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    Clinical Trial Results:
    Open-label evaluation of the population pharmacokinetic profile, safety, tolerability, and efficacy of intravenous tapentadol solution for injection for the treatment of post-surgical pain in children aged from birth to less than 2 years, including preterm neonates.

    Summary
    EudraCT number
    		 2014-002259-24
    Trial protocol
    		 HU   PL   GB   ES   CZ   FR   DE  
    Global end of trial date
    27 Sep 2018

    Results information
    Results version number
    		 v2(current)
    This version publication date
    16 Feb 2019
    First version publication date
    13 Jul 2017
    Other versions
    		 v1
    Version creation reason
    • New data added to full data set
    • Correction of full data set
    - Completion of dataset for Subgroup 4

    Trial information

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    Trial identification
    Sponsor protocol code
    KF5503-73
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 U1111-1157-3228
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52099
    Public contact
    Grünenthal Clinical Trial Helpdesk, Grünenthal GmbH, +49 241569 3223, Clinical-Trials@grunenthal.com
    Scientific contact
    Grünenthal Clinical Trial Helpdesk, Grünenthal GmbH, +49 241569 3223, Clinical-Trials@grunenthal.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000018-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Nov 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 Sep 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Sep 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was to collect serum concentration data of tapentadol and its major metabolite tapentadol-O-glucuronide after the administration of a single dose of intravenous tapentadol solution for injection (tapentadol IV) in children aged from birth to less than 2 years, including preterm neonates, after a qualifying procedure that routinely produced moderate to severe acute pain requiring opioid treatment. The concentration data was to be used to characterize the pharmacokinetic parameters of tapentadol using a population pharmacokinetic approach. This was to enable data-based recommendations for the use of tapentadol in children of different ages.
    Protection of trial subjects
    The trial was conducted according to ICH-GCP guidelines, the applicable local law, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The competent authorities approved the trial as required by national regulations. Regulatory authorities were notified of the trial and amendments as required by national regulations. Subjects have been confined to the trial site until completion of End of Treatment assessments. This trial has been designed to protect the interests of the child subjects, including minimizing the risk to subjects and ensuring compliance with the recommendations made by an EMEA ad hoc working party (2008) regarding the amount of blood to be drawn as well as the monitoring of children in a controlled environment (post-operative setting that provides intensive monitoring).
    Background therapy
    		 All prior/concomitant medication/therapies were allowed as per standard of care, unless a medication was explicitly prohibited. Medications for the treatment of adverse events were allowed according to the investigator’s judgment and post-operative standard of care. During surgery and peri-operatively, the use of pre-medications, intraoperative medications, and opioid analgesics were allowed according to the usual standard of care. Non-opioid analgesics were allowed after the end of surgery/anesthesia according to medical judgment and standard of care.
    Evidence for comparator
    		 NA
    Actual start date of recruitment
    23 Apr 2015
    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
    Spain: 1
    Country: Number of subjects enrolled
    Poland: 36
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    France: 1
    Country: Number of subjects enrolled
    Hungary: 6
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    10
    Newborns (0-27 days)
    10
    Infants and toddlers (28 days-23 months)
    26
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 First subject was enrolled on 23 Apr 2015 and last subject for the final analysis completed the trial on 27 Sep 2018. The trial followed a staggered recruitment, starting with the recruitment of subjects in the eldest age group. Exposure and safety of at least 4 subjects had been assessed before enrollment in the next younger age group started.

    Pre-assignment
    Screening details
    		 The parents of 46 subjects signed an informed consent; 40 subjects were allocated to tapentadol IV, 38 were treated. 6 subjects dropped out before allocation to treatment and 2 subjects after allocation but before receiving tapentadol IV: 6 subjects did not meet inclusion and exclusion criteria and the parents of 2 subjects withdrew consent.

