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    Clinical Trial Results:
    An evaluation of the efficacy and safety of tapentadol oral solution in the treatment of post-operative acute pain requiring opioid treatment in pediatric subjects aged from birth to less than 18 years old.

    Summary
    EudraCT number
    2012-004359-35
    Trial protocol
    SE   DE   GB   ES   AT   FR   PL   HR   HU   BG   CZ  
    Global end of trial date
    14 Mar 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    22 Sep 2019
    First version publication date
    15 Jun 2017
    Other versions
    v1
    Version creation reason
    • New data added to full data set
    Data for subjects below the age of 2 years (including premature infants) are added

    Trial information

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    Trial identification
    Sponsor protocol code
    KF5503/65
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02081391
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    IND: 108134, Grünenthal: KF5503/65, Depomed: R331333PAI3037
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52078
    Public contact
    Grünenthal Trial Information Desk, Grünenthal GmbH, +49 241569 3223, Clinical-Trials@grunenthal.com
    Scientific contact
    Grünenthal Trial Information Desk, 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
    28 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    14 Mar 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    14 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This trial was performed to meet requirements for pediatric development plans agreed with authorities in 2 regions (Paediatric Committee of the European Medicines Agency [EU PDCO] and United States Food and Drug Administration [US FDA]). Main objectives of the trial for EU PDCO/US FDA: Efficacy and safety of tapentadol oral solution in children and adolescents who had undergone surgery that, in the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment. Efficacy was analysed based on the total amount of supplemental opioid analgesic medication used over 24 hours (EU PDCO) and 12 hours (US FDA) following initiation of IMP. Data for the EU part (in subjects aged 2 years to less than 18 years old) were presented in Version 1 of this record. Treatment of subjects aged less than 2 years old for the completion of the US part (subjects from birth to less than 17 years old) was completed in March 2019, results are added in Version 2 of the record.
    Protection of trial subjects
    The trial was conducted according to Good Clinical Practice guidelines, the applicable local laws, 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. An independent data monitoring committee was established to oversee subject’s safety in ongoing tapentadol trials in the pediatric population. Subjects were carefully observed, especially during the first hour after the initiation of IMP. Vital signs (respiratory rate, systolic and diastolic blood pressure, and pulse rate), sedation score, and oxygen saturation were measured before each dose of IMP was given. Respiratory rate and heart rate had to be constantly monitored for 24 hours after first does of IMP and afterwards according local standard of care. Oxygen saturation had to be monitored constantly using pulse oximetry from before first dose of IMP until 4 hours after the last dose of IMP.
    Background therapy
    At some time after the surgery, the subject had started on nurse-controlled or patient-controlled analgesia (NCA/PCA) with morphine or hydromorphone according to the standard of care. Medications for the treatment of adverse events were allowed according to the investigator’s judgment and post-operative standard of care e.g., clinically relevant respiratory depression treated with naloxone, and nausea/vomiting treated with antiemetics, which may have been given prophylactically according to the standard of care. In exceptional cases, if a subject had unbearable pain despite using NCA/PCA, an additional bolus of morphine or hydromorphone was allowed using either the NCA/PCA pump system or by an intravenous bolus injection.
    Evidence for comparator
    N/A
    Actual start date of recruitment
    19 Feb 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
    Poland: 45
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Croatia: 12
    Country: Number of subjects enrolled
    Bulgaria: 15
    Country: Number of subjects enrolled
    Czech Republic: 13
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hungary: 9
    Country: Number of subjects enrolled
    United States: 93
    Worldwide total number of subjects
    216
    EEA total number of subjects
    123
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    6
    Infants and toddlers (28 days-23 months)
    17
    Children (2-11 years)
    95
    Adolescents (12-17 years)
    98
    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 trial started on 19 Feb 2015 with the enrollment of the first subject. Recruitment for the EU PDCO set (subjects aged 2 years to less than 18 years old) was completed on 05 Dec 2016 with the last subject out (LSO). Recruitment of the remaining subjects aged less than 2 years old for the US FDA population was completed on 14 Mar 2019 (LSO).

    Pre-assignment
    Screening details
    A total of 216 subjects (or parents/caregivers) gave informed consent to participate in the trial, 180 of these subjects were allocated to study drug (investigational medicinal product = IMP) and 175 subjects received IMP (56 subjects on placebo and 119 subjects on tapentadol).

    Pre-assignment period milestones
    Number of subjects started
    216
    Number of subjects completed
    180 [1]

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Adverse event, non-fatal: 1
    Reason: Number of subjects
    Consent withdrawn by the parent(s) or subjects: 4
    Reason: Number of subjects
    Inclusion criteria not met /exclusion criteria met: 28
    Reason: Number of subjects
    Other not specified: 3
    Notes
    [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1.
    Justification: A total of 180 subjects were allocated to IMP. Thereof, 5 subjects were allocated but not treated because after allocation, these were violating inclusion/exclusion criteria (2), consent was withdrawn (2) or for other reasons (1). A total of 175 subjects received IMP (56 subjects on placebo and 119 subjects on tapentadol).
    Period 1
    Period 1 title
    12-h treatment period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The trial was double-blinded to prevent bias. The blind was broken for the EU PDCO set before recruitment of the <6 month-old subjects in the US FDA set was completed. Subjects not belonging to the EU PDCO set (<2 years old) remained blinded (as independent randomization lists were used for subjects aged less than 2 years old) and were unblinded only after the data base was locked for all subjects from birth to less than 2 years old who were included in the US FDA <2 years population.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    12-h treatment period - Overall (EU PDCO)
    Arm description
    All male and female subjects aged 2 years to less than 18 years who received at least 1 dose of IMP were considered for this arm. Subject had undergone surgery that, in the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment via nurse-controlled analgesia (NCA) or patient-controlled analgesia (PCA) .
    Arm type
    Overall

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    12-h treatment period - Tapentadol (EU PDCO)
    Arm description
    This arm includes all subjects who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.
    Arm type
    Experimental

    Investigational medicinal product name
    Tapentadol oral solution
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dose administered depended on the subject's body weight. The dose to be administered was 1.25 mg/kg during the first 24 hours (the maximum individual dose of tapentadol was 100 mg). The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.

    Arm title
    12-h treatment period - Placebo (EU PDCO)
    Arm description
    This arm includes all subjects who received at least 1 dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dose administered depended on the subject's body weight. The dose to be administered was 1.25 mg/kg during the first 24 hours (equivalent to tapentadol). The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.

    Arm title
    12-h treatment period - Overall (US FDA <2 years)
    Arm description
    All male and female subjects aged from birth (at least 37 weeks gestational age) to less than 2 years who received at least 1 dose of tapentadol OS or placebo were considered for this arm. Subjects had undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment via NCA.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    12-h treatment period - Tapentadol (US FDA <2 years)
    Arm description
    This arm includes all subjects from birth to less than 2 years of age who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.
    Arm type
    Experimental

    Investigational medicinal product name
    Tapentadol oral solution
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dose administered depended on the subject's body weight. The dose to be administered was 1.25 mg/kg during the first 24 hours (the maximum individual dose of tapentadol was 100 mg). Subjects aged 30 days to <6 months old were to be administered a dose of 0.5 mg/kg or placebo, neonates from birth to <30 days old a dose of 0.1 mg/kg during the first 24 hours. The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.

    Arm title
    12-h treatment period - Placebo (US FDA <2 years)
    Arm description
    This arm includes all subjects from birth to less than 2 years of age who received at least one dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo oral solution
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dose administered depended on the subject's body weight. The dose to be administered was 1.25 mg/kg during the first 24 hours (the maximum individual dose of tapentadol was 100 mg). Subjects aged 30 days to <6 months old were to be administered a dose of 0.5 mg/kg or placebo, neonates from birth to <30 days old a dose of 0.1 mg/kg during the first 24 hours. The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.

    Number of subjects in period 1
    12-h treatment period - Overall (EU PDCO) 12-h treatment period - Tapentadol (EU PDCO) 12-h treatment period - Placebo (EU PDCO) 12-h treatment period - Overall (US FDA <2 years) 12-h treatment period - Tapentadol (US FDA <2 years) 12-h treatment period - Placebo (US FDA <2 years)
    Started
    160
    108
    52
    15
    11
    4
    Completed
    136
    90
    46
    14
    10
    4
    Not completed
    24
    18
    6
    1
    1
    0
         Consent withdrawn by the parent(s) or subjects
    5
    3
    2
    -
    -
    -
         Physician decision
    5
    4
    1
    -
    -
    -
         Other
    3
    2
    1
    -
    -
    -
         Lack of efficacy
    3
    3
    -
    -
    -
    -
         Adverse event, non-fatal
    6
    4
    2
    -
    -
    -
         Recovery (opioid analgesic no longer needed)
    2
    2
    -
    1
    1
    -
    Period 2
    Period 2 title
    24-h treatment/trial completion
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The trial was double-blinded to prevent bias. The blind was broken for the EU PDCO set before recruitment of the less than 2 year olds in the US FDA set was completed. Subjects less than 2 years old in the US FDA set remained blinded (as independent randomization lists were used for subjects aged less than 2 years old), and were unblinded only after the database was locked for all subjects included in the US FDA <2 years set (subjects from birth to less than 2 years old).

