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    Clinical Trial Results:
    Open-label evaluation of the pharmacokinetic profile, safety, and efficacy of tapentadol oral solution for the treatment of post-surgical pain in children and adolescents aged from 2 years to less than 18 years.

    Summary
    EudraCT number
    		 2013-002016-27
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    24 Feb 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Feb 2016
    First version publication date
    02 Aug 2015
    Other versions
    Summary report(s)
    		 ClinicalTrialsGov summary

    Trial information

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    Trial identification
    Sponsor protocol code
    KF5503/68
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01729728
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 IND: 116020
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr 6, Aachen, Germany, 52078
    Public contact
    Grünenthal Clinical Trial Helpdesk, Grünenthal GmbH, 49 241 569 3223, Clinical-Trials@grunenthal.com
    Scientific contact
    Grünenthal Clinical Trial Helpdesk, Grünenthal GmbH, 49 241 569 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
    28 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    24 Feb 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Feb 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacokinetic profile of tapentadol and its major metabolite tapentadol-O-glucuronide after the administration of a single dose of tapentadol oral solution in children and adolescents aged from 2 years to less than 18 years after a surgical procedure that routinely produces acute severe post-surgical pain.
    Protection of trial subjects
    The trial was conducted according to ICH-GCP guidelines, the applicable local laws, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Regulatory authorities were notified of the trial and amendments as required by national regulations, and where necessary relevant authorization was obtained. Furthermore, the competent authorities were notified of this trial in accordance with national requirements. The communication with the child or adolescent was done by staff who had experience with the informing of minors. The subject was asked for assent. This trial was designed to protect the interests of the children and adolescent subjects, including minimizing 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
    		 The trial enrolled healthy male or female subjects aged from 3 years to less than 18 years who had completed either dental surgery or a tonsillectomy and subjects aged 2 years to less than 3 years who had undergone ear, nose, or throat surgery (including but not limited to tonsillectomy). During anesthesia, the use of pre-medication, intraoperative medication and opioid analgesics were allowed according to the usual standard of care. During surgery, very short-acting benzodiazepines (i.e., t1/2 4 hours) and local anesthetics were allowed. It was expected that local anesthetics, such as those used for dental procedures, may take about 1 hour to 4 hours to dissipate. After the end of anesthesia, no opioid analgesics were given. Non-opioid analgesics were allowed. The interval between the last administration of a non-opioid analgesic and the administration of tapentadol oral solution was at least 30 minutes. After administration of tapentadol oral solution non-opioid analgesics were allowed as supplemental analgesic medication for persistent pain. Subjects were encouraged, but not required, to wait at least 1 hour after the intake of tapentadol oral solution before receiving further supplemental non-opioid analgesic medication. Morphine or another opioid were given according to medical judgment and usual standard of care if the subject continued to have persistent intolerable pain (subject perception) 2 hours or more after the administration of tapentadol oral solution despite having received a non-opioid analgesic.
    Evidence for comparator
    		 Not applicable - no comparator was used in this trial.
    Actual start date of recruitment
    15 Nov 2012
    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
    United States: 86
    Worldwide total number of subjects
    86
    EEA total number of subjects
    0
    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)
    61
    Adolescents (12-17 years)
    25
    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
    		 The first subject was enrolled on the 15 Nov 2012 and the last participant completed the trial on the 24 Feb 2014.

    Pre-assignment
    Screening details
    		 Consent was obtained for 86 subjects in the trial. 66 subjects were allocated and received study drug (investigational medicinal product). Pharmacokinetic data was obtained for the planned 56 subjects.

    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
    		 Adolescents
    Arm description
    		 Single dose of Tapentadol Oral Solution in Adolescents Age 12 to Less than 18 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tapentadol Oral Solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 1mg/kg body weight

    Arm title
    		 Children aged 6 to less than 12 years
    Arm description
    		 Single Dose of Tapentadol Oral Solution in Children Age 6 to less than 12 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tapentadol Oral Solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 1mg/kg body weight

    Arm title
    		 Children aged 2 to less than 6 years
    Arm description
    		 Single Dose of Tapentadol Oral Solution in Children Age 2 to less than 6 years.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Tapentadol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Single dose of 1mg/kg body weight

    Number of subjects in period 1 [1]
    		Adolescents Children aged 6 to less than 12 years Children aged 2 to less than 6 years
    Started
    21
    28
    17
    Completed
    20
    22
    16
    Not completed
    1
    6
    1
         Adverse event, non-fatal
    -
    6
    -
         Protocol deviation
    1
    -
    1
    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: Consent was obtained for 86 subjects. 66 subjects received IMP. Pharmacokinetic data was obtained for the planned 56 subjects.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Adolescents
    Reporting group description
    		 Single dose of Tapentadol Oral Solution in Adolescents Age 12 to Less than 18 years.