    Pre-assignment period milestones
    Number of subjects started
    		 46
    Number of subjects completed
    		 38

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Inclusion criteria not met/exclusion criteria met: 6
    Reason: Number of subjects
    		 Parents of subjects withdrew consent: 2
    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Age group 1: 6 months to less than 2 years
    Arm description
    		 Infants and toddlers aged 6 months to less than 2 years at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tapentadol solution for injection
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single dose of tapentadol solution for injection as a continuous, constant-rate, intravenous infusion over 1 hour. The dose administered depended on the gestational and postnatal age. Subjects aged 6 months to less than 2 years were to receive a dose of 0.4 mg/kg. The IMP has been given when the subject was considered clinically stable.

    Arm title
    		 Age group 2: 1 month to less than 6 months
    Arm description
    		 Infants aged 1 month to less than 6 months at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tapentadol solution for injection
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single dose of tapentadol solution for injection as a continuous, constant-rate, intravenous infusion over 1 hour. The dose administered depended on the gestational and postnatal age. Subjects aged 1 month to less than 6 months were to receive a dose of 0.4 mg/kg. The IMP has been given when the subject was considered clinically stable.

    Arm title
    		 Age group 3: birth to less than 1 month
    Arm description
    		 Newborns and infants from birth (must be of at least 37 weeks gestational age) to less than 1 month at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tapentadol solution for injection
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single dose of tapentadol solution for injection as a continuous, constant-rate, intravenous infusion over 1 hour. The planned dose to be administered depended on the gestational and postnatal age. Subjects with a postnatal age of equal or more than 7 days were to receive a dose of 0.4 mg/kg. Subjects with a postnatal age of less than 7 days were to receive a dose of 0.3 mg/kg. The IMP has been given when the subject was considered clinically stable.

    Arm title
    		 Age group 4: preterm born subjects
    Arm description
    		 Preterm born subjects from birth with a postmenstrual age of equal or less than 41 weeks and a gestational age of 24 weeks to less than 37 weeks at the time of allocation to IMP, who received any amount of intravenous tapentadol solution for injection.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tapentadol solution for injection
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Subjects received a single dose of tapentadol solution for injection as a continuous, constant-rate, intravenous infusion over 1 hour. Depending on their gestational age and postnatal age, subjects were to receive a dose of either 0.3 mg/kg or 0.4 mg/kg as per dosing instruction in the protocol. The IMP has been given when the subject was considered clinically stable.

    Number of subjects in period 1 [1]
    		Age group 1: 6 months to less than 2 years Age group 2: 1 month to less than 6 months Age group 3: birth to less than 1 month Age group 4: preterm born subjects
    Started
    10
    11
    9
    8
    Completed
    10
    11
    9
    8
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The pre-assignment period gives details for all subjects that signed an informed consent but were not treated.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Age group 1: 6 months to less than 2 years
    Reporting group description
    		 Infants and toddlers aged 6 months to less than 2 years at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.

    Reporting group title
    Age group 2: 1 month to less than 6 months
    Reporting group description
    		 Infants aged 1 month to less than 6 months at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.

    Reporting group title
    Age group 3: birth to less than 1 month
    Reporting group description
    		 Newborns and infants from birth (must be of at least 37 weeks gestational age) to less than 1 month at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.

    Reporting group title
    Age group 4: preterm born subjects
    Reporting group description
    		 Preterm born subjects from birth with a postmenstrual age of equal or less than 41 weeks and a gestational age of 24 weeks to less than 37 weeks at the time of allocation to IMP, who received any amount of intravenous tapentadol solution for injection.