    Arms
    Are arms mutually exclusive
    No

    Arm title
    24-h treatment/trial completion - Overall (EU PDCO)
    Arm description
    All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of IMP and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).
    Arm type
    Overall

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    24-h treatment/trial completion - Tapentadol (EU PDCO)
    Arm description
    All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of tapentadol oral solution and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).
    Arm type
    Experimental

    Investigational medicinal product name
    Tapentadol oral solution
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dose administered depended on the subject's body weight. The dose to be administered was 1.25 mg/kg during the first 24 hours (the maximum individual dose of tapentadol was 100 mg). The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.

    Arm title
    24-h treatment/trial completion - Placebo (EU PDCO)
    Arm description
    All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of placebo and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dose administered depended on the subject's body weight. The dose to be administered was 1.25 mg/kg during the first 24 hours (equivalent to tapentadol). The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.

    Arm title
    24-h treatment/trial completion - Overall (US FDA <2 years)
    Arm description
    All male and female subjects aged below 2 years who received at least 1 dose of IMP and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    24-h treatment/trial completion - Tapentadol (US FDA <2 years)
    Arm description
    All male and female subjects aged below 2 years who received at least 1 dose of tapentadol and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).
    Arm type
    Experimental

    Investigational medicinal product name
    Tapentadol oral solution
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dose administered depended on the subject's body weight. The dose to be administered was 1.25 mg/kg during the first 24 hours (the maximum individual dose of tapentadol was 100 mg). Subjects aged 30 days to <6 months old were to be administered a dose of 0.5 mg/kg or placebo, neonates from birth to <30 days old a dose of 0.1 mg/kg during the first 24 hours. The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.

    Arm title
    24-h treatment/trial completion - Placebo (US FDA <2 years)
    Arm description
    All male and female subjects aged below 2 years who received at least 1 dose of placebo and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    The dose administered depended on the subject's body weight. The dose to be administered was 1.25 mg/kg during the first 24 hours (equivalent to tapentadol). Subjects aged 30 days to <6 months old were to be administered a dose of 0.5 mg/kg or placebo, neonates from birth to <30 days old a dose of 0.1 mg/kg during the first 24 hours. The dosing interval was 4 hours (range ±15 minutes). If the subject was sleeping at the time of the scheduled dose, they were woken to take the IMP within a maximum of 6 hours after the previous dose. The dose of IMP was given as soon as possible after the subject was awake. The administration of IMP was based on the investigator’s judgment of the subject’s condition and sedation level.

    Number of subjects in period 2
    24-h treatment/trial completion - Overall (EU PDCO) 24-h treatment/trial completion - Tapentadol (EU PDCO) 24-h treatment/trial completion - Placebo (EU PDCO) 24-h treatment/trial completion - Overall (US FDA <2 years) 24-h treatment/trial completion - Tapentadol (US FDA <2 years) 24-h treatment/trial completion - Placebo (US FDA <2 years)
    Started
    136
    90
    46
    14
    10
    4
    Completed
    91
    63
    28
    13
    9
    4
    Not completed
    45
    27
    18
    1
    1
    0
         Physician decision
    15
    10
    5
    -
    -
    -
         Other
    7
    3
    4
    -
    -
    -
         Lack of efficacy
    4
    1
    3
    -
    -
    -
         Adverse event, non-fatal
    1
    1
    -
    -
    -
    -
         Recovery (opioid analgesic no longer needed)
    16
    11
    5
    1
    1
    -
         Technical Problems
    2
    1
    1
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    12-h treatment period - Overall (EU PDCO)
    Reporting group description
    All male and female subjects aged 2 years to less than 18 years who received at least 1 dose of IMP were considered for this arm. Subject had undergone surgery that, in the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment via nurse-controlled analgesia (NCA) or patient-controlled analgesia (PCA) .

    Reporting group title
    12-h treatment period - Tapentadol (EU PDCO)
    Reporting group description
    This arm includes all subjects who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.

    Reporting group title
    12-h treatment period - Placebo (EU PDCO)
    Reporting group description
    This arm includes all subjects who received at least 1 dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.

    Reporting group title
    12-h treatment period - Overall (US FDA <2 years)
    Reporting group description
    All male and female subjects aged from birth (at least 37 weeks gestational age) to less than 2 years who received at least 1 dose of tapentadol OS or placebo were considered for this arm. Subjects had undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment via NCA.

    Reporting group title
    12-h treatment period - Tapentadol (US FDA <2 years)
    Reporting group description
    This arm includes all subjects from birth to less than 2 years of age who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.

    Reporting group title
    12-h treatment period - Placebo (US FDA <2 years)
    Reporting group description
    This arm includes all subjects from birth to less than 2 years of age who received at least one dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.

    Notes
    [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline characteristics are reported for all 175 treated subjects. Reporting is done separately for the Full Analysis Set for the EU PDCO (160 subjects aged 2 to less than 18 years) and for the US FDA <2 years group (15 subjects aged from birth to less than 2 years).
    Reporting group values
    12-h treatment period - Overall (EU PDCO) 12-h treatment period - Tapentadol (EU PDCO) 12-h treatment period - Placebo (EU PDCO) 12-h treatment period - Overall (US FDA <2 years) 12-h treatment period - Tapentadol (US FDA <2 years) 12-h treatment period - Placebo (US FDA <2 years) Total
    Number of subjects
    160 108 52 15 11 4 175
    Age categorical
    Units: Subjects
        Children (2-11 years)
    82 55 27 0 0 0 82
        Adolescents (12-17 years)
    78 53 25 0 0 0 78
        Birth to less than 28 days
    0 0 0 3 2 1 3
        28 days to less than 2 years
    0 0 0 12 9 3 12
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.7 ± 4.7 10.8 ± 4.7 10.4 ± 4.8 0.67 ± 0.53 0.74 ± 0.53 0.48 ± 0.57 -
    Gender categorical
    Units: Subjects
        Female
    76 53 23 7 5 2 83
        Male
    84 55 29 8 6 2 92
    Type of opioid analgesia used
    Units: Subjects
        Hydromorphone
    51 33 18 1 1 0 52
        Morphine
    109 75 34 14 10 4 123
    Height
    Units: centimeter
        arithmetic mean (standard deviation)
    144.4 ± 28.2 145 ± 27.7 143.3 ± 29.5 70.1 ± 9.6 71.8 ± 9.3 65.3 ± 10.2 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    42.8 ± 21.08 43.09 ± 21.72 42.22 ± 19.88 7.61 ± 2.72 7.97 ± 2.58 6.63 ± 3.26 -
    Body Mass index
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    18.92 ± 4.03 18.83 ± 4.13 19.12 ± 3.84 14.89 ± 2.05 14.95 ± 2.07 14.73 ± 2.31 -
    Amount of morphine or hydromorphone taken prior to IMP
    Amount of morphine or hydromorphone taken prior to IMP documented within 24 hours prior to first IMP administration.
    Units: milligram(s)/kilogram
        arithmetic mean (standard deviation)
    0.55 ± 1.07 0.59 ± 1.2 0.45 ± 0.71 0.28 ± 0.22 0.26 ± 0.26 0.3 ± 99999.9 -

    End points

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    End points reporting groups
    Reporting group title
    12-h treatment period - Overall (EU PDCO)
    Reporting group description
    All male and female subjects aged 2 years to less than 18 years who received at least 1 dose of IMP were considered for this arm. Subject had undergone surgery that, in the investigator’s opinion, would reliably produce moderate to severe pain requiring opioid treatment via nurse-controlled analgesia (NCA) or patient-controlled analgesia (PCA) .

    Reporting group title
    12-h treatment period - Tapentadol (EU PDCO)
    Reporting group description
    This arm includes all subjects who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.

    Reporting group title
    12-h treatment period - Placebo (EU PDCO)
    Reporting group description
    This arm includes all subjects who received at least 1 dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.

