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    Clinical Trial Results:
    The Impact of Target Temperature Management on Drug Metabolism

    Summary
    EudraCT number
    		 2018-002226-22
    Trial protocol
    		 AT  
    Global end of trial date
    17 Jun 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    17 Jun 2022
    First version publication date
    17 Jun 2022
    Other versions
    Summary report(s)
    		 Publicaiton

    Trial information

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    Trial identification
    Sponsor protocol code
    2.0
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Medical University of Vienna
    Sponsor organisation address
    Währinger Gürtel 18-20, Vienna, Austria, 1090
    Public contact
    Department of Emergency Medicine, Medical University of Vienna, +43 14040019640, post_akh_ls_6d@akhwien.at
    Scientific contact
    Department of Emergency Medicine, Medical University of Vienna, +43 14040019640, post_akh_ls_6d@akhwien.at
    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
    01 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jun 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jun 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To compare the half-life of pantoprazole during cooling and after rewarming
    Protection of trial subjects
    The study was of an observational nature and only patients, who received pantoprazole as part of their standard treatment, were included. Thus, no patient received a drug other than their standard treatment. Blood sampling was performed using existing central or peripheral venous or arterial catheters.
    Background therapy
    		 Patients received standard of care after cardiac arrest. The study did not interfere with standard of care at any time.
    Evidence for comparator
    		 We compared the pharmacokinetics of pantoprazole during three periods after cardiac arrest within the same patient: 1) mild therapeutic hypothermia 2) after rewarming, at ICU 3) after recovery, at normal ward. No comparator substance (e.g. placebo) was used within the study.
    Actual start date of recruitment
    25 May 2019
    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
    Austria: 16
    Worldwide total number of subjects
    16
    EEA total number of subjects
    16
    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)
    13
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Screening depended mainly on in- and exclusion criteria, but also on availability of the study team.

    Period 1
    Period 1 title
    Main (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Target Temperature Management
    Arm description
    		 all patients received a 40mg bolus infusion of pantoprazole as soon as target temperature (32-34 degrees Celsius) was reached
    Arm type
    		 Experimental

    Investigational medicinal product name
    pantoprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    40mg intravenous bolus infusion

    Arm title
    		 Rewarming
    Arm description
    		 40mg bolus infusion as soon as normal body temperature was reached
    Arm type
    		 Active comparator

    Investigational medicinal product name
    pantoprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    40mg intravenous bolus infusion

    Arm title
    		 Recovered
    Arm description
    		 After patients have almost completely recovered and were treated at the normal ward, the third study period was conducted. Patients received a 40mg intravenous bolus of pantoprazole.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    pantoprazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for infusion
    Routes of administration
    Intravenous bolus use
    Dosage and administration details
    40mg intravenous bolus infusion

    Number of subjects in period 1
    		Target Temperature Management Rewarming Recovered
    Started
    16
    16
    10
    Completed
    16
    16
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Main
    Reporting group description
    		 16 patients were eligible for inclusion and completed the TTM period (=target temperature management), the rewarming period (=after rewarming at the ICU) and 10 of these 16 patients entered the recovered period (=at normal ward). Six patients either died or had poor neurologic outcome and couldn't provide informed consent for participation in period 3. For period 1 and 2 the EC waived informed consent.

    Reporting group values
    		 Main Total
    Number of subjects
    		 16 16
    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)
    		 13 13
        From 65-84 years
    		 3 3
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 53 (46 to 62) -
    Gender categorical
    Units: Subjects
        Female
    		 3 3
        Male
    		 13 13
    Subject analysis sets

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who completed the three trials (each patient took part in up to three periods, that were compared with each other)

    Subject analysis sets values
    		 Per Protocol
    Number of subjects
    10
    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)
    9
        From 65-84 years
    1
        85 years and over
    0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    53 (46,25 to 60,5)
    Gender categorical
    Units: Subjects
        Female
    3
        Male
    7

    End points

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    End points reporting groups
    Reporting group title
    Target Temperature Management
    Reporting group description
    		 all patients received a 40mg bolus infusion of pantoprazole as soon as target temperature (32-34 degrees Celsius) was reached

    Reporting group title
    Rewarming
    Reporting group description
    		 40mg bolus infusion as soon as normal body temperature was reached

    Reporting group title
    Recovered
    Reporting group description
    		 After patients have almost completely recovered and were treated at the normal ward, the third study period was conducted. Patients received a 40mg intravenous bolus of pantoprazole.

    Subject analysis set title
    Per Protocol
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who completed the three trials (each patient took part in up to three periods, that were compared with each other)

    Primary: terminal elimination half-life

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    End point title
    		 terminal elimination half-life
    End point description
    End point type
    Primary
    End point timeframe
    24h per period
    End point values
    		 Target Temperature Management Rewarming Recovered
    Number of subjects analysed
    10 [1]
    10
    10
    Units: h
        median (inter-quartile range (Q1-Q3))
    2.4 (1.8 to 4.8)
    2.8 (2.1 to 6.8)
    1.2 (0.9 to 2.3)
    Notes
    [1] - only patients who completed all three periods were included in the final analysis
    Statistical analysis title
    		 Friedman ANOVA
    Statistical analysis description
    comparing the three periods, including 10 patients who completed the three periods.
    Comparison groups
    Target Temperature Management v Rewarming v Recovered
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.001 [3]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [2] - included n=10 who completed all three study periods
    [3] - a significant difference was found