    Reporting group values
    		 Age group 1: 6 months to less than 2 years Age group 2: 1 month to less than 6 months Age group 3: birth to less than 1 month Age group 4: preterm born subjects Total
    Number of subjects
    		 10 11 9 8 38
    Age categorical
    Units: Subjects
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 8 8
        Newborns (0-27 days)
    		 0 0 9 0 9
        Infants and toddlers (28 days-23 months)
    		 10 11 0 0 21
    Age continuous
    Units: days
        arithmetic mean (standard deviation)
    		 423 ( 158.4 ) 95.2 ( 41.8 ) 15.3 ( 6.4 ) 35.0 ( 37.7 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 4 2 4 10
        Male
    		 10 7 7 4 28
    Height
    Units: centimeter
        arithmetic mean (standard deviation)
    		 82.1 ( 8.2 ) 62.7 ( 7.2 ) 53.6 ( 4.4 ) 48.8 ( 3.8 ) -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 11.16 ( 2.18 ) 6.36 ( 1.64 ) 3.68 ( 0.58 ) 2.51 ( 0.76 ) -
    Body Mass index
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    		 16.48 ( 1.53 ) 15.95 ( 1.86 ) 12.82 ( 1.31 ) 10.39 ( 2.12 ) -
    Gestational Age
    Gestational age was only required for subgroups 3 and 4.
    Units: weeks
        arithmetic mean (standard deviation)
    		 0 ( 0 ) 0 ( 0 ) 38.2 ( 1.2 ) 30.9 ( 4.3 ) -
    Postmenstrual age
    Post menstrual age was only required for subgroup 4.
    Units: weeks
        arithmetic mean (standard deviation)
    		 0 ( 0 ) 0 ( 0 ) 0 ( 0 ) 35.6 ( 3.0 ) -
    FLACC (Face, Legs, Activity,Cry, Consolability) scale
    The pre-dose measurement was used as baseline value for calculation of change in pain intensity. The FLACC Scale was developed by the Department of Anesthesiology, University of Michigan Medical School and Health Systems. It is a behavioral scale for scoring postoperative pain in young children. This tool includes five categories of pain behaviors, including facial expression, leg movement, activity, cry, and consolability. Each of the five categories (F) Face; (L) Legs; (A) Activity; (C) Cry; (C) Consolability is scored from 0-2, which results in a total score between zero and ten.
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 4.7 ( 3.2 ) 4.9 ( 1.9 ) 3.8 ( 2.6 ) 2.9 ( 2.5 ) -

    End points

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    End points reporting groups
    Reporting group title
    Age group 1: 6 months to less than 2 years
    Reporting group description
    		 Infants and toddlers aged 6 months to less than 2 years at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.

    Reporting group title
    Age group 2: 1 month to less than 6 months
    Reporting group description
    		 Infants aged 1 month to less than 6 months at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.

    Reporting group title
    Age group 3: birth to less than 1 month
    Reporting group description
    		 Newborns and infants from birth (must be of at least 37 weeks gestational age) to less than 1 month at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.

    Reporting group title
    Age group 4: preterm born subjects
    Reporting group description
    		 Preterm born subjects from birth with a postmenstrual age of equal or less than 41 weeks and a gestational age of 24 weeks to less than 37 weeks at the time of allocation to IMP, who received any amount of intravenous tapentadol solution for injection.

    Primary: Serum Concentrations of Tapentadol after a single dose of tapentadol solution for injection

