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    Clinical Trial Results:
    Postoperative pain treatment after elective cardiac surgery using patient-controlled target-controlled infusion (TCI-PCA) with hydromorphone vs. patient-controlled analgesia (PCA) with morphine

    Summary
    EudraCT number
    		 2014-004088-19
    Trial protocol
    		 DE  
    Global end of trial date
    01 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    23 Apr 2020
    First version publication date
    23 Apr 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TCI-PCA-002
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02483221
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Universitätsklinikum Erlangen
    Sponsor organisation address
    Maximiliansplatz 2, Erlangen, Germany, 91054
    Public contact
    Anästhesiologische Klinik, Universitätsklinikum Erlangen, +49 91318542363, christian.jeleazcov@kfa.imed.uni-erlangen.de
    Scientific contact
    Anästhesiologische Klinik, Universitätsklinikum Erlangen, +49 91318542363, christian.jeleazcov@kfa.imed.uni-erlangen.de
    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 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 Dec 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Comparison of analgesic efficiency of hydromorphone TCI-PCA vs. conventional morphine PCA in the early postoperative period.
    Protection of trial subjects
    Assessment of pain (Numerical Rating Scale, NRS 0-10) Assessment of sedation (Modified Observer’s Assessment of Alertness/Sedation Scale, MOAAS) Monitoring of arterial blood pressure, peripheral arterial oxygen saturation (SpO2), heart rate and respiratory rate Laboratory data were determined regularly by blood gas analysis
    Background therapy
    		 Throughout the study, patients were treated and monitored according to standard protocols of the ICU. Propofol infusion until weaning from mechanical ventilation. Vasoactive drugs were infused depending on clinical demand to maintain the mean arterial pressure in a range of 70-90 mmHg. Dobutamine, noradrenaline and glycerylnitrate infusions were routinely used. If vasoactive control was insufficient, adrenalin was administered instead of dobutamine.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Apr 2015
    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: 50
    Worldwide total number of subjects
    50
    EEA total number of subjects
    50
    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)
    23
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment start: 27.04.2015 Recruitment end: 29.11.2016 Total number of screened subjects: 728 Total number of enrolled subjects: 50

    Pre-assignment
    Screening details
    		 Inclusion criteria: Male and female Elective cardiac surgery with thoracotomy Age 40-85 y. ASA<4 EF>40% BMI<35 kg/m2 Exclusion criteria: Allergy to opioids, diabetes mellitus, renal, neurological, psychiatric, chronic inflammatory disease Drug abuse

    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
    		 TCI-PCA-Hydromorphone
    Arm description
    		 Intravenous Patient-Controlled Analgesia with Target-Controlled Infusion of hydromorphone
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Hydromorphone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Target controlled infusion with target plasma and effect site concentrations between 0.8 and 10 ng/ml in predefined increasing steps with a lock-out time of 15 min on patient request and in predefined decreasing steps on lack of patient request.

    Arm title
    		 PCA-Morphine
    Arm description
    		 Patient Controlled Analgesia with morphine
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Morphine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Patient Controlled Analgesia: bolus doses of 2 mg morphine hydrochloride in one minute on patient's request with a lockout time of 10 min

    Number of subjects in period 1
    		TCI-PCA-Hydromorphone PCA-Morphine
    Started
    25
    25
    Completed
    23
    21
    Not completed
    2
    4
         Did not receive treatment, delayed operation
    -
    4
         Adverse event, non-fatal
    1
    -
         delayed extubation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TCI-PCA-Hydromorphone
    Reporting group description
    		 Intravenous Patient-Controlled Analgesia with Target-Controlled Infusion of hydromorphone

    Reporting group title
    PCA-Morphine
    Reporting group description
    		 Patient Controlled Analgesia with morphine

    Reporting group values
    		 TCI-PCA-Hydromorphone PCA-Morphine Total
    Number of subjects
    		 25 25 50
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 13 10 23
        From 65-84 years
    		 12 15 27
    Age continuous
    Units: years
        median (full range (min-max))
    		 64 (46 to 84) 66 (44 to 79) -
    Gender categorical
    Units: Subjects
        Female
    		 4 3 7
        Male
    		 21 22 43
    Body weight
    Units: kg
        median (full range (min-max))
    		 86 (45 to 107) 82 (63 to 115) -

    End points

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    End points reporting groups
    Reporting group title
    TCI-PCA-Hydromorphone
    Reporting group description
    		 Intravenous Patient-Controlled Analgesia with Target-Controlled Infusion of hydromorphone

    Reporting group title
    PCA-Morphine
    Reporting group description
    		 Patient Controlled Analgesia with morphine

    Primary: Pain in rest

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    End point title
    		 Pain in rest
    End point description
    Pain in rest (assessed using the Numerical Rating Scale, NRS 0-10)
    End point type
    Primary
    End point timeframe
    from extubation until end of observation period (8:00 in the morning of the next day)
    End point values
    		 TCI-PCA-Hydromorphone PCA-Morphine
    Number of subjects analysed
    23 [1]
    21 [2]
    Units: Points
        median (full range (min-max))
    2 (0 to 4)
    1 (0 to 5)
    Notes
    [1] - 2 subjects were excluded due to: Incomplete data (n=2)
    [2] - 4 subjects were excluded due to: Did not receive intervention, delayed operation(n=4)
    Statistical analysis title
    		 TCI-PCA versus PCA
    Statistical analysis description
    NRS scores in rest were tested for significant difference between the two groups
    Comparison groups
    TCI-PCA-Hydromorphone v PCA-Morphine
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.33
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.29
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.65
         upper limit
    		 1.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.46

