Adverse event reporting additional description
    No adverse events were reported because of insertion of an arterial line or blood sampling from an arterial line
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    transplantation patients
    Reporting group description
    		 all patients treated with tacrolimus

    Serious adverse events
    		 transplantation patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 transplantation patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 30 (96.67%)
    Blood and lymphatic system disorders
    anemia
    Additional description: Hb <6 mmol/L
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    6
    Endocrine disorders
    Electrolyte imbalance
    Additional description: hypophosphatemia, hypomagnesemia, hypokalemia, hypernatremia
         subjects affected / exposed
    16 / 30 (53.33%)
         occurrences all number
    16
    Hypoproteinaemia
    Additional description: Albumin < 30 g/L
         subjects affected / exposed
    7 / 30 (23.33%)
         occurrences all number
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Apr 2012
    The study changed from single center to multi center for optimizing inclusion of patients

    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.
    No study violations or deviations are made. All patients fulfilled the entry criteria. Yet, results are analyzed and cannot be shown.
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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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