    Reporting group title
    12-h treatment period - Overall (US FDA <2 years)
    Reporting group description
    All male and female subjects aged from birth (at least 37 weeks gestational age) to less than 2 years who received at least 1 dose of tapentadol OS or placebo were considered for this arm. Subjects had undergone surgery that, in the investigator's opinion, would reliably produce moderate to severe pain requiring opioid treatment via NCA.

    Reporting group title
    12-h treatment period - Tapentadol (US FDA <2 years)
    Reporting group description
    This arm includes all subjects from birth to less than 2 years of age who received at least 1 dose of tapentadol oral solution. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.

    Reporting group title
    12-h treatment period - Placebo (US FDA <2 years)
    Reporting group description
    This arm includes all subjects from birth to less than 2 years of age who received at least one dose of placebo. 12-hour treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.
    Reporting group title
    24-h treatment/trial completion - Overall (EU PDCO)
    Reporting group description
    All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of IMP and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).

    Reporting group title
    24-h treatment/trial completion - Tapentadol (EU PDCO)
    Reporting group description
    All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of tapentadol oral solution and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).

    Reporting group title
    24-h treatment/trial completion - Placebo (EU PDCO)
    Reporting group description
    All male and female subjects aged 2 years to less than 18 years and received at least 1 dose of placebo and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).

    Reporting group title
    24-h treatment/trial completion - Overall (US FDA <2 years)
    Reporting group description
    All male and female subjects aged below 2 years who received at least 1 dose of IMP and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).

    Reporting group title
    24-h treatment/trial completion - Tapentadol (US FDA <2 years)
    Reporting group description
    All male and female subjects aged below 2 years who received at least 1 dose of tapentadol and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).

    Reporting group title
    24-h treatment/trial completion - Placebo (US FDA <2 years)
    Reporting group description
    All male and female subjects aged below 2 years who received at least 1 dose of placebo and did not discontinue treatment before or at 12 hours of treatment are considered for this arm. Subjects completing this period were defined as those subjects who did not discontinue treatment before 24 hours (24 hours treatment period completers) and completed the trial by attending the follow up visit (24 hours trial completers).

    Subject analysis set title
    FAS-EU - Overall
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set included allocated and treated EU PDCO subjects aged 2 years to less than 18 years old. If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.

    Subject analysis set title
    FAS-EU - Tapentadol
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This subject analysis set included all EU PDCO subjects aged 2 years to less than 18 years old who were allocated to Tapentadol and received at least one dose of IMP. If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.

    Subject analysis set title
    FAS-EU - Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    This subject analysis set included all EU PDCO subjects aged 2 years to less than 18 years old who were allocated to placebo and received at least one dose of IMP. If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.

    Subject analysis set title
    SAF-EU - Tapentadol
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This subject analysis set included all EU PDCO subjects aged 2 years to less than 18 years old who were allocated to Tapentadol and received at least one dose of IMP.

    Subject analysis set title
    SAF-EU - Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This subject analysis set included subjects aged 2 years to less than 18 years old who were allocated to placebo and received at least one dose of IMP.

    Subject analysis set title
    FAS-US <2 years - Overall
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set for the US FDA analysis in children below 2 years includes subjects less than 2 years old that are allocated and treated. If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.

    Subject analysis set title
    FAS-US <2 years - Tapentadol
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set for the US FDA analysis in children below 2 years includes subjects less than 2 years old who were allocated to tapentadol oral solution and received at least one dose of treatment. If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.

    Subject analysis set title
    FAS-US <2 years - Placebo
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set for the US FDA analysis in children below 2 years includes subjects less than 2 years old who were allocated to placebo oral solution and received at least one dose of treatment. If by error a subject did not receive the allocated medication, the subject was evaluated as allocated following the intention-to-treat principle.

    Subject analysis set title
    SAF-US <2 years - Tapentadol
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This subject analysis set for the US FDA comprised subjects below 2 years of age who were allocated to tapentadol and received at least one dose of IMP.

    Subject analysis set title
    SAF-US <2 years - Placebo
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    This subject analysis set for the US FDA comprised subjects below 2 years of age who were allocated to placebo and received at least 1 dose of IMP.

    Primary: Total amount of supplemental opioid analgesic medication used within 24 hours after first IMP

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    End point title
    Total amount of supplemental opioid analgesic medication used within 24 hours after first IMP
    End point description
    The primary efficacy endpoint for the EU PDCO (and secondary endpoint for the US FDA) was the total amount of supplemental opioid analgesic medication (SOAM) used in the FAS-EU (from 2 years to <18 years old) within the first 24 hours after first IMP intake. Supplemental opioid analgesia was expressed in mg/kg of morphine i.v. equivalents.
    End point type
    Primary
    End point timeframe
    up to 24 hours
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    108
    52
    Units: milligram(s)/kilogram
        least squares mean (standard error)
    0.14 ± 0.03
    0.24 ± 0.03
    Statistical analysis title
    Difference Tapentadol –Placebo
    Statistical analysis description
    The endpoint was analyzed using an analysis of variance model. This included treatment, baseline age group and the used supplemental opioid analgesic as factors. For subjects discontinuing treatment before 24 hours for any other reason than no further need of opioid analgesics or switch to exclusively oral opioid analgesics, cumulative supplemental opioid analgesia over the respective time period was based on the observed supplemental opioid use up to the time of the subject’s discontinuation.
    Comparison groups
    FAS-EU - Tapentadol v FAS-EU - Placebo
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0154
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.18
         upper limit
    -0.02
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.04

    Primary: Total amount of supplemental opioid analgesic medication used within 12 hours after first IMP

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    End point title
    Total amount of supplemental opioid analgesic medication used within 12 hours after first IMP
    End point description
    The primary efficacy endpoint for the US FDA (and secondary endpoint for the EU PDCO) was the total amount of supplemental opioid analgesic medication (SOAM) used in the FAS-EU (from 2 years to <18 years old) within the first 12 hours after first IMP intake. Supplemental opioid analgesia was expressed in mg/kg of morphine i.v. equivalents. The overall SOAM use was low in subjects aged <2 years compared to older children. Given the small sample size in the age groups <2 years, conclusions are limited and based on descriptive statistics. The average SOAM use was numerically higher for subjects treated with tapentadol compared to placebo during both 12 hours (0.03 compared to 0.01 mg/kg, respectively) and 24 hours (0.054 compared to 0.016 mg/kg, respectively) after first dose of IMP whereas the median use was lower with tapentadol compared to placebo for the 12-hour endpoint (0.00 mg/kg compared to 0.01 mg/kg).
    End point type
    Primary
    End point timeframe
    up to 12 hours
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    108
    52
    Units: milligram(s)/kilogram
        least squares mean (standard error)
    0.08 ± 0.01
    0.13 ± 0.02
    Statistical analysis title
    Difference Tapentadol - Placebo
    Statistical analysis description
    The endpoint was analyzed using an analysis of variance model. This included treatment, baseline age group and the used supplemental opioid analgesic as factors. For subjects discontinuing treatment before 12 hours for any other reason than no further need of opioid analgesics or switch to exclusively oral opioid analgesics, cumulative supplemental opioid analgesia over the respective time period was based on the observed supplemental opioid use up to the time of the subject’s discontinuation.
    Comparison groups
    FAS-EU - Tapentadol v FAS-EU - Placebo
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0404
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.05
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.09
         upper limit
    0
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.02

    Secondary: Total amount of supplemental opioid analgesic medication received, assessed in 12 hour intervals from 24 hours to 96 hours after the first dose of IMP

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    End point title
    Total amount of supplemental opioid analgesic medication received, assessed in 12 hour intervals from 24 hours to 96 hours after the first dose of IMP
    End point description
    Total amount of supplemental opioid analgesic medication received, assessed in 12 hour intervals from 24 hours to 96 hours after the first dose of IMP. Supplemental opioid analgesia was expressed in mg/kg of morphine i.v. equivalents. Data for subjects <2 years (FAS-US <2 years) are very limited only (1 subject per group) and are not presented separately: tapentadol 0.02, placebo 0.003 mg/kg from >24 hours to 36 hours and no use at all from >36 hours to 48 hours.
    End point type
    Secondary
    End point timeframe
    24 to 96 hours after IMP
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    52
    108
    Units: milligram(s)/kilogram
    arithmetic mean (standard deviation)
        24h - 36h (N=38/19)
    0.08 ± 0.09
    0.14 ± 0.21
        36h - 48h (N=30/12)
    0.06 ± 0.09
    0.06 ± 0.12
        48h - 60h (N=20/8)
    0.05 ± 0.1
    0.06 ± 0.14
        60h - 72h (N=10/6)
    0.06 ± 0.08
    0.03 ± 0.07
        72h - 84h (N=3/2)
    0 ± 0
    0 ± 0
    No statistical analyses for this end point