    Primary: Pain under inspiration

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    End point title
    		 Pain under inspiration
    End point description
    Pain under deep inspiration (assessed using the Numerical Rating Scale, NRS 0-10)
    End point type
    Primary
    End point timeframe
    from extubation until end of observation period (8:00 in the morning of the next day)
    End point values
    		 TCI-PCA-Hydromorphone PCA-Morphine
    Number of subjects analysed
    23 [3]
    21 [4]
    Units: Points
        median (full range (min-max))
    4 (0 to 7)
    3.5 (0 to 7)
    Notes
    [3] - 2 subjects were excluded due to: Incomplete data (n=2)
    [4] - 4 subjects were excluded due to: Did not receive intervention, delayed operation (n=4)
    Statistical analysis title
    		 TCI-PCA versus PCA
    Statistical analysis description
    NRS scores under inspiration were tested for significant difference between the two groups
    Comparison groups
    TCI-PCA-Hydromorphone v PCA-Morphine
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.85
         upper limit
    		 1.41
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.56

    Secondary: Sedation score

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    End point title
    		 Sedation score
    End point description
    Depth of sedation, assessed by the Modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S, 0-5)
    End point type
    Secondary
    End point timeframe
    from extubation until end of observation period (8:00 in the morning of the next day)
    End point values
    		 TCI-PCA-Hydromorphone PCA-Morphine
    Number of subjects analysed
    23 [5]
    21 [6]
    Units: Points
        median (full range (min-max))
    5 (5 to 5)
    5 (4 to 5)
    Notes
    [5] - 2 subjects were excluded due to: Incomplete data (n=2)
    [6] - 4 subjects were excluded due to: Did not receive intervention, delayed operation (n=4)
    Statistical analysis title
    		 TCI-PCA versus PCA
    Statistical analysis description
    MOAA/S scores were tested for significant difference between the two groups
    Comparison groups
    TCI-PCA-Hydromorphone v PCA-Morphine
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.13
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.04
         upper limit
    		 0.23
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.07

    Secondary: PONV

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    End point title
    		 PONV
    End point description
    Incidence of postoperative nausea and vomiting
    End point type
    Secondary
    End point timeframe
    from extubation until end of observation period (8:00 in the morning of the next day)
    End point values
    		 TCI-PCA-Hydromorphone PCA-Morphine
    Number of subjects analysed
    23 [7]
    21 [8]
    Units: number
    8
    7
    Notes
    [7] - 2 subjects were excluded due to: Incomplete data (n=2)
    [8] - 4 subjects were excluded due to: Did not receive intervention, delayed operation (n=4)
    Statistical analysis title
    		 TCI-PCA versus PCA
    Statistical analysis description
    Incidence of postoperative nausea and vomiting was tested for significant difference between the two groups
    Comparison groups
    TCI-PCA-Hydromorphone v PCA-Morphine
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.46
         upper limit
    		 2.38

    Secondary: Respiration rate

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    End point title
    		 Respiration rate
    End point description
    End point type
    Secondary
    End point timeframe
    from extubation until end of observation period (8:00 in the morning of the next day)
    End point values
    		 TCI-PCA-Hydromorphone PCA-Morphine
    Number of subjects analysed
    23 [9]
    21 [10]
    Units: breaths per min
        arithmetic mean (standard deviation)
    15 ( 2 )
    16 ( 4 )
    Notes
    [9] - 2 subjects were excluded due to: Incomplete data (n=2)
    [10] - 4 subjects were excluded due to: Did not receive intervention, delayed operation (n=4)
    Statistical analysis title
    		 TCI-PCA versus PCA
    Statistical analysis description
    Respiration rates were tested for significant difference between the two groups
    Comparison groups
    TCI-PCA-Hydromorphone v PCA-Morphine
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.35
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 1.1
    Variability estimate
    Standard error of the mean
    Dispersion value
    1

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of treatment with hydromorphone or morphine on the first study day (day of surgery) until 8:00 AM of the second study day (1st postoperative day)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    TCI-PCA-Hydromorphone
    Reporting group description
    		 Intravenous Patient-Controlled Analgesia with Target-Controlled Infusion of hydromorphone

    Reporting group title
    PCA-Morphine
    Reporting group description
    		 Patient Controlled Analgesia with morphine

    Serious adverse events
    		 TCI-PCA-Hydromorphone PCA-Morphine
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Bradycardia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 TCI-PCA-Hydromorphone PCA-Morphine
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    19 / 25 (76.00%)
    15 / 21 (71.43%)
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Hypertonia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Cardiopulmonary bypass occlusion
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Delirium
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Nausea
         subjects affected / exposed
    7 / 25 (28.00%)
    7 / 21 (33.33%)
         occurrences all number
    9
    7
    Vomiting
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Dizziness
         subjects affected / exposed
    1 / 25 (4.00%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Shivering
         subjects affected / exposed
    4 / 25 (16.00%)
    4 / 21 (19.05%)
         occurrences all number
    4
    4
    Delayed recovery from anaesthesia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Restlessness
         subjects affected / exposed
    4 / 25 (16.00%)
    4 / 21 (19.05%)
         occurrences all number
    4
    4
    Hypothermia
         subjects affected / exposed
    1 / 25 (4.00%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Pain
         subjects affected / exposed
    0 / 25 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Respiratory depression
         subjects affected / exposed
    1 / 25 (4.00%)
    3 / 21 (14.29%)
         occurrences all number
    1
    3
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    2 / 25 (8.00%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0

    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
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