    Reporting group title
    Children aged 6 to less than 12 years
    Reporting group description
    		 Single Dose of Tapentadol Oral Solution in Children Age 6 to less than 12 years.

    Reporting group title
    Children aged 2 to less than 6 years
    Reporting group description
    		 Single Dose of Tapentadol Oral Solution in Children Age 2 to less than 6 years.

    Reporting group values
    		 Adolescents Children aged 6 to less than 12 years Children aged 2 to less than 6 years Total
    Number of subjects
    		 21 28 17 66
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 28 17 45
        Adolescents (12-17 years)
    		 21 0 0 21
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 15.5 ( 1.6 ) 8.3 ( 1.6 ) 3.4 ( 1.1 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 17 8 34
        Male
    		 12 11 9 32
    American Society of Anesthisiology Physical Status
    Units: Subjects
        P1
    		 21 26 16 63
        P2
    		 0 2 1 3
    Prior Medication
    Units: Subjects
        Prior medication
    		 21 28 17 66
    Concomitant medication
    Units: Subjects
        Concomitant medication
    		 17 21 15 53
        No concomitant medication
    		 4 7 2 13
    Type of surgery
    Units: Subjects
        Dental surgery
    		 16 0 0 16
        Tonsillectomy
    		 5 28 17 50
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    		 61.3 ( 9.78 ) 28.85 ( 5.89 ) 16.34 ( 2.2 ) -
    Height
    Units: meter
        arithmetic mean (standard deviation)
    		 1.706 ( 0.107 ) 1.329 ( 0.111 ) 1.017 ( 0.081 ) -

    End points

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    End points reporting groups
    Reporting group title
    Adolescents
    Reporting group description
    		 Single dose of Tapentadol Oral Solution in Adolescents Age 12 to Less than 18 years.

    Reporting group title
    Children aged 6 to less than 12 years
    Reporting group description
    		 Single Dose of Tapentadol Oral Solution in Children Age 6 to less than 12 years.

    Reporting group title
    Children aged 2 to less than 6 years
    Reporting group description
    		 Single Dose of Tapentadol Oral Solution in Children Age 2 to less than 6 years.

    Primary: Pharmacokinetic Profile of Serum Concentrations of Tapentadol after a Single Dose of Tapentadol Oral Solution in Adolescents

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    End point title
    		 Pharmacokinetic Profile of Serum Concentrations of Tapentadol after a Single Dose of Tapentadol Oral Solution in Adolescents [1] [2]
    End point description
    Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after IMP administration
    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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic profiles for the different arms are reported as separate endpoints, as the pharmacokinetic sampling schemes differ between the different age groups. Sampling schemes were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    End point values
    		 Adolescents
    Number of subjects analysed
    19 [3]
    Units: nanogram(s) / milliliter
    arithmetic mean (standard deviation)
        15 minutes after administration (N = 19)
    23.2 ( 34 )
        30 minutes after administration (N=18)
    45.6 ( 33 )
        1 hour after administration (N=18)
    49.4 ( 21.2 )
        2 hours after administration (N=18)
    43.1 ( 14.2 )
        4 hours after administration (N=17)
    32.8 ( 10.8 )
        6 hours after administration (N=18)
    22.3 ( 11.9 )
        11 hours after administration (N=18)
    8.14 ( 6.35 )
        15 hours after administration (N=17)
    3.66 ( 3.26 )
    Notes
    [3] - Subjects with pharmacokinetic data available.
    No statistical analyses for this end point

    Primary: Pharmacokinetic Profile of Serum Concentrations of Tapentadol-O-glucuronide After a Single Dose Tapentadol Oral Solution in Adolescents

