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    Clinical Trial Results:
    Combined drug Approach to Prevent Ischemia-reperfusion injury during Transplantation of Livers (CAPITL): a first-in-men study

    Summary
    EudraCT number
    		 2012-001960-31
    Trial protocol
    		 BE  
    Global end of trial date
    14 Feb 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Mar 2023
    First version publication date
    28 Mar 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    S54348
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02251041
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UZLeuven
    Sponsor organisation address
    Herestraat 49, Leuven, Belgium,
    Public contact
    Diethard Monbaliu, UZ Leuven, +32 (0)16342361, diethard.monbaliu@uzleuven.be
    Scientific contact
    Diethard Monbaliu, UZ Leuven, +32 (0)16342361, diethard.monbaliu@uzleuven.be
    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
    14 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Feb 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Feb 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate - the safety of the drug combination/multifactorial modulation - the effectiveness of the drug combination/multifactorial modulation in reducing the peak of aspartate amino transferase (AST) – a surrogate marker of ischemia-reperfusion injury (IRI) - after liver transplantation.
    Protection of trial subjects
    Trial subjects were monitored closely in the first days after intervention.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    11 Aug 2014
    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
    Belgium: 72
    Worldwide total number of subjects
    72
    EEA total number of subjects
    72
    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)
    45
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Adults waitlisted for a first solitary full-size liver transplantation were considered for enrollment at the time of liver offer. Each patient participating in the trial gave his/her informed consent prior to entry into the trial.

    Pre-assignment
    Screening details
    		 Out of 310 screened subjects, 93 were found eligible, enrolled and randomized; 21 subjects were excluded (1 screen failure, 20 technical failures), resulting in 36 subjects per study arm.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 combined drug approach
    Arm description
    		 In the study arm, a combined-drug approach was given in addition to standard-of-care: following static cold preservation, donor livers were infused with epoprostenol (ex-situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia, and intravenous anti-thrombin-III, infliximab, apotransferrin, recombinant erythropoietin-β, c1-inhibitor and glutathione during the anhepatic and reperfusion phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    C1-inhibitor
    Investigational medicinal product code
    Other name
    Cetor, Cinryze®
    Pharmaceutical forms
    Powder for solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 1000 U Way and duration of administration: IV – 5 minutes Timing of administration: 10 minutes before reperfusion

    Investigational medicinal product name
    Antithrombin III
    Investigational medicinal product code
    Other name
    Atenativ®
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 3000 IU Way and duration of administration: IV – 15 minutes Timing of administration: Start of anhepatic phase

    Investigational medicinal product name
    EPO-β
    Investigational medicinal product code
    Other name
    Neorecormon®
    Pharmaceutical forms
    Solution for injection/infusion in pre-filled syringe
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 30.000 IU + 30.000 IU Way and duration of administration: IV – 2 minutes Timing of administration: 13-15 minutes before reperfusion + 6 hours after reperfusion

    Investigational medicinal product name
    Melatonin
    Investigational medicinal product code
    Other name
    Circadin®
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Dosage: 6 mg Way of administration: orally Timing of administration: on the ward before the transplantation

    Investigational medicinal product name
    Epoprostenol
    Investigational medicinal product code
    Other name
    Flolan®
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intrahepatic use
    Dosage and administration details
    Dose: 500 µg Way of administration: Flush through the vena porta during the bench table Timing of administration: Ex-situ during the bench table before the implantation

    Investigational medicinal product name
    Glutathione
    Investigational medicinal product code
    Other name
    Tationil 600®
    Pharmaceutical forms
    Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 3 g Way and duration of administration: IV – 2 minutes Timing of administration: 2-4 minutes before reperfusion

    Investigational medicinal product name
    Infliximab
    Investigational medicinal product code
    Other name
    Remicade®
    Pharmaceutical forms
    Powder for concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 3 mg/Kg Way and duration of administration: IV – 3 hours Timing of administration: Start of anhepatic phase after infusion of Antihrombin III; Interruption of the infusion during the administration of Glutathione; Restarted 15 minutes after reperfusion

    Investigational medicinal product name
    Vitamin E suspension
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 500 mg Way of administration: Orally Timing of administration: On the ward before the transplantation

    Investigational medicinal product name
    Apotransferrin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dose: 170 mg/kg Way and duration of administration: IV – 3 hours Timing of administration: Start of anhepatic phase; Interruption for sequential administration of erythropoietin, C1-inhibitor and Glutathione; Restarted 15 minutes after reperfusion

    Arm title
    		 Control group
    Arm description
    		 Standard of Care
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		combined drug approach Control group
    Started
    36
    36
    Completed
    32
    33
    Not completed
    4
    3
         Adverse event, serious fatal
    4
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    combined drug approach
    Reporting group description
    		 In the study arm, a combined-drug approach was given in addition to standard-of-care: following static cold preservation, donor livers were infused with epoprostenol (ex-situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia, and intravenous anti-thrombin-III, infliximab, apotransferrin, recombinant erythropoietin-β, c1-inhibitor and glutathione during the anhepatic and reperfusion phase.