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    End point title
    		 Serum Concentrations of Tapentadol after a single dose of tapentadol solution for injection [1]
    End point description
    Pharmacokinetic evaluation based on serum concentrations of tapentadol from blood samples taken within 10 hours of a single dose of IMP administration at 3 time points per subject. Subjects have been allocated to one of 4 different blood sampling schedules as per protocol. Serum pharmacokinetic samples have been analyzed to determine concentrations of tapentadol using validated liquid chromatography-tandem mass spectrometry bioanalytical assays. All subjects who had quantifiable serum concentrations have been included in the descriptive pharmacokinetic analysis. Summary statistics were only be determined if at least 2 observations per time point were above lower limit of quantification. SD has not been calculated if N = 1.
    End point type
    Primary
    End point timeframe
    up to 10 hours
    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: Serum concentration analyzed for tapentadol.
    End point values
    		 Age group 1: 6 months to less than 2 years Age group 2: 1 month to less than 6 months Age group 3: birth to less than 1 month Age group 4: preterm born subjects
    Number of subjects analysed
    10 [2]
    11 [3]
    9 [4]
    8 [5]
    Units: nanogram(s)/millilitre
    arithmetic mean (standard deviation)
        15 min after start of IMP (N=4/4/3/2)
    188 ( 332.44 )
    18.2 ( 12.63 )
    51.0 ( 61.76 )
    30.5 ( 3.27 )
        30 min after start of IMP (N=2/3/2/2)
    46.2 ( 16.00 )
    38.2 ( 11.03 )
    25.7 ( 9.4 )
    23.9 ( 9.33 )
        1 hour after start of IMP (N=4/4/3/2)
    68.9 ( 23.72 )
    51.4 ( 19.69 )
    56.8 ( 14.29 )
    37.5 ( 28.73 )
        1.25 hour after start of IMP (N=2/2/2/2)
    57.7 ( 14.47 )
    67.2 ( 15.87 )
    38.6 ( 3.68 )
    26.1 ( 16.07 )
        1.5 hour after start of IMP (N=2/2/2/2)
    118.1 ( 100.58 )
    113.1 ( 101.32 )
    37.5 ( 8.35 )
    41.3 ( 2.51 )
        2 hours after start of IMP (N=2/3/2/2)
    46.6 ( 6.81 )
    45.2 ( 3.14 )
    37.6 ( 11.97 )
    29.4 ( 0.71 )
        3 hours after start of IMP (N=2/2/2/2)
    32.5 ( 12.71 )
    39.3 ( 18.54 )
    25.7 ( 0.48 )
    33.6 ( 5.50 )
        4 hours after start of IMP (N=2/2/2/2)
    17.6 ( 14.57 )
    35.2 ( 6.22 )
    19.2 ( 2.35 )
    12.2 ( 5.43 )
        6 hours after start of IMP (N=4/4/3/2)
    20.9 ( 19.14 )
    10.2 ( 5.01 )
    18.3 ( 3.03 )
    29.7 ( 23.97 )
        7 hours after start of IMP (N=2/2/2/2)
    10.2 ( 3.83 )
    17.9 ( 19.45 )
    12.7 ( 5.06 )
    22.8 ( 6.03 )
        8 hours after start of IMP (N=2/3/2/2)
    8.6 ( 3.39 )
    12.7 ( 9.16 )
    10.7 ( 5.78 )
    7.6 ( 6.72 )
        10 hours after start of IMP (N=2/1/2/2)
    12.4 ( 12.38 )
    11.46 ( 0 )
    5.3 ( 3.46 )
    4.4 ( 0.18 )
    Notes
    [2] - Pharmacokinetic Set N= number of subjects with observed values per time point and age group.
    [3] - Pharmacokinetic Set N= number of subjects with observed values per time point and age group.
    [4] - Pharmacokinetic Set N= number of subjects with observed values per time point and age group.
    [5] - Pharmacokinetic Set N= number of subjects with observed values per time point and age group.
    No statistical analyses for this end point

    Primary: Serum Concentrations of Tapentadol-O-glucuronide after a single dose of tapentadol solution for injection