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    End point title
    		 Pharmacokinetic Profile of Serum Concentrations of Tapentadol-O-glucuronide After a Single Dose Tapentadol Oral Solution in Adolescents [4] [5]
    End point description
    Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in subjects. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [4] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic profiles for the different arms are reported as separate endpoints, as the pharmacokinetic sampling schemes differ between the different age groups. Sampling schemes were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    End point values
    		 Adolescents
    Number of subjects analysed
    18 [6]
    Units: nanogram(s)/milliliter
    arithmetic mean (standard deviation)
        15 minutes after administration (N = 18)
    404 ( 581 )
        30 minutes after administration (N=17)
    855 ( 672 )
        1 hour after administration (N=17)
    1424 ( 542 )
        2 hours after administration (N=18)
    1202 ( 366 )
        4 hours after administration (N=17)
    824 ( 191 )
        6 hours after administration (N=18)
    497 ( 138 )
        11 hours after administration (N=18)
    150 ( 69 )
        15 hours after administration (N=17)
    66.9 ( 35.4 )
    Notes
    [6] - Subjects with pharmacokinetic data available.
    No statistical analyses for this end point

    Primary: Pharmacokinetic Profile of Serum Concentrations of Tapentadol After a Single Dose of Tapentadol Oral Solution in Children Age 6 to less than 12 years

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    End point title
    		 Pharmacokinetic Profile of Serum Concentrations of Tapentadol After a Single Dose of Tapentadol Oral Solution in Children Age 6 to less than 12 years [7] [8]
    End point description
    Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [7] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic profiles for the different arms are reported as separate endpoints, as the pharmacokinetic sampling schemes differ between the different age groups. Sampling schemes were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    End point values
    		 Children aged 6 to less than 12 years
    Number of subjects analysed
    22 [9]
    Units: nanogram(s)/milliliter
    arithmetic mean (standard deviation)
        15 minutes to 1 hour after administration (N = 22)
    36.5 ( 21.8 )
        1 to 4 hours after administration (N=22)
    36.5 ( 15.7 )
        4 to 11 hours after administration (N=22)
    13.5 ( 6.52 )
        11 to 15 hours after administration (N=22)
    3.71 ( 1.96 )
    Notes
    [9] - Subjects with pharmacokinetic data available.
    No statistical analyses for this end point

    Primary: Pharmacokinetic Profile of Serum Concentrations of Tapentadol-O-glucuronide After a Single Dose of Tapentadol Oral Solution in Children Age 6 to less than 12 years

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    End point title
    		 Pharmacokinetic Profile of Serum Concentrations of Tapentadol-O-glucuronide After a Single Dose of Tapentadol Oral Solution in Children Age 6 to less than 12 years [10] [11]
    End point description
    Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after dosing
    Notes
    [10] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic profiles for the different arms are reported as separate endpoints, as the pharmacokinetic sampling schemes differ between the different age groups. Sampling schemes were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model
    End point values
    		 Children aged 6 to less than 12 years
    Number of subjects analysed
    22 [12]
    Units: nanogram(s)/milliliter
    arithmetic mean (standard deviation)
        15 minutes to 1 hour after administration (N = 20)
    676 ( 343 )
        1 to 4 hours after administration (N=22)
    900 ( 330 )
        4 to 11 hours after administration (N=22)
    321 ( 123 )
        11 to 15 hours after administration (N=22)
    86.3 ( 37.8 )
    Notes
    [12] - Subjects with pharmacokinetic data available.
    No statistical analyses for this end point

    Primary: Pharmacokinetic Profile of Serum Concentrations of Tapentadol After a Single Dose of Tapentadol Oral Solution in Children Age 3 to less than 6 years

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    End point title
    		 Pharmacokinetic Profile of Serum Concentrations of Tapentadol After a Single Dose of Tapentadol Oral Solution in Children Age 3 to less than 6 years [13] [14]
    End point description
    Mean and Standard Deviation of Serum Concentrations of Tapentadol. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 0.2 ng/mL.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [13] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic profiles for the different arms are reported as separate endpoints, as the pharmacokinetic sampling schemes differ between the different age groups. Sampling schemes were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    End point values
    		 Children aged 2 to less than 6 years
    Number of subjects analysed
    11
    Units: nanogram(s)/milliliter
    arithmetic mean (standard deviation)
        15 minutes after administration (N=11)
    30.1 ( 19.2 )
        4 to 11 hours after administration (N=11)
    26.4 ( 10.7 )
    No statistical analyses for this end point