    Secondary: Changes from baseline in pain intensity using the FLACC scale in children from 2 years to less than 6 years

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    End point title
    Changes from baseline in pain intensity using the FLACC scale in children from 2 years to less than 6 years
    End point description
    The Face, Legs, Activity, Cry, Consolability (FLACC) scale was used for children from 2 years to less than 6 years, or in older children who were not able to report their pain using the other scales. It 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 5 categories F, L, A, C, and C is scored from 0-2, which results in a total score between 0 and 10. The Pain intensity scores have been obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible. Pain intensity scores and change from baseline values have been summarized descriptively for each time point.
    End point type
    Secondary
    End point timeframe
    Change from baseline to first dose of IMP until the 8th dose of IMP and End of Treatment
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    23
    13
    Units: units on a scale
    arithmetic mean (standard deviation)
        30-60 mins after 1st IMP (N=22/13)
    1.1 ± 1.93
    1.9 ± 1.75
        Before 2nd dose of IMP (N=23/13)
    1.4 ± 1.92
    1.3 ± 1.75
        Before 3rd dose of IMP (N=23/13)
    1.7 ± 2.08
    1.6 ± 1.89
        Before 4th dose of IMP (N=21/12)
    1.4 ± 1.99
    1.3 ± 2.06
        Before 5th dose of IMP (N=20/11)
    1.8 ± 1.82
    1.9 ± 2.02
        Before 6th dose of IMP (N=19/8)
    1.6 ± 1.89
    2.3 ± 2.55
        Before 7th dose of IMP (N=19/8)
    1.6 ± 2.24
    2.1 ± 2.59
        Before 8th dose of IMP (N=13/5)
    1.2 ± 1.59
    2.2 ± 3.35
        End of Treatment (N=23/13)
    2.4 ± 2.52
    2 ± 2.79
    No statistical analyses for this end point

    Secondary: Changes from baseline in pain intensity using the Faces Pain Scale in children aged 6 years to less than 12 years

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    End point title
    Changes from baseline in pain intensity using the Faces Pain Scale in children aged 6 years to less than 12 years
    End point description
    For children aged 6 years (if possible) to less than 12 years, the pain intensity has been assessed by the use of the Faces Pain Scale-Revised (FPS-R). The FPS-R is a validated self-report measure of pain intensity developed for children. 6 facial representations were used to indicate how much the pain hurts. It was adapted from the Faces Pain Scale to make it possible to score the sensation of pain on the widely accepted 0-to-10 metric. The Pain intensity scores have been obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible Pain intensity scores and change from baseline values have been summarized descriptively for each time point
    End point type
    Secondary
    End point timeframe
    Change from baseline to first dose of IMP until the 8th dose of IMP and End of Treatment
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    32
    14
    Units: units on a scale
    arithmetic mean (standard deviation)
        30-60 mins after 1st IMP (N=30/14)
    1 ± 1.72
    0.7 ± 1.86
        Before 2nd dose of IMP (N=27/12)
    1 ± 2.5
    0.5 ± 2.84
        Before 3rd dose of IMP (N=26/12)
    1 ± 2.35
    -0.2 ± 2.17
        Before 4th dose of IMP (N=24/12)
    1.3 ± 2.33
    -0.3 ± 3.7
        Before 5th dose of IMP (N=24/11)
    0.8 ± 2.75
    0 ± 2.19
        Before 6th dose of IMP (N=23/10)
    0.5 ± 2.43
    0.2 ± 2.2
        Before 7th dose of IMP (N=21/9)
    2 ± 2.37
    0.7 ± 2.24
        Before 8th dose of IMP (N=14/9)
    1.3 ± 2.55
    0.2 ± 2.73
        End of Treatment (N=32/14)
    2.8 ± 2.93
    3.4 ± 3.56
    No statistical analyses for this end point

    Secondary: Changes from baseline in pain intensity using the Visual Analog Scale in children aged 12 years to less than 18 years

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    End point title
    Changes from baseline in pain intensity using the Visual Analog Scale in children aged 12 years to less than 18 years
    End point description
    For children aged 12 years to less than 18 years, the pain intensity has been assessed by the use of a Visual analog scale (VAS). The subject were asked to draw a single line to indicate the current level of pain intensity on a 100 mm line (visual analog scale - VAS) by marking a point on the line in response to: “My pain right now is”. The mark was scored between “no pain” and “pain as bad as it could be”. A value of 0 indicates "no pain". A value of 100 indicates "pain as bad as it could be". The Pain intensity scores have been obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible. Pain intensity scores and change from baseline values have been summarized descriptively for each time point.
    End point type
    Secondary
    End point timeframe
    Change from baseline to first dose of IMP until the 8th dose of IMP and End of Treatment
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    53
    25
    Units: units on a scale
    arithmetic mean (standard deviation)
        30-60 mins after 1st IMP (N=50/25)
    8 ± 18.67
    6.4 ± 19.58
        Before 2nd dose of IMP (N=48/24)
    6.5 ± 23.61
    6 ± 19.36
        Before 3rd dose of IMP (N=44/22)
    13.1 ± 25.09
    5.9 ± 22.11
        Before 4th dose of IMP (N=44/22)
    8.8 ± 29.01
    5.1 ± 21.7
        Before 5th dose of IMP (N=42/20)
    13 ± 22.92
    -2.7 ± 34.4
        Before 6th dose of IMP (N=38/17
    13 ± 24.74
    6.6 ± 28.4
        Before 7th dose of IMP (N=28/13)
    10.7 ± 25.77
    15 ± 20.27
        Before 8th dose of IMP (N=19/7)
    12.2 ± 28.91
    11.9 ± 14.6
        End of Treatment (N=51/25)
    11 ± 27.87
    11.4 ± 28.47
    No statistical analyses for this end point

    Secondary: CGIC by investigator/clinician after completion of the double-blind IMP treatment

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    End point title
    CGIC by investigator/clinician after completion of the double-blind IMP treatment
    End point description
    The Clinical Global Impression of Change (CGIC) has been assessed at the End of Treatment Visit. The investigator rated the subject’s global improvement and satisfaction with the treatment on a 7-point scale that ranges from “very much improved” to “very much worse” with ”no change” as the mid-point. Results have been summarized descriptively.
    End point type
    Secondary
    End point timeframe
    End of Treatment Visit
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo FAS-US <2 years - Tapentadol FAS-US <2 years - Placebo
    Number of subjects analysed
    108
    52
    11
    4
    Units: category
        Very much improved
    15
    12
    3
    1
        Much improved
    58
    22
    2
    2
        Minimally improved
    18
    8
    1
    1
        No change
    11
    4
    2
    0
        Minimally worse
    3
    2
    1
    0
        Much worse
    1
    1
    0
    0
        Very much worse
    0
    0
    0
    0
        Missing
    2
    3
    2
    0
    No statistical analyses for this end point

    Secondary: PGIC by subject/parent/legal guardian after completion of the double-blind IMP treatment

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    End point title
    PGIC by subject/parent/legal guardian after completion of the double-blind IMP treatment
    End point description
    The Patient Global Impression of Change (PGIC) has been assessed at the End of Treatment Visit. Subjects verbally rated their impression of overall status with 1 of 7 possible responses (very much improved, much improved, minimally improved, no change, minimally worse, much worse, very much worse). If the subjects were not capable of completing the questionnaire the parent/legal guardian may have completed the questionnaire on behalf of the subject. Results have been summarized descriptively.
    End point type
    Secondary
    End point timeframe
    End of Treatment Visit
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo FAS-US <2 years - Tapentadol FAS-US <2 years - Placebo
    Number of subjects analysed
    108
    52
    11
    4
    Units: category
        Very much improved
    16
    11
    4
    3
        Much improved
    53
    23
    1
    1
        Minimally improved
    21
    12
    1
    0
        No change
    13
    3
    2
    0
        Minimally worse
    1
    0
    0
    0
        Much worse
    1
    0
    0
    0
        Very much worse
    0
    0
    0
    0
        Missing
    3
    3
    3
    0
    No statistical analyses for this end point