    Secondary: Area under the time-concentration curve

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    End point title
    		 Area under the time-concentration curve
    End point description
    Area under the time concentration curve from 0-24h of pantoprazole after 40mg bolus infusion
    End point type
    Secondary
    End point timeframe
    24 hours per period
    End point values
    		 Target Temperature Management Rewarming Recovered
    Number of subjects analysed
    10 [4]
    10 [5]
    10 [6]
    Units: ng/mL*h
        median (inter-quartile range (Q1-Q3))
    12.7 (9.6 to 22.6)
    9.8 (7.6 to 18.6)
    7.2 (5.9 to 9.5)
    Notes
    [4] - only 10 subjects completed all three periods for the comparison of the pharmacokinetics
    [5] - only 10 subjects completed all three periods for the comparison of the pharmacokinetics
    [6] - only 10 subjects completed all three periods for the comparison of the pharmacokinetics
    Statistical analysis title
    		 Friedman ANOVA
    Statistical analysis description
    comparison of all three groups in one analysis
    Comparison groups
    Target Temperature Management v Rewarming v Recovered
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.027 [8]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [7] - n=10 because the same ten subjects completed all three periods
    [8] - there was a significant difference between the three study periods

    Secondary: Volume of Distribution

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    End point title
    		 Volume of Distribution
    End point description
    three study periods were compared with each other. 10 patients completed the three periods and were therefore eligible for comparison. The Volume of distribution is presented in the unit L (Liters).
    End point type
    Secondary
    End point timeframe
    24h per period
    End point values
    		 Target Temperature Management Rewarming Recovered
    Number of subjects analysed
    10 [9]
    10 [10]
    10 [11]
    Units: Liters
        median (inter-quartile range (Q1-Q3))
    11.4 (10.2 to 12.7)
    16.5 (14.3 to 21.2)
    12.5 (8 to 15.6)
    Notes
    [9] - only 10 subjects completed all three periods for the comparison of the pharmacokinetics
    [10] - only 10 subjects completed all three periods for the comparison of the pharmacokinetics
    [11] - only 10 subjects completed all three periods for the comparison of the pharmacokinetics
    Statistical analysis title
    		 Friedman ANOVA
    Statistical analysis description
    all three periods were compared with each other using a Friedman ANOVA
    Comparison groups
    Target Temperature Management v Rewarming v Recovered
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.001 [12]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [12] - there was a significant difference between the three study periods.

    Secondary: Clearance

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    End point title
    		 Clearance
    End point description
    The main comparison was performed in 10 patients, who completed all three study periods.
    End point type
    Secondary
    End point timeframe
    0-24h after each dose,
    End point values
    		 Target Temperature Management Rewarming Recovered
    Number of subjects analysed
    10 [13]
    10 [14]
    10 [15]
    Units: L/h
        median (inter-quartile range (Q1-Q3))
    2.9 (1.7 to 4.0)
    3.9 (2.0 to 4.9)
    5.5 (3.9 to 6.5)
    Notes
    [13] - Ten patients completed the three study periods and were included in the final analysis
    [14] - Ten patients completed the three study periods and were included in the final analysis
    [15] - Ten patients completed the three study periods and were included in the final analysis
    Statistical analysis title
    		 Friedman Anova
    Statistical analysis description
    all three periods were compares in one statistical test - a Friedman ANOVA
    Comparison groups
    Target Temperature Management v Rewarming v Recovered
    Number of subjects included in analysis
    30
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.027 [16]
    Method
    		 ANOVA
    Confidence interval
    Notes
    [16] - There was a significant difference between the three study periods.

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    First visit of each patient to last visit of each individual patient. This was depending on the clinical course of the patients and lasted up to 19 days until all three study periods were completed.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    3.0
    Reporting groups
    Reporting group title
    Full Analysis Set
    Reporting group description
    		 Due to the observational nature of the study and the critical illness of the patients, only serious adverse events were documented.

    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: This was a non-interventional, observational study in patients who have undergone a successful cardiopulmonary resuscitation. Pantoprazole was part of their standard of care and we quantified pharmacokinetics. Thus, we have only recorded serious adverse events, but no non-serious adverse events.
    Serious adverse events
    		 Full Analysis Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 16 (37.50%)
         number of deaths (all causes)
    5
         number of deaths resulting from adverse events
    0
    Nervous system disorders
    Hypoxic brain damage
    Additional description: In five subjects treating physicians diagnosed a hypoxic brain damage after initial cardiac arrest. Because of poor prognosis treatment was withdrawn. There was no causal relationship with the study. Of note, pantoprazole was part of standard of care
         subjects affected / exposed
    5 / 16 (31.25%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 5
    Hepatobiliary disorders
    Hypoxic hepatitis
    Additional description: In one patient a hypoxic hepatitis was diagnosed after initial cardiac arrest. There was no causal relationship with the study or the study drug. Pantoprazole was part of standard of care.
         subjects affected / exposed
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
    Additional description: Two patients developed an acute kidney failure after initial cardiac arrest. There was no causal relationship with the study or the study drug. Of note, pantoprazole was part of the standard of care.
         subjects affected / exposed
    2 / 16 (12.50%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Full Analysis Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 16 (0.00%)

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Feb 2019
    The study was initially submitted as an interventional trial in patients undergoing cardiopulmonary resuscitation. The IMPs included paracetamol, erythromycin and pantoprazole. However, as we couldn't provide sufficient evidence for the individual benefit of the participating subjects, we were only able to conduct a non-interventional study investigating the pharmacokinetics of pantoprazole. Hence, due to the non-interventional nature of the study, the Ethics Committee did not demand a EudraCT entry. However, since the current EudraCT entry was still opened, we decided to enter study data as far as possible. The Amendment date relates to the last change of the study protocol, which in its final version describes a non-interventional study focusing on the pharmacokinetics of pantoprazole.

    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.
    16 patients were included in total. However, six couldn't participate in the last period due to death or poor neurologic outcome. Hence, the final population consists of 10 patients.
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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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