    Primary: Pharmacokinetic Profile of Serum Concentrations of Tapentadol-O-glucuronide After a Single Dose of Tapentadol Oral Solution in Children Age 3 to less than 6 years

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    End point title
    		 Pharmacokinetic Profile of Serum Concentrations of Tapentadol-O-glucuronide After a Single Dose of Tapentadol Oral Solution in Children Age 3 to less than 6 years [15] [16]
    End point description
    Mean and Standard Deviation of Serum Concentrations of Tapentadol-O-glucuronide. Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Tapentadol-O-glucuronide concentrations were measured in participants. Serum was analyzed by means of liquid chromatography coupled to tandem mass spectrometry with a lower limit of quantification (LLOQ) at 10 ng/mL.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [15] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic profiles for the different arms are reported as separate endpoints, as the pharmacokinetic sampling schemes differ between the different age groups. Sampling schemes were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    End point values
    		 Children aged 2 to less than 6 years
    Number of subjects analysed
    11
    Units: nanogram(s)/milliliter
    arithmetic mean (standard deviation)
        15 minutes to 1 hour after administration (N = 10)
    494 ( 377 )
        4 to 11 hours after administration (N=11)
    504 ( 112 )
    No statistical analyses for this end point

    Primary: Non-Compartmental Pharmacokinetic (PK) Parameter of Tapentadol Area Under the Concentration-Time Curve (AUC0-15) After a Single Dose of Tapentadol in Adolescents

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    End point title
    		 Non-Compartmental Pharmacokinetic (PK) Parameter of Tapentadol Area Under the Concentration-Time Curve (AUC0-15) After a Single Dose of Tapentadol in Adolescents [17] [18]
    End point description
    Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age. The area under the curve from dose to 15 hours (AUC 0-15) is a summary measure of data from each pharmacokinetic blood sample taken over the 15 hour time period. The area is that below the line fitted to the data points. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [17] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic sampling schemes differ between the different age groups, and only a frequent pharmacokinetic sampling scheme as applicable for this arm allows for determination of non-compartmental pharmacokinetic parameters.
    End point values
    		 Adolescents
    Number of subjects analysed
    18 [19]
    Units: ng*hr/mL
        arithmetic mean (full range (min-max))
    302 (218 to 636)
    Notes
    [19] - Subjects with pharmacokinetic data.
    No statistical analyses for this end point

    Primary: Non-Compartmental Pharmacokinetic (PK) Parameter: Cmax (Maximum Concentration) of Tapentadol After a Single Dose of Tapentadol in Adolescents

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    End point title
    		 Non-Compartmental Pharmacokinetic (PK) Parameter: Cmax (Maximum Concentration) of Tapentadol After a Single Dose of Tapentadol in Adolescents [20] [21]
    End point description
    Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol (active drug) is assessed during absorption and distribution. The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of active drug observed in the blood sample.
    End point type
    Primary
    End point timeframe
    Up 15 hours after IMP administration
    Notes
    [20] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic sampling schemes differ between the different age groups, and only a frequent pharmacokinetic sampling scheme as applicable for this arm allows for determination of non-compartmental pharmacokinetic parameters.
    End point values
    		 Adolescents
    Number of subjects analysed
    18 [22]
    Units: nanogram(s)/milliliter
        arithmetic mean (standard error)
    67.5 ( 26.3 )
    Notes
    [22] - Subjects with pharmacokinetic data.
    No statistical analyses for this end point

    Primary: Non-Compartmental Pharmacokinetic (PK) Parameter: Time to Maximum Concentration (Tmax) of Tapentadol After a Single Dose of Tapentadol in Adolescents

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    End point title
    		 Non-Compartmental Pharmacokinetic (PK) Parameter: Time to Maximum Concentration (Tmax) of Tapentadol After a Single Dose of Tapentadol in Adolescents [23] [24]
    End point description
    Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in participants 12 years to less than 18 years of age. The time to maximum concentration is derived from the area under the curve from dose to 15 hours (AUC 0-15). The Tmax is the time after dosing at which the maximum concentration of the tapentadol (active drug) occurs. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [23] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic sampling schemes differ between the different age groups, and only a frequent pharmacokinetic sampling scheme as applicable for this arm allows for determination of non-compartmental pharmacokinetic parameters.
    End point values
    		 Adolescents
    Number of subjects analysed
    18 [25]
    Units: hour(s)
        arithmetic mean (standard deviation)
    1.4 ( 1.1 )
    Notes
    [25] - Subjects with pharmacokinetic data.
    No statistical analyses for this end point