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    End point title
    		 Serum Concentrations of Tapentadol-O-glucuronide after a single dose of tapentadol solution for injection [6]
    End point description
    Pharmacokinetic evaluation based on serum concentrations of tapentadol O- glucuronide from blood samples taken within 10 hours of a single dose of IMP administration at 3 time points per subject. Subjects have been allocated to one of 4 different blood sampling schedules as per protocol. Serum pharmacokinetic samples have been analyzed to determine concentrations of tapentadol -O- glucuronide using validated liquid chromatography-tandem mass spectrometry bioanalytical assays. All subjects who had quantifiable serum concentrations have been included in the descriptive pharmacokinetic analysis. Summary statistics were only be determined if at least 2 observations per time point were above lower limit of quantification. SD has not been calculated if N = 1. At the 15 minutes time point the PK samples for all subjects were below the lower limit of quantification. Therefore, this time point has not been listed.
    End point type
    Primary
    End point timeframe
    up to 10 hours
    Notes
    [6] - 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: Serum concentration analyzed for tapentadol-O-glucuronide.
    End point values
    		 Age group 1: 6 months to less than 2 years Age group 2: 1 month to less than 6 months Age group 3: birth to less than 1 month Age group 4: preterm born subjects
    Number of subjects analysed
    10 [7]
    11 [8]
    9 [9]
    8 [10]
    Units: nanogram(s)/millilitre
    arithmetic mean (standard deviation)
        30 min after start of IMP (N=2/2/1/2)
    24.7 ( 7.86 )
    19.5 ( 12.73 )
    12.26 ( 0 )
    26.3 ( 13.34 )
        1 hour after start of IMP (N=4/4/3/2)
    90.1 ( 57.03 )
    81.2 ( 34.93 )
    63.1 ( 15.62 )
    157.0 ( 133.29 )
        1.25 hour after start of IMP (N=2/2/2/2)
    213.7 ( 16.76 )
    128.5 ( 121.5 )
    208.7 ( 153.98 )
    59.4 ( 58.56 )
        1.5 hour after start of IMP (N=2/2/2/2)
    108.8 ( 26.14 )
    165.2 ( 30.97 )
    92.6 ( 53.12 )
    54.6 ( 0.11 )
        2 hours after start of IMP (N=2/3/2/2)
    171.8 ( 28.14 )
    126.9 ( 79.85 )
    159.4 ( 67.74 )
    244.9 ( 0.42 )
        3 hours after start of IMP (N=2/2/2/2)
    171.5 ( 81.81 )
    186.6 ( 28.35 )
    153.4 ( 50.06 )
    92.1 ( 8.63 )
        4 hours after start of IMP (N=2/2/2/2)
    99.2 ( 31.76 )
    223.5 ( 48.65 )
    486.4 ( 398.53 )
    149.8 ( 153.36 )
        6 hours after start of IMP (N=4/4/3/2)
    99.2 ( 18.28 )
    158.7 ( 130.02 )
    267.3 ( 49.73 )
    117.7 ( 87.90 )
        7 hours after start of IMP (N=2/2/2/2)
    70.0 ( 25.72 )
    88.4 ( 48.54 )
    186.6 ( 48.86 )
    146.3 ( 15.41 )
        8 hours after start of IMP (N=2/3/2/2)
    115.9 ( 28.72 )
    99.7 ( 24.54 )
    221.4 ( 38.4 )
    222.1 ( 206.75 )
        10 hours after start of IMP (N=2/1/2/2)
    153.6 ( 99.22 )
    158 ( 0 )
    407.5 ( 278.03 )
    148.1 ( 126.44 )
    Notes
    [7] - Pharmacokinetic Set N= number of subjects with observed values per time point and age group.
    [8] - Pharmacokinetic Set N= number of subjects with observed values per time point and age group.
    [9] - Pharmacokinetic Set N= number of subjects with observed values per time point and age group.
    [10] - Pharmacokinetic Set N= number of subjects with observed values per time point and age group.
    No statistical analyses for this end point

    Secondary: Change in pain intensity using the Face, Legs, Activity, Cry, Consolability scale