    Secondary: Time to first and time to second NCA/PCA after the first dose of IMP

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    End point title
    Time to first and time to second NCA/PCA after the first dose of IMP
    End point description
    The time to first and time to second nurse-controlled/patient-controlled analgesia (NCA/PCA) after the first dose of IMP were summarized descriptively using time-to-event methods and displayed by relevant treatment groups. Subjects who completed the End of Treatment Visit before their first/second use of NCA/PCA or subjects who terminated treatment before their first/second use of NCA/PCA were censored at the End of Treatment Visit. Time-to-event variables are reported using Kaplan-Meier analyses. Therefore, values might remain missing if the survival function does not reach a respective threshold. This is indicated by 9999.9.
    End point type
    Secondary
    End point timeframe
    Time to first and second NCA/PCA administration
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo FAS-US <2 years - Tapentadol FAS-US <2 years - Placebo
    Number of subjects analysed
    108 [1]
    52 [2]
    11 [3]
    4 [4]
    Units: minute
    median (confidence interval 95%)
        Time to first NCA/PCA administration
    183 (90 to 446)
    131.5 (74 to 216)
    960.0 (80.0 to 9999.9)
    155.0 (124.0 to 9999.9)
        Time to second NCA/PCA administration
    572 (321 to 1993)
    388 (194 to 820)
    9999.9 (210.0 to 9999.9)
    9999.9 (500.0 to 9999.9)
    Notes
    [1] - 81 subjects with time to first NCA administration, 66 subjects with time to second administration.
    [2] - 46 subjects with time to first NCA administration, 37 subjects with time to second administration.
    [3] - 6 subjects with time to first NCA administration, 4 subjects with time to second administration.
    [4] - 3 subjects with time to first NCA administration, 1 subject with time to second administration.
    No statistical analyses for this end point

    Secondary: Time from first dose of IMP until IMP treatment discontinuation due to lack of efficacy

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    End point title
    Time from first dose of IMP until IMP treatment discontinuation due to lack of efficacy
    End point description
    The distributions of the time from the first dose of IMP to treatment discontinuation due to lack of efficacy were summarized descriptively using time-to-event methods. Subjects who reach the maximum duration of treatment (72 h) were censored at 72 h after first IMP intake. Subjects who discontinued during the Treatment Period for reasons other than lack of efficacy were censored at the time of the decision to discontinue treatment. Due to the low number of subjects with events, the median and the corresponding confidence interval could not be calculated. The time to treatment discontinuation due to lack of efficacy was longer in the tapentadol than in the placebo group. The hazard ratio (SE) of 2.15 (1.52) indicates that subjects on tapentadol discontinued later due to lack of efficacy than subjects on placebo (p = 0.2681 [Log-rank test]). This analysis was not performed for subjects <2 years old. There was no subject with a premature IMP discontinuation due to lack of efficacy.
    End point type
    Secondary
    End point timeframe
    up to 72 hours
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    108
    52
    Units: Subjects
        Number of censored subjects
    104
    48
        Number of subjects with event
    4
    4
    No statistical analyses for this end point

    Secondary: Palatability of the IMP after the first dose

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    End point title
    Palatability of the IMP after the first dose
    End point description
    Palatability of the study medication (IMP) after dosing in subjects aged 2 years to less than 18 years old was assessed using a 5-point verbal rating scale. Palatability has been assessed by asking the following question “How does the medication taste?”. The categorical verbal rating ranged from really good, good, a bit good/a bit bad, bad, and really bad. Responses were summarized. Missing values were not imputed. Palatability was not planned to be analyzed in subjects <2 years old.
    End point type
    Secondary
    End point timeframe
    After first dose of IMP
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    108
    52
    Units: category
        Really bad
    13
    2
        Bad
    28
    2
        A bit bad / a bit good
    36
    10
        Good
    24
    24
        Really good
    6
    11
        Missing
    1
    3
    No statistical analyses for this end point

    Secondary: Palatability of the IMP after the last dose

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    End point title
    Palatability of the IMP after the last dose
    End point description
    Palatability of the study medication (IMP) after dosing in subjects aged 2 years to less than 18 years old was assessed using a 5-point verbal rating scale. Palatability has been assessed by asking the following question “How does the medication taste?”. The categorical verbal rating ranged from really good, good, a bit good/a bit bad, bad, and really bad. Responses were summarized. Missing values were not imputed. Palatability was not planned to be analyzed in subjects <2 years old.
    End point type
    Secondary
    End point timeframe
    End of Treatment Visit
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    108
    52
    Units: category
        Really bad
    14
    1
        Bad
    15
    3
        A bit bad / a bit good
    38
    14
        Good
    28
    16
        Really good
    5
    12
        Missing
    8
    6
    No statistical analyses for this end point

    Secondary: Acceptability of the IMP after the first dose

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    End point title
    Acceptability of the IMP after the first dose
    End point description
    The Acceptability of the study medication (IMP) after dosing in subjects aged 2 years to less than 18 years old was assessed using a 5-point verbal rating scale. Acceptability has been assessed by asking the following question “Swallowing the medication is ...”. The categorical verbal rating ranged from was really easy, easy, a bit easy/a bit difficult, difficult, and really difficult. Responses were summarized. Missing values were not imputed. Acceptability was not planned to be analyzed in subjects <2 years old.
    End point type
    Secondary
    End point timeframe
    After first dose of IMP
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    108
    52
    Units: category
        Really Difficult
    1
    0
        Difficult
    7
    3
        A Bit Difficult / A Bit Easy
    17
    7
        Easy
    46
    20
        Really Easy
    35
    19
        Missing
    2
    3
    No statistical analyses for this end point

    Secondary: Acceptability of the IMP after the last dose

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    End point title
    Acceptability of the IMP after the last dose
    End point description
    The Acceptability of the study medication (IMP) after dosing in subjects aged 2 years to less than 18 years old was assessed using a 5-point verbal rating scale. Acceptability has been assessed by asking the following question “Swallowing the medication is ...”. The categorical verbal rating ranged from was really easy, easy, a bit easy/a bit difficult, difficult, and really difficult. Responses were summarized. Missing values were not imputed. Acceptability was not planned to be analyzed in subjects <2 years old.
    End point type
    Secondary
    End point timeframe
    End of Treatment Visit
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo
    Number of subjects analysed
    108
    52
    Units: category
        Really Difficult
    3
    0
        Difficult
    6
    2
        A Bit Difficult / A Bit Easy
    9
    6
        Easy
    43
    18
        Really Easy
    39
    20
        Missing
    8
    6
    No statistical analyses for this end point

    Secondary: Changes from baseline in pain intensity using the FLACC scale in children from birth to <2 years

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    End point title
    Changes from baseline in pain intensity using the FLACC scale in children from birth to <2 years
    End point description
    The Face, Legs, Activity, Cry, Consolability (FLACC) scale was used for children from birth to less than 6 years, or in older children who were not able to report their pain using the other scales. It 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 5 categories F, L, A, C, and C is scored from 0-2, which results in a total score between 0 and 10. The Pain intensity scores have been obtained before and after first dose of IMP, and before each subsequent dose of IMP, whenever possible. Pain intensity scores and change from baseline values were summarized descriptively for each time point. Standard deviations were not calculated for 4 or less subjects, as indicated by 9999.9.
    End point type
    Secondary
    End point timeframe
    Change from baseline to first dose of IMP until the 8th dose of IMP and End of Treatment
    End point values
    FAS-US <2 years - Tapentadol FAS-US <2 years - Placebo
    Number of subjects analysed
    11
    4
    Units: units on a scale
    arithmetic mean (standard deviation)
        30-60 min after 1st IMP (N=11/4)
    1.4 ± 2.87
    2.8 ± 9999.9
        Before 2nd dose of IMP (N=11/4)
    0.7 ± 3.61
    1.0 ± 9999.9
        Before 3rd dose of IMP (N=10/4)
    2.0 ± 2.16
    -1.3 ± 9999.9
        Before 4th dose of IMP (N=10/4)
    1.3 ± 3.16
    0.0 ± 9999.9
        Before 5th dose of IMP (N=10/4)
    1.4 ± 3.03
    2.0 ± 9999.9
        Before 6th dose of IMP (N=10/4)
    2.02 ± 2.91
    2.5 ± 9999.9
        Before 7th dose of IMP (N=8/3)
    1.9 ± 2.64
    2.0 ± 9999.9
        Before 8th dose of IMP (N=5/2)
    3.8 ± 1.92
    -0.5 ± 9999.9
        End of Treatment (N=11/4)
    2.1 ± 3.35
    3.5 ± 9999.9
    No statistical analyses for this end point

    Other pre-specified: Suicidal ideation/behavior in subjects aged 6 years or older using the Columbia Suicide Severity Rating Scale (C-SSRS) scores before IMP and at the end of the trial