    Primary: Non-Compartmental Pharmacokinetic (PK) Parameter of Tapentadol-O-glucuronide Area Under the Concentration-Time Curve (AUC 0-15) After a Single Dose of Tapentadol in Adolescents

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    End point title
    		 Non-Compartmental Pharmacokinetic (PK) Parameter of Tapentadol-O-glucuronide Area Under the Concentration-Time Curve (AUC 0-15) After a Single Dose of Tapentadol in Adolescents [26] [27]
    End point description
    Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in subjects 12 years to less than 18 years of age. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol-O-glucuronide (metabolite) is assessed during absorption and distribution.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [26] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic sampling schemes differ between the different age groups, and only a frequent pharmacokinetic sampling scheme as applicable for this arm allows for determination of non-compartmental pharmacokinetic parameters.
    End point values
    		 Adolescents
    Number of subjects analysed
    18
    Units: ng*hr/mL
        arithmetic mean (full range (min-max))
    7082 (4946 to 9689)
    No statistical analyses for this end point

    Primary: Non-Compartmental Pharmacokinetic (PK) Parameter: Time to Maximum Concentration (Tmax) of Tapentadol-O-glucuronide After a Single Dose of Tapentadol in Adolescents

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    End point title
    		 Non-Compartmental Pharmacokinetic (PK) Parameter: Time to Maximum Concentration (Tmax) of Tapentadol-O-glucuronide After a Single Dose of Tapentadol in Adolescents [28] [29]
    End point description
    Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Serum samples for pharmacokinetic analysis were obtained using frequent sampling techniques in subjects 12 years to less than 18 years of age. The time to maximum concentration is derived from the area under the curve from dose to 15 hours (AUC 0-15). The Tmax is the time after dosing at which the maximum concentration of the tapentadol-O-glucuronide (metabolite) occurs. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [28] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic sampling schemes differ between the different age groups, and only a frequent pharmacokinetic sampling scheme as applicable for this arm allows for determination of non-compartmental pharmacokinetic parameters.
    End point values
    		 Adolescents
    Number of subjects analysed
    18 [30]
    Units: nanogram(s)/milliliter
        arithmetic mean (standard deviation)
    1.7 ( 1.19 )
    Notes
    [30] - Subjects with pharmacokinetic data available.
    No statistical analyses for this end point

    Primary: Non-Compartmental Pharmacokinetic (PK) Parameter: Cmax (Maximum Concentration) of Tapentadol-O-glucuronide After a Single Dose of Tapentadol in Adolescents

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    End point title
    		 Non-Compartmental Pharmacokinetic (PK) Parameter: Cmax (Maximum Concentration) of Tapentadol-O-glucuronide After a Single Dose of Tapentadol in Adolescents [31] [32]
    End point description
    Tapentadol-O-glucuronide is the metabolite of tapentadol. Metabolites are sometimes referred to as "breakdown products". The body alters the administered medication to a metabolite so that it can be more easily or quickly removed from the body. Serum samples (frequent sampling) were drawn at 0.25, 0.5, 1, 2, 4, 6, 11, and 15 hours. The concentration of tapentadol-O-glucuronide (metabolite) is assessed to study absorption and distribution. The maximum concentration is derived from the Area Under the Curve, from dose to 15 hours (AUC 0-15). It is the highest amount of metabolite observed in the blood sample.
    End point type
    Primary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [31] - 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: The sample sizes for the age groups were not chosen based on statistical considerations of clinical endpoints, but were selected to limit the exposure in pediatric subjects whilst providing sufficient data to explore a population pharmacokinetic model.
    [32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: The pharmacokinetic sampling schemes differ between the different age groups, and only a frequent pharmacokinetic sampling scheme as applicable for this arm allows for determination of non-compartmental pharmacokinetic parameters.
    End point values
    		 Adolescents
    Number of subjects analysed
    18 [33]
    Units: nanogram(s)/milliliter
        arithmetic mean (standard error)
    1487 ( 495 )
    Notes
    [33] - Subjects with pharmacokinetic data available.
    No statistical analyses for this end point

    Secondary: Pain Intensity Assessments Using the Visual Analog Scale (VAS) in Adolescents