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    End point title
    		 Change in pain intensity using the Face, Legs, Activity, Cry, Consolability scale
    End point description
    The change from baseline in pain intensity was assessed using the Face, Legs, Activity, Cry, Consolability scale (FLACC scale) at 15 minutes, 30 minutes, and at 1, 2, 4, 6, 8, 12, and 15 hours after a single dose of tapentadol solution for injection. The FLACC scale was developed by the Department of Anesthesiology, University of Michigan Medical School and Health Systems. It is a behavioral scale for scoring postoperative pain in young and non-verbal children. This tool includes 5 categories of pain behaviors, including facial expression (F), leg movement (L), activity (A), cry (C), and consolability (C). Each of the 5 categories is scored 0, 1, or 2, which results in a total score between 0 and 10. The pain intensity scores were summarized descriptively per scheduled time point.
    End point type
    Secondary
    End point timeframe
    up to 15 hours
    End point values
    		 Age group 1: 6 months to less than 2 years Age group 2: 1 month to less than 6 months Age group 3: birth to less than 1 month Age group 4: preterm born subjects
    Number of subjects analysed
    10 [11]
    11 [12]
    9 [13]
    8 [14]
    Units: units on a scale
    arithmetic mean (standard deviation)
        + 15 min (N=10/10/9/8)
    -1.5 ( 1.7 )
    -2.6 ( 2.2 )
    -1.2 ( 3.1 )
    -0.9 ( 2.2 )
        + 30 min (N=10/10/9/8)
    -3.7 ( 2.9 )
    -4.3 ( 2.3 )
    -2.9 ( 3.0 )
    -0.9 ( 2.4 )
        + 1 hour (N=10/10/9/8)
    -4.7 ( 3.2 )
    -4.9 ( 1.9 )
    -3.6 ( 2.7 )
    -1.9 ( 2.9 )
        + 2 hours (N=10/10/9/8)
    -4.2 ( 4.0 )
    -4.1 ( 3.4 )
    -3.0 ( 3.2 )
    -1.9 ( 3.0 )
        + 4 hours (N=10/10/9/8)
    -4.6 ( 3.2 )
    -4.5 ( 2.1 )
    -2.4 ( 3.6 )
    -1.8 ( 2.9 )
        + 6 hours (N=9/10/7/7)
    -4.7 ( 2.9 )
    -3.7 ( 3.1 )
    -3.0 ( 3.2 )
    -1.7 ( 3.7 )
        + 8 hours (N=10/10/9/8)
    -4.3 ( 3.1 )
    -3.8 ( 3.0 )
    -2.2 ( 3.6 )
    -1.3 ( 3.7 )
        + 12 hours (N=10/10/9/8)
    -4.4 ( 3.3 )
    -4.7 ( 1.9 )
    -3.2 ( 3.3 )
    -1.9 ( 2.6 )
        + 15 hours (N=10/10/9/8)
    -4.7 ( 3.2 )
    -4.1 ( 2.1 )
    -2.4 ( 3.5 )
    -1.5 ( 2.5 )
    Notes
    [11] - Full Analysis Set N= number of subjects with observed values per time point and age group.
    [12] - Full Analysis Set N= number of subjects with observed values per time point and age group.
    [13] - Full Analysis Set N= number of subjects with observed values per time point and age group.
    [14] - Full Analysis Set N= number of subjects with observed values per time point and age group.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any Adverse Events (AE) that started at or after the start of the iv administration of the IMP or starting before IMP administration and worsened in intensity after the start of the IMP up to the end of the therapeutic reach of last administration of IMP.
    Adverse event reporting additional description
    The therapeutic reach is the time after treatment completion that a subject is still considered to be potentially affected by a study drug. For intravenous tapentadol solution for injection, the therapeutic reach is defined as 48 hours after the end of the IMP intake (i.e., end of IV infusion). Adverse event were report by age group and overall.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Age group 1: 6 months to less than 2 years
    Reporting group description
    		 Infants and toddlers aged 6 months to less than 2 years at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.

    Reporting group title
    Age group 2: 1 month to less than 6 months
    Reporting group description
    		 Infants aged 1 month to less than 6 months at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.

    Reporting group title
    Age group 3: birth to less than 1 month
    Reporting group description
    		 Newborns and infants from birth (must be of at least 37 weeks gestational age) to less than 1 month at the time of allocation to IMP who received any amount of intravenous tapentadol solution for injection.