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    End point title
    Suicidal ideation/behavior in subjects aged 6 years or older using the Columbia Suicide Severity Rating Scale (C-SSRS) scores before IMP and at the end of the trial
    End point description
    The assessment of suicidal ideation and behavior was a voluntary assessment to determine development of such behaviors after treatment of subjects with IMP. Suicidal ideation and behavior was assessed using the Columbia-Suicide Severity Rating Scale at baseline ("baseline" questionnaire) and at the end of treatment ("since last visit" questionnaire). Results were presented in a subject data listing.
    End point type
    Other pre-specified
    End point timeframe
    Baseline and End of Treatment Visit
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    47
    24
    Units: Subjects
        Suicidal ideation (N=47/24)
    0
    0
        Suicidal behaviour (N=45/22)
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Sedation scores using the University of Michigan Sedation Scale before first dose of IMP

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    End point title
    Sedation scores using the University of Michigan Sedation Scale before first dose of IMP
    End point description
    Sedation scores were obtained before each dose of IMP and summarized descriptively as a categorical variable.
    End point type
    Other pre-specified
    End point timeframe
    before first dose of IMP
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo FAS-US <2 years - Tapentadol FAS-US <2 years - Placebo
    Number of subjects analysed
    108
    52
    11
    4
    Units: category
        Awake and alert
    63
    37
    4
    2
        Minimally sedated
    35
    13
    3
    0
        Moderately sedated
    8
    2
    3
    2
        Deeply sedated
    1
    0
    1
    0
        Unarousable
    0
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Sedation scores using the University of Michigan Sedation Scale before 8th administration of IMP

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    End point title
    Sedation scores using the University of Michigan Sedation Scale before 8th administration of IMP
    End point description
    Sedation scores were obtained before each dose of IMP and summarized descriptively as a categorical variable.
    End point type
    Other pre-specified
    End point timeframe
    before 8th administration of IMP
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo FAS-US <2 years - Tapentadol FAS-US <2 years - Placebo
    Number of subjects analysed
    108
    52
    11
    4
    Units: Subjects
    number (not applicable)
        Awake and alert
    30
    14
    2
    1
        Minimally sedated
    9
    5
    2
    1
        Moderately sedated
    4
    1
    1
    0
        Deeply sedated
    2
    1
    0
    0
        Unarousable
    0
    0
    0
    0
        Missing
    1
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Number of subjects discontinuing the trial due to TEAEs and drug-related adverse events

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    End point title
    Number of subjects discontinuing the trial due to TEAEs and drug-related adverse events
    End point description
    The number of subjects with at least 1 treatment emergent adverse event (TEAE) and drug-related TEAEs leading to discontinuation from the trial (i.e. TEAE with “countermeasures”: “trial discontinuation”) is provided.
    End point type
    Other pre-specified
    End point timeframe
    From first administration of IMP until the time of the subject-related end of trial.
    End point values
    FAS-EU - Tapentadol FAS-EU - Placebo FAS-US <2 years - Tapentadol FAS-US <2 years - Placebo
    Number of subjects analysed
    108
    52
    11
    4
    Units: Subjects
    0
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal vital signs – Diastolic Blood Pressure

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    End point title
    Percentage of subjects who develop abnormal vital signs – Diastolic Blood Pressure
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    107
    52
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    75.7
    73.1
    36.4
    25.0
        Alert (low/high)
    24.3
    26.9
    63.6
    75.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal vital signs – Systolic Blood Pressure

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    End point title
    Percentage of subjects who develop abnormal vital signs – Systolic Blood Pressure
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    107
    52
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    70.1
    67.3
    63.6
    50.0
        Alert (low/high)
    29.9
    32.7
    36.4
    50.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal vital signs – Heart Rate

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    End point title
    Percentage of subjects who develop abnormal vital signs – Heart Rate
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    107
    52
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    34.6
    26.9
    54.5
    50.0
        Alert (low/high)
    65.4
    73.1
    45.5
    50.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal vital signs – Respiratory Rate

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    End point title
    Percentage of subjects who develop abnormal vital signs – Respiratory Rate
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    107
    52
    10
    4
    Units: percent
    number (not applicable)
        Non-alert
    42.1
    48.1
    30.0
    50.0
        Alert (low/high)
    57.9
    51.9
    70.0
    50.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Hemoglobin

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Hemoglobin
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    94
    40
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    69.1
    60
    45.5
    100
        Alert (low/high)
    30.9
    40
    54.5
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Mean Corpuscular Volume

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Mean Corpuscular Volume
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    91
    39
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    85.7
    74.4
    81.8
    75.0
        Alert (low/high)
    14.3
    25.6
    18.2
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Hematocrit

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Hematocrit
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    91
    39
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    82.4
    74.4
    27.3
    50.0
        Alert (low/high)
    17.6
    25.6
    72.7
    50.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Mean Corpuscular Hemoglobin

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Mean Corpuscular Hemoglobin
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    94
    40
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
    63.6
    75.0
        Alert (low/high)
    0
    0
    36.4
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Red blood cell count

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Red blood cell count
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    94
    40
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
    90.9
    100
        Alert (low/high)
    0
    0
    9.1
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Mean Corpuscular Hemoglobin Concentration

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Mean Corpuscular Hemoglobin Concentration
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    91
    39
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
    81.8
    50.0
        Alert (low/high)
    0
    0
    18.2
    50.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Platelet count

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Platelet count
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    92
    39
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    96.7
    94.9
    63.6
    100
        Alert (low/high)
    3.3
    5.1
    36.4
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - White blood cell count

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - White blood cell count
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    94
    40
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    86.2
    97.5
    100
    100
        Alert (low/high)
    13.8
    2.5
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Sodium

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Sodium
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    97
    42
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    97.6
    81.8
    100
        Alert (low/high)
    0
    2.4
    18.2
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Lipase

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Lipase
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    97
    42
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    95.9
    100
    90.9
    50.0
        Alert (low/high)
    4.1
    0
    9.1
    50.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Potassium

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Potassium
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    90
    37
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    95.6
    100
    81.8
    75.0
        Alert (low/high)
    4.4
    0
    18.2
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Triglycerides

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Triglycerides
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    97
    42
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
    81.8
    50.0
        Alert (low/high)
    0
    0
    18.2
    50.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Chloride

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Chloride
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    97
    42
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
    90.9
    100
        Alert (low/high)
    0
    0
    9.1
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Total Bilirubin

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Total Bilirubin
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    96
    41
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
    81.8
    75.0
        Alert (low/high)
    0
    0
    18.2
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Bicarbonate

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Bicarbonate
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    96
    41
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
    90.9
    100
        Alert (low/high)
    0
    0
    9.1
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Alkaline Phosphatase

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Alkaline Phosphatase
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    97
    41
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    97.9
    100
    90.9
    75.0
        Alert (low/high)
    2.1
    0
    9.1
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Blood Urea Nitrogen

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Blood Urea Nitrogen
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    97
    41
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
    54.5
    75.0
        Alert (low/high)
    0
    0
    45.5
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Creatine kinase

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Creatine kinase
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    94
    40
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    80.9
    77.5
    72.7
    75.0
        Alert (low/high)
    19.1
    22.5
    27.3
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Creatinine

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Creatinine
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    97
    41
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
    90.9
    100
        Alert (low/high)
    0
    0
    9.1
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Lactic Acid Dehydrogenase

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Lactic Acid Dehydrogenase
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    74
    27
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    97.3
    100
    81.8
    75.0
        Alert (low/high)
    2.7
    0
    18.2
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Uric acid

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Uric acid
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    97
    42
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    99
    97.6
    54.5
    25.0
        Alert (low/high)
    1
    2.4
    45.5
    75.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Alanine aminotransferase

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Alanine aminotransferase
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    96
    40
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    96.9
    100
    90.9
    50.0
        Alert (low/high)
    3.1
    0
    9.1
    50.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Calcium

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Calcium
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    97
    42
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    97.9
    95.2
    90.9
    100
        Alert (low/high)
    2.1
    4.8
    9.1
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Aspartate aminotransferase

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Aspartate aminotransferase
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    89
    36
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    97.8
    100
    72.7
    75.0
        Alert (low/high)
    2.2
    0
    27.3
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Phosphate

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Phosphate
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    92
    37
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    98.9
    97.3
    81.8
    75.0
        Alert (low/high)
    1.1
    2.7
    18.2
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Glucose

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Glucose
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    92
    37
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    98.9
    100
    72.7
    100
        Alert (low/high)
    1.1
    0
    27.3
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Total Protein