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    End point title
    		 Pain Intensity Assessments Using the Visual Analog Scale (VAS) in Adolescents [34]
    End point description
    At predefined times after investigational medicinal product administration participants in the Arms with Adolescents (age 12 to less than 18 years) were asked to rate their pain on 100 mm line (visual analog scale - VAS) by marking a point on the line in response to: “My pain at this time is”. The mark was scored between “no pain” and ” pain as bad as it could be”. The distance was then measured by a clinician and reported. A value of 0 indicates "no pain". A value of 100 indicates "pain as bad as it could be".
    End point type
    Secondary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pain intensity was assessed using age appropriate pain scales. Therefore, different pain scales were used for the different arms, and are thus reported separately.
    End point values
    		 Adolescents
    Number of subjects analysed
    21
    Units: units on a scale
    arithmetic mean (standard deviation)
        Pre-dosing
    71.5 ( 13.3 )
        15 minutes after dosing
    63.6 ( 24.4 )
        30 minutes after dosing
    53.2 ( 27.3 )
        1 hour after dosing
    46.3 ( 26.5 )
        2 hours after dosing
    34 ( 24.6 )
        4 hours after dosing
    43.5 ( 26.8 )
        6 hours after dosing
    34.8 ( 24.3 )
        11 hours after dosing
    32.7 ( 21.1 )
        15 hours after dosing
    33.4 ( 20.1 )
    No statistical analyses for this end point

    Secondary: Pain Intensity Assessments Using the McGrath Color Analog Scale in Adolescent Subjects and Children Age 6 years and older

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    End point title
    		 Pain Intensity Assessments Using the McGrath Color Analog Scale in Adolescent Subjects and Children Age 6 years and older [35]
    End point description
    Pain intensity assessments were with a 0 (no pain) to 10 (worst pain) scored McGrath color analog scale (CAS) in participants aged 6 years to less than 18 years, i.e. in Adolescents and Older Children. Subjects were presented with the CAS and instructed to place the sliding bar on the color that best represented their pain intensity level at the time of assessment. The CAS is a pocket size tool used to measure the self-reported pain intensity of the older participants. The CAS consists of a 145 mm long triangular shaped strip of plastic, varying in width and hue from 1 mm wide and light pink hue at the bottom (and text no pain), to 3 mm wide and deep red hue at the top (most pain). This instrument includes 2 sides. One side shows the color pain intensity scale as described and the other shows a graduated scale, which provides a specific numeric value for the subject-reported level of pain.
    End point type
    Secondary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pain intensity was assessed using age appropriate pain scales. Therefore, different pain scales were used for the different arms, and are thus reported separately.
    End point values
    		 Adolescents Children aged 6 to less than 12 years
    Number of subjects analysed
    21 [36]
    28 [37]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Pre-dose
    6.643 ( 1.461 )
    4.67 ( 1.602 )
        15 minutes after dosing
    6.131 ( 2.18 )
    3.071 ( 1.718 )
        30 minutes after dosing
    5.262 ( 2.311 )
    2.571 ( 1.824 )
        1 hour after dosing
    4.393 ( 2.299 )
    2.407 ( 1.723 )
        2 hours after dosing
    3.475 ( 2.173 )
    2.292 ( 1.793 )
        4 hours after dosing
    4.2 ( 2.113 )
    2.341 ( 1.899 )
        6 hours after dosing
    3.438 ( 1.96 )
    2.636 ( 2.152 )
        11 hours after dosing
    3.35 ( 1.836 )
    3.352 ( 1.851 )
        15 hours after dosing
    3.288 ( 1.578 )
    3.568 ( 2.549 )
    Notes
    [36] - Subjects with data available.
    [37] - Subjects with data available.
    No statistical analyses for this end point

    Secondary: Pain Intensity Assessments Using the Faces Pain Scale (Revised) in Children Age 3 to Less Than 12 Years