    Reporting group title
    Control group
    Reporting group description
    		 Standard of Care

    Reporting group values
    		 combined drug approach Control group Total
    Number of subjects
    		 36 36 72
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 28 28 56
        From 65-84 years
    		 8 8 16
        85 years and over
    		 0 0 0
    Age continuous
    Adults aged 18 years or older, who were waitlisted for a first solitary full-size liver transplantation and who consented in writing to the study when entering the waiting list, were screened for eligibility at the time of liver offer.
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 57 (45.5 to 70) 59 (48 to 67.5) -
    Gender categorical
    Units: Subjects
        Female
    		 9 11 20
        Male
    		 27 25 52

    End points

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    End points reporting groups
    Reporting group title
    combined drug approach
    Reporting group description
    		 In the study arm, a combined-drug approach was given in addition to standard-of-care: following static cold preservation, donor livers were infused with epoprostenol (ex-situ, portal vein); recipients were given oral α-tocopherol and melatonin prior to anesthesia, and intravenous anti-thrombin-III, infliximab, apotransferrin, recombinant erythropoietin-β, c1-inhibitor and glutathione during the anhepatic and reperfusion phase.

    Reporting group title
    Control group
    Reporting group description
    		 Standard of Care

    Primary: Peak AST

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    End point title
    		 Peak AST
    End point description
    End point type
    Primary
    End point timeframe
    Peak AST within the first 72 hours following reperfusion
    End point values
    		 combined drug approach Control group
    Number of subjects analysed
    36
    36
    Units: U/L
        geometric mean (confidence interval 95%)
    1262.9 (946.3 to 1685.4)
    1451.2 (1097.4 to 1936.7)
    Statistical analysis title
    		 Linear regression model
    Comparison groups
    combined drug approach v Control group
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Regression, Linear
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Within 1 year post transplantation
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Physician's wording
    Dictionary version
    0
    Reporting groups
    Reporting group title
    combined drug approach
    Reporting group description
    		 -

    Reporting group title
    Control group
    Reporting group description
    		 -

    Serious adverse events
    		 combined drug approach Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 36 (16.67%)
    4 / 36 (11.11%)
         number of deaths (all causes)
    4
    3
         number of deaths resulting from adverse events
    4
    3
    Injury, poisoning and procedural complications
    Bleeding time abnormal
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical failure
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Arrhythmia
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Renal failure
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 1
    0 / 2
    Respiratory failure
         subjects affected / exposed
    1 / 36 (2.78%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Portal vein thrombosis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 combined drug approach Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 36 (100.00%)
    36 / 36 (100.00%)
    Injury, poisoning and procedural complications
    Bleeding
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    other surgical complications
         subjects affected / exposed
    7 / 36 (19.44%)
    3 / 36 (8.33%)
         occurrences all number
    7
    3
    Cardiac disorders
    Cardiac failure
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Arrhythmia
         subjects affected / exposed
    5 / 36 (13.89%)
    4 / 36 (11.11%)
         occurrences all number
    5
    4
    General disorders and administration site conditions
    Renal impairment
         subjects affected / exposed
    9 / 36 (25.00%)
    10 / 36 (27.78%)
         occurrences all number
    9
    10
    Pleural effusion
         subjects affected / exposed
    3 / 36 (8.33%)
    4 / 36 (11.11%)
         occurrences all number
    3
    4
    Urinary tract infection
         subjects affected / exposed
    3 / 36 (8.33%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    Respiratory insufficiency
         subjects affected / exposed
    1 / 36 (2.78%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    Portal vein thrombosis
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1
    Infections and infestations
    Pneumonia bacterial
         subjects affected / exposed
    2 / 36 (5.56%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    Sepsis
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    Bacterial infection
         subjects affected / exposed
    2 / 36 (5.56%)
    0 / 36 (0.00%)
         occurrences all number
    2
    0
    Fungal infection
         subjects affected / exposed
    1 / 36 (2.78%)
    0 / 36 (0.00%)
         occurrences all number
    1
    0
    donor preservation solution infection
         subjects affected / exposed
    10 / 36 (27.78%)
    6 / 36 (16.67%)
         occurrences all number
    10
    6
    donor aorta patch infection
         subjects affected / exposed
    8 / 36 (22.22%)
    9 / 36 (25.00%)
         occurrences all number
    8
    9
    Wound infection
         subjects affected / exposed
    0 / 36 (0.00%)
    1 / 36 (2.78%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Oct 2014
    Change in randomisation Ancillary studies : secondary use of biopsies and blood samples
    04 Dec 2014
    Addition of informed consent in German
    10 Jun 2015
    Grammar changes in French IC Cetor replaced by Cinryze
    31 Jul 2015
    Changes in reporting of medication post transplantation during follow-up
    08 Mar 2016
    Adding 'acute liver failure' to the exclusion criteria

    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
    For support, Contact us.
    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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