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Total Protein
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    97
    42
    11
    4
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
    72.7
    75.0
        Alert (low/high)
    0
    0
    27.3
    25.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal laboratory parameter - Glomerular filtration rate

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Glomerular filtration rate
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    95
    40
    0 [5]
    0 [6]
    Units: percent
    number (not applicable)
        Non-alert
    97.9
    100
        Alert (low/high)
    2.1
    0
    Notes
    [5] - No subject with data for end of treatment.
    [6] - No subject with data for end of treatment.
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - RR Duration

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    End point title
    Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - RR Duration
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    101
    48
    10
    4
    Units: percent
    number (not applicable)
        Non-alert
    58.4
    45.8
    80.0
    50.0
        Alert (low/high)
    41.6
    54.2
    20.0
    50.0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - PR Duration

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    End point title
    Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - PR Duration
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    100
    48
    10
    4
    Units: percent
    number (not applicable)
        Non-alert
    97
    100
    70.0
    100
        Alert (low/high)
    3
    0
    30.0
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - QRS Duration

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    End point title
    Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - QRS Duration
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    101
    48
    10
    4
    Units: percent
    number (not applicable)
        Non-alert
    75.2
    79.2
    80.0
    100
        Alert (low/high)
    24.8
    20.8
    20.0
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - QT Duration

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    End point title
    Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - QT Duration
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    101
    48
    10
    4
    Units: percent
    number (not applicable)
        Non-alert
    69.3
    66.7
    10.0
    0
        Alert (low/high)
    30.7
    33.3
    90.0
    100
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - QTcF

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    End point title
    Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - QTcF
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    101
    48
    10
    4
    Units: percent
    number (not applicable)
        Non-alert
    95
    100
    100
    100
        Alert (low/high)
    5
    0
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - Heart Rate

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    End point title
    Percentage of subjects who develop abnormal 12-lead electrocardiogram (ECG) parameters - Heart Rate
    End point description
    The percentage of subjects who develop an abnormal value during the treatment period was calculated based on sponsor defined alert ranges.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    101
    48
    10
    4
    Units: percent
    number (not applicable)
        Non-alert
    96
    97.9
    100
    100
        Alert (low/high)
    4
    2.1
    0
    0
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in vital signs parameters – Diastolic Blood Pressure

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    End point title
    Changes from baseline in vital signs parameters – Diastolic Blood Pressure
    End point description
    Descriptive statistics for the change of value from baseline to subsequent IMP administrations. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to before the 8th dose of IMP
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    43
    21
    4
    2
    Units: mm/Hg
        arithmetic mean (standard deviation)
    1 ± 11.74
    4.7 ± 11.66
    -7.3 ± 14.59
    7.0 ± 11.31
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in vital signs parameters – Systolic Blood Pressure

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    End point title
    Changes from baseline in vital signs parameters – Systolic Blood Pressure
    End point description
    Descriptive statistics for the change of value from baseline to subsequent IMP administrations. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to before the 8th dose of IMP
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    43
    21
    4
    2
    Units: mm/Hg
        arithmetic mean (standard deviation)
    -3.7 ± 11.72
    0 ± 9.84
    -13.5 ± 26.64
    9.5 ± 14.85
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in vital signs parameters – Heart Rate

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    End point title
    Changes from baseline in vital signs parameters – Heart Rate
    End point description
    Descriptive statistics for the change of value from baseline to subsequent IMP administrations. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to before the 8th dose of IMP
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    43
    21
    5
    2
    Units: beats per minute
        arithmetic mean (standard deviation)
    -3.5 ± 18.83
    -3.4 ± 17.41
    -9.4 ± 13.99
    1.5 ± 4.95
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in vital signs parameters – Respiratory Rate

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    End point title
    Changes from baseline in vital signs parameters – Respiratory Rate
    End point description
    Descriptive statistics for the change of value from baseline to subsequent IMP administrations. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to before the 8th dose of IMP
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    43
    21
    5
    2
    Units: breaths per minute
        arithmetic mean (standard deviation)
    -0.3 ± 6.33
    2.8 ± 4.55
    9.0 ± 12.33
    13.0 ± 8.49
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Hemoglobin

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    End point title
    Changes from baseline in safety laboratory parameters - Hemoglobin
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    87
    37
    Units: g/L
        arithmetic mean (standard deviation)
    -4.7 ± 12.3
    -2.6 ± 14.5
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Mean Corpuscular Volume

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    End point title
    Changes from baseline in safety laboratory parameters - Mean Corpuscular Volume
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    85
    36
    Units: fL
        arithmetic mean (standard deviation)
    -0.16 ± 3.23
    0.17 ± 3.78
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Hematocrit

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    End point title
    Changes from baseline in safety laboratory parameters - Hematocrit
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    85
    36
    Units: fraction of blood volume
        arithmetic mean (standard deviation)
    -0.014 ± 0.04
    -0.009 ± 0.047
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Mean Corpuscular Hemoglobin

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    End point title
    Changes from baseline in safety laboratory parameters - Mean Corpuscular Hemoglobin
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    87
    37
    Units: pg
        arithmetic mean (standard deviation)
    -0.02 ± 0.85
    0.22 ± 0.79
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Red blood cell count

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    End point title
    Changes from baseline in safety laboratory parameters - Red blood cell count
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    87
    37
    Units: TI/L
        arithmetic mean (standard deviation)
    -0.153 ± 0.431
    -0.108 ± 0.498
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Mean Corpuscular Hemoglobin Concentration

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    End point title
    Changes from baseline in safety laboratory parameters - Mean Corpuscular Hemoglobin Concentration
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated based on central laboratory data. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    85
    36
    Units: g/L
        arithmetic mean (standard deviation)
    0.9 ± 13.6
    1.3 ± 18.2
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Platelet count

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    End point title
    Changes from baseline in safety laboratory parameters - Platelet count
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    80
    36
    Units: GI/L
        arithmetic mean (standard deviation)
    -8.1 ± 66.3
    -15.4 ± 57.6
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - White blood cell count

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    End point title
    Changes from baseline in safety laboratory parameters - White blood cell count
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    87
    37
    Units: GI/L
        arithmetic mean (standard deviation)
    -3.705 ± 5.366
    -3.656 ± 4.431
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Sodium

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    End point title
    Changes from baseline in safety laboratory parameters - Sodium
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    93
    41
    Units: mmol/L
        arithmetic mean (standard deviation)
    -1.8 ± 4.6
    -1.7 ± 4.3
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Lipase

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    End point title
    Changes from baseline in safety laboratory parameters - Lipase
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    93
    41
    Units: U/L
        arithmetic mean (standard deviation)
    4.6 ± 63.3
    5.5 ± 22.8
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Potassium

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    End point title
    Changes from baseline in safety laboratory parameters - Potassium
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    82
    33
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.09 ± 0.71
    -0.13 ± 0.59
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Triglycerides

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    End point title
    Changes from baseline in safety laboratory parameters - Triglycerides
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    93
    41
    Units: mmol/L
        arithmetic mean (standard deviation)
    0.202 ± 0.442
    0.086 ± 0.75
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Chloride

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    End point title
    Changes from baseline in safety laboratory parameters - Chloride
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    93
    41
    Units: mmol/L
        arithmetic mean (standard deviation)
    -3.6 ± 4.3
    -2.1 ± 4.9
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Total Bilirubin

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    End point title
    Changes from baseline in safety laboratory parameters - Total Bilirubin
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    91
    40
    Units: umol/L
        arithmetic mean (standard deviation)
    -1.154 ± 5.046
    -1.775 ± 5.526
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Bicarbonate

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    End point title
    Changes from baseline in safety laboratory parameters - Bicarbonate
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    91
    40
    Units: mmol/L
        arithmetic mean (standard deviation)
    2.24 ± 3.11
    1.21 ± 3.56
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Alkaline Phosphatase

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    End point title
    Changes from baseline in safety laboratory parameters - Alkaline Phosphatase
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    92
    40
    Units: U/L
        arithmetic mean (standard deviation)
    -11.1 ± 28.2
    -16.8 ± 31.7
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Blood Urea Nitrogen

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    End point title
    Changes from baseline in safety laboratory parameters - Blood Urea Nitrogen
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    93
    39
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.561 ± 1.45
    -0.672 ± 1.514
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Creatine kinase

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    End point title
    Changes from baseline in safety laboratory parameters - Creatine kinase
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    85
    35
    Units: U/L
        arithmetic mean (standard deviation)
    121.2 ± 709.4
    168.8 ± 576.5
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Creatinine