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    End point title
    		 Pain Intensity Assessments Using the Faces Pain Scale (Revised) in Children Age 3 to Less Than 12 Years [38]
    End point description
    This assessment tool was used in 3 to less than 12 year old participants. The Faces Pain Scale (Revised) [FPS-R] score as allocated to a selected face by the subject. There are 6 faces and the subject is asked to indicate on a face to express how much it hurts. The numeric value 0 (no pain) to 10 (very much pain) is read off the reverse side of the scale by the clinician. The protocol pre-specified that the Faces Pain Scale (Revised) would not be administered in the very young subjects (aged 2 to less than 3 years).
    End point type
    Secondary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [38] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pain intensity was assessed using age appropriate pain scales. Therefore, different pain scales were used for the different arms, and are thus reported separately.
    End point values
    		 Children aged 6 to less than 12 years Children aged 2 to less than 6 years
    Number of subjects analysed
    28
    12 [39]
    Units: units on a scale
    arithmetic mean (standard deviation)
        Pre-dose
    4.8 ( 1.6 )
    6.8 ( 3.2 )
        15 minutes after dosing
    3.5 ( 1.8 )
    4.5 ( 3.2 )
        30 minutes after dosing
    2.9 ( 1.8 )
    2.8 ( 3.2 )
        1 hour after dosing
    2.4 ( 1.6 )
    1.8 ( 3.3 )
        2 hours after dosing
    2.6 ( 1.7 )
    1.2 ( 2.9 )
        4 hours after dosing
    2.5 ( 1.6 )
    3.5 ( 3.2 )
        6 hours after dosing
    2.7 ( 2.1 )
    1.8 ( 2.3 )
        11 hours after dosing
    2.7 ( 1.7 )
    2.3 ( 2.4 )
        15 hours after dosing
    3.5 ( 2.2 )
    2.8 ( 2.9 )
    Notes
    [39] - 2 year old subjects were excluded.
    No statistical analyses for this end point

    Secondary: Pain Intensity Assessment Using the Face, Legs, Activity, Cry, Consolability Scale Children Age 2 to Less Than 6 Years

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    End point title
    		 Pain Intensity Assessment Using the Face, Legs, Activity, Cry, Consolability Scale Children Age 2 to Less Than 6 Years [40]
    End point description
    The Face Legs Activity Cry Consolability (FLACC) Scale was developed by the Department of Anesthesiology, University of Michigan Medical School and Health Systems. The FLACC Scale is a behavioral scale for scoring postoperative pain in children between the ages of two months and seven years or in persons unable to communicate. In this trial the scale was used in the young and very young children, i.e. in participants aged 2 to less than 6 years. This tool includes five categories of pain behaviors, including facial expression, leg movement, activity, cry, and consolability the clinician observes the participant for 5 minutes or more and scores each category with a 0, 1 or 2. The scores are added together for a total score ranging from 0 (no pain) to 10 (worst pain). The higher the total score the higher the pain. The protocol pre-specified that the young (3 to less than 6 year olds) and very young children (2 to less than 3 year olds) will be reported as one group.
    End point type
    Secondary
    End point timeframe
    Up to 15 hours after IMP administration
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Pain intensity was assessed using age appropriate pain scales. Therefore, different pain scales were used for the different arms, and are thus reported separately.
    End point values
    		 Children aged 2 to less than 6 years
    Number of subjects analysed
    17
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Pre-dose
    4.2 ( 2.2 )
        15 minutes after dosing
    1.8 ( 1.6 )
        30 minutes after dosing
    1.2 ( 1.6 )
        1 hour after dosing
    1.1 ( 1.4 )
        2 hours after dosing
    0.8 ( 1.1 )
        4 hours after dosing
    1.5 ( 1.7 )
        6 hours after dosing
    0.8 ( 1.6 )
        11 hours after dosing
    0.9 ( 2.1 )
        15 hours after dosing
    0.8 ( 1.2 )
    No statistical analyses for this end point

    Secondary: Sum of Pain Intensity Differences Over the 4 Hours After Dosing Derived From the Different Pain Scales and for Children Age 2 to less than 18