    Reporting group title
    Age group 4: preterm born subjects
    Reporting group description
    		 Preterm born subjects from birth with a postmenstrual age of equal or less than 41 weeks and a gestational age of 24 weeks to less than 37 weeks at the time of allocation to IM, who received any amount of intravenous tapentadol solution for injection.

    Reporting group title
    Overall
    Reporting group description
    		 -

    Serious adverse events
    		 Age group 1: 6 months to less than 2 years Age group 2: 1 month to less than 6 months Age group 3: birth to less than 1 month Age group 4: preterm born subjects Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    0 / 38 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Age group 1: 6 months to less than 2 years Age group 2: 1 month to less than 6 months Age group 3: birth to less than 1 month Age group 4: preterm born subjects Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 11 (27.27%)
    5 / 9 (55.56%)
    2 / 8 (25.00%)
    11 / 38 (28.95%)
    Investigations
    Oxygen saturation decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    2 / 9 (22.22%)
    1 / 8 (12.50%)
    3 / 38 (7.89%)
         occurrences all number
    0
    0
    4
    1
    5
    Weight decreased
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia neonatal
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    2 / 9 (22.22%)
    0 / 8 (0.00%)
    2 / 38 (5.26%)
         occurrences all number
    0
    0
    2
    0
    2
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    2
    0
    0
    0
    2
    Vaccination site injury
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    0
    0
    1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 11 (9.09%)
    1 / 9 (11.11%)
    1 / 8 (12.50%)
    4 / 38 (10.53%)
         occurrences all number
    1
    1
    1
    1
    4
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    1
    0
    1
    Skin and subcutaneous tissue disorders
    Rash macular
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 11 (9.09%)
    0 / 9 (0.00%)
    0 / 8 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    1
    0
    0
    1
    Psychiatric disorders
    Nervousness
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    0 / 9 (0.00%)
    1 / 8 (12.50%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    0
    1
    1
    Infections and infestations
    Infectious pleural effusion
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    1
    0
    1
    Sepsis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 11 (0.00%)
    1 / 9 (11.11%)
    0 / 8 (0.00%)
    1 / 38 (2.63%)
         occurrences all number
    0
    0
    1
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 Jan 2015
    - To clarify subject’s discontinuation from IMP if a serious adverse event occurs or an adverse event that is detrimental to the health of a subject. - To request the documentation of the heart rate during periods of oxygen desaturation. - State that the best approximation for expected adverse drug reactions for tapentadol IV solution is provided in the adverse drug reaction table for tapentadol IR tablets in the investigator’s brochure.
    24 Feb 2016
    - Specify the effect of the dead space volume of the infusion set for the IMP on the timing of subsequent assessments and blood sampling for pharmacokinetics. - Allow starting IMP before 24 hours after cardiac surgery if the subject is hemodynamically stable. - Clarify the medication restrictions for mothers of a newborn or breastfeeding mothers. - Allow other metabolites of tapentadol than tapentadol-O-glucuronide to be measured. - Adaptation of inclusion/exclusion criteria related to body weight, physical status, ECG, mechanical ventilation.
    04 May 2016
    - Implement dosing instructions for children aged less than 7 days old (postnatal).
    17 Nov 2016
    - The gestational age of preterm babies was widened to extend the coverage of the expected target population who will benefit from the treatment with tapentadol IV in the future. - The inclusion and exclusion criteria were adapted to better reflect the medical condition and standard of care of subjects in age subgroup 4. - The dosing instructions for children in age subgroup 4 were updated.
    17 Nov 2016
    - Due to the small blood volumes of preterm babies (age subgroup 4), blood sampling was restricted to a minimum and to align with the standard of care. - The timeline of the trial was extended. Safety experience from post-marketing data in adults was updated.
    04 Jan 2018
    - To lower the allowed gestational age from 30 weeks to 24 weeks, and supply appropriate dosing recommendations for these subjects. - To allow subjects with a painful procedure to be recruited to age subgroup 4 as an alternative to painful surgery.

    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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