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    End point title
    		 Sum of Pain Intensity Differences Over the 4 Hours After Dosing Derived From the Different Pain Scales and for Children Age 2 to less than 18
    End point description
    Different pain intensity assessment tools were used in the different age groups. Therefore the sum of pain intensities were calculated and are reported for each age group based on the tool used. Adolescents - Age 12 to Less than 18 Years - VAS (100 mm Visual Analog Scale) [Theoretical Range: -400 to + 400], Age 6 to Less Than 12 Years - CAS (McGrath color analog scale) [Theoretical Range: -40 to + 40], Young and Very young children - Age to less than 6 Years - FLACC (Face, Legs, Activity, Cry, and Consolability score) [Theoretical Range: -40 to + 40]. A mean score of zero indicates that there was no pain intensity change over the 4 hours. The positive values indicate that in the group as a whole the sum of all pain intensity values over the first 4 hours lead to a reduction in pain in the time period.
    End point type
    Secondary
    End point timeframe
    Up to 4 hours after IMP administration
    End point values
    		 Adolescents Children aged 6 to less than 12 years Children aged 2 to less than 6 years
    Number of subjects analysed
    20 [41]
    22 [42]
    16 [43]
    Units: units on a scale
        arithmetic mean (standard deviation)
    106.282 ( 75.35 )
    9.698 ( 7.61 )
    11.831 ( 8.193 )
    Notes
    [41] - SPID based on VAS
    [42] - SPID based on CAS
    [43] - SPID based on FLACC
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Any adverse event that started on the intake of tapentadol up to 48 hours thereafter.
    Adverse event reporting additional description
    For tapentadol oral solution, the therapeutic reach is defined as 48 hours after intake.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Adolescents
    Reporting group description
    		 Single dose of Tapentadol Oral Solution in Adolescents Age 12 to Less than 18 years.

    Reporting group title
    Children aged 6 to less than 12 years
    Reporting group description
    		 Single Dose of Tapentadol Oral Solution in Children Age 6 to less than 12 years.

    Reporting group title
    Children aged 2 to less than 6 years
    Reporting group description
    		 Single Dose of Oral Solution in Children Age 2 to less than 6 years.

    Serious adverse events
    		 Adolescents Children aged 6 to less than 12 years Children aged 2 to less than 6 years
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 3.6%
    Non-serious adverse events
    		 Adolescents Children aged 6 to less than 12 years Children aged 2 to less than 6 years
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 21 (57.14%)
    20 / 28 (71.43%)
    6 / 17 (35.29%)
    Investigations
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    1
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac murmur
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 21 (14.29%)
    3 / 28 (10.71%)
    0 / 17 (0.00%)
         occurrences all number
    3
    3
    0
    Headache
         subjects affected / exposed
    2 / 21 (9.52%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    2
    0
    2
    Somnolence
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    Tremor
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Infusion site irritation
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Pyrexia
         subjects affected / exposed
    1 / 21 (4.76%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
         occurrences all number
    1
    1
    0
    Vessel puncture site bruise
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Diplopia
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal upper pain
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Constipation
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Enlarged uvula
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Nausea
         subjects affected / exposed
    6 / 21 (28.57%)
    9 / 28 (32.14%)
    1 / 17 (5.88%)
         occurrences all number
    6
    12
    1
    Vomiting
         subjects affected / exposed
    3 / 21 (14.29%)
    8 / 28 (28.57%)
    0 / 17 (0.00%)
         occurrences all number
    3
    9
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 28 (0.00%)
    2 / 17 (11.76%)
         occurrences all number
    0
    0
    2
    Epistaxis
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Nasal discomfort
         subjects affected / exposed
    0 / 21 (0.00%)
    0 / 28 (0.00%)
    1 / 17 (5.88%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0
    Rash
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Infections and infestations
    Otitis media
         subjects affected / exposed
    1 / 21 (4.76%)
    0 / 28 (0.00%)
    0 / 17 (0.00%)
         occurrences all number
    1
    0
    0
    Otitis media viral
         subjects affected / exposed
    0 / 21 (0.00%)
    1 / 28 (3.57%)
    0 / 17 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Sep 2012
    This amendment reflected the feedback from regulatory authorities, and implemented correction of inconsistencies in the original protocol including minor editorial changes. This amendment was implemented before the start of subject recruitment.
    26 Mar 2013
    This amendment enabled the enrollment of children aged 3 years to less than 6 years. An interim analysis of safety and pharmacokinetic data from this trial was required regarding the need for dose determination and validation via population pharmacokinetic models prior to the start of other trials investigating the efficacy of tapentadol in moderate to severe acute and chronic pain in the pediatric population.
    20 Aug 2013
    This amendment enabled the enrollment of children aged 2 years to less than 3 years.

    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.
    Another opioid may have been given according to medical judgment/standard of care if the subject had persistent intolerable pain 2 hours or more after administration of tapentadol oral solution even if a non-opioid analgesic had been administered.
    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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