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    End point title
    Changes from baseline in safety laboratory parameters - Creatinine
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    93
    39
    Units: umol/L
        arithmetic mean (standard deviation)
    -5.473 ± 12.207
    -9.564 ± 11.208
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Lactic Acid Dehydrogenase

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    End point title
    Changes from baseline in safety laboratory parameters - Lactic Acid Dehydrogenase
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    50
    16
    Units: U/L
        arithmetic mean (standard deviation)
    -3.2 ± 80.2
    9.6 ± 41.3
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Uric acid

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    End point title
    Changes from baseline in safety laboratory parameters - Uric acid
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    93
    41
    Units: umol/L
        arithmetic mean (standard deviation)
    -28.086 ± 52.747
    -44.244 ± 70.778
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Alanine transaminase

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    End point title
    Changes from baseline in safety laboratory parameters - Alanine transaminase
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    90
    38
    Units: U/L
        arithmetic mean (standard deviation)
    4.644 ± 20.952
    1.316 ± 7.256
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Calcium

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    End point title
    Changes from baseline in safety laboratory parameters - Calcium
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    93
    41
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.021 ± 0.266
    -0.012 ± 0.207
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Aspartate transaminase

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    End point title
    Changes from baseline in safety laboratory parameters - Aspartate transaminase
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    79
    28
    Units: U/L
        arithmetic mean (standard deviation)
    2.532 ± 44.521
    2.929 ± 15.309
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Phosphorus

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    End point title
    Changes from baseline in safety laboratory parameters - Phosphorus
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    86
    36
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.118 ± 0.34
    -0.117 ± 0.419
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Glucose

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    End point title
    Changes from baseline in safety laboratory parameters - Glucose
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    86
    36
    Units: mmol/L
        arithmetic mean (standard deviation)
    -0.927 ± 2.569
    -0.314 ± 1.472
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Total Protein

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    End point title
    Changes from baseline in safety laboratory parameters - Total Protein
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    93
    41
    Units: g/L
        arithmetic mean (standard deviation)
    1.1 ± 6
    1 ± 6.6
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in safety laboratory parameters - Glomerular filtration rate

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    End point title
    Changes from baseline in safety laboratory parameters - Glomerular filtration rate
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated. For subjects <2 years of age, an analysis could not be performed since only local laboratory samples were obtained from these subjects and a meaningful analysis was not feasible.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    91
    38
    Units: mL/min/1.73m2
        arithmetic mean (standard deviation)
    21.264 ± 45.339
    32.868 ± 43.3
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in 12-lead ECG parameters (2 years to <18 years)

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    End point title
    Changes from baseline in 12-lead ECG parameters (2 years to <18 years)
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo
    Number of subjects analysed
    99
    46
    Units: milliseconds
    arithmetic mean (standard deviation)
        PR Duration (N=97/45)
    2.1 ± 16.8
    5.3 ± 14.2
        QRS Duration (N=99/46)
    -1.2 ± 8.4
    -0.1 ± 6.1
        QT Duration (N=99/46)
    -4.2 ± 36.2
    -14.9 ± 36.9
        QTcF (N=99/46)
    -7.6 ± 25.6
    -17.7 ± 23.2
        RR Duration (N=99/46)
    8.5 ± 136.6
    1.8 ± 147.3
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in 12-lead ECG parameters - Heart Rate

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    End point title
    Changes from baseline in 12-lead ECG parameters - Heart Rate
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF-EU - Tapentadol SAF-EU - Placebo SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    98
    46
    10
    4
    Units: beats per minute
        arithmetic mean (standard deviation)
    -3.9 ± 22.6
    -0.6 ± 19.5
    5.7 ± 19.0
    16.0 ± 10.1
    No statistical analyses for this end point

    Other pre-specified: Changes from baseline in 12-lead ECG parameters (from birth to <2 years)

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    End point title
    Changes from baseline in 12-lead ECG parameters (from birth to <2 years)
    End point description
    Descriptive statistics for the change of value from baseline to end of treatment. The mean difference and standard deviation was calculated.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end of treatment
    End point values
    SAF-US <2 years - Tapentadol SAF-US <2 years - Placebo
    Number of subjects analysed
    11
    4
    Units: milliseconds
    arithmetic mean (standard deviation)
        PR Duration (N=9/4)
    -2.9 ± 15.5
    -1.0 ± 14.5
        QRS Duration (N=10/4)
    1.4 ± 10.1
    -5.8 ± 7.0
        QT Duration (N=10/4)
    -11.6 ± 27.0
    -24.3 ± 27.0
        QTcF (N=10/4)
    -7.0 ± 24.7
    -17.3 ± 30.9
        RR Duration (N=10/4)
    -32.9 ± 74.0
    -51.8 ± 29.9
    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 first administration of IMP or starting before the first dose of IMP and worsened in intensity after the first administration of 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 IMP intake that a subject is still considered to be potentially affected by a study drug. For tapentadol oral solution, the therapeutic reach is defined as 48 hours after (last) IMP intake. Adverse events are listed by treatment and overall.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Overall (EU PDCO) – Safety Set
    Reporting group description
    All subjects aged 2 years to below 18 years who received at least 1 dose of IMP.

    Reporting group title
    Tapentadol (EU PDCO) - Safety Set
    Reporting group description
    All subjects aged 2 years to below 18 years who received at least 1 dose of Tapentadol oral solution.

    Reporting group title
    Placebo (EU PDCO) - Safety Set
    Reporting group description
    All subjects aged 2 years to below 18 years who received at least 1 dose of placebo.

    Reporting group title
    Overall (US FDA <2 years) - Safety Set
    Reporting group description
    All subjects from birth to below 2 years who received at least 1 dose of IMP.

    Reporting group title
    Tapentadol (US FDA <2 years) - Safety Set
    Reporting group description
    All subjects from birth to below 2 years who received at least 1 dose of tapentadol oral solution.

    Reporting group title
    Placebo (US FDA <2 years) - Safety Set
    Reporting group description
    All subjects from birth to below 2 years who received at least 1 dose of placebo oral solution.

    Serious adverse events
    Overall (EU PDCO) – Safety Set Tapentadol (EU PDCO) - Safety Set Placebo (EU PDCO) - Safety Set Overall (US FDA <2 years) - Safety Set Tapentadol (US FDA <2 years) - Safety Set Placebo (US FDA <2 years) - Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 160 (1.25%)
    2 / 108 (1.85%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Nervous system disorders
    Seizure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Abscess
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Overall (EU PDCO) – Safety Set Tapentadol (EU PDCO) - Safety Set Placebo (EU PDCO) - Safety Set Overall (US FDA <2 years) - Safety Set Tapentadol (US FDA <2 years) - Safety Set Placebo (US FDA <2 years) - Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    87 / 160 (54.38%)
    61 / 108 (56.48%)
    26 / 52 (50.00%)
    9 / 15 (60.00%)
    6 / 11 (54.55%)
    3 / 4 (75.00%)
    General disorders and administration site conditions
    Chest pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Face oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Infusion site pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 108 (0.00%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    11 / 160 (6.88%)
    10 / 108 (9.26%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    20
    19
    1
    0
    0
    0
    Psychiatric disorders
    Agitation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    Anxiety
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 108 (0.00%)
    2 / 52 (3.85%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    Hallucinations, Mixed
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Initial Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 160 (1.25%)
    0 / 108 (0.00%)
    2 / 52 (3.85%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    Withdrawal syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 108 (0.00%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Injury, poisoning and procedural complications
    Anaemia Postoperative
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 160 (1.25%)
    1 / 108 (0.93%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    Transfusion Reaction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Administration related reaction
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 108 (0.00%)
    0 / 52 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Investigations
    Alanine aminotransferase Increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    Blood Urea Decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Haematocrit Decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 108 (0.00%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Haemoglobin Decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 160 (1.25%)
    1 / 108 (0.93%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    Hepatic Enzyme Increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Oxygen saturation decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 160 (2.50%)
    3 / 108 (2.78%)
    1 / 52 (1.92%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    5
    4
    1
    1
    1
    0
    Po2 Decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    Red blood cell count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 108 (0.00%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Respiratory rate decreased
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 108 (0.00%)
    0 / 52 (0.00%)
    1 / 15 (6.67%)
    0 / 11 (0.00%)
    1 / 4 (25.00%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Cardiac disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Haemorrhagic Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Thrombocytopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Sinus Tachycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    3 / 160 (1.88%)
    2 / 108 (1.85%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    2
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Bradypnoea
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 108 (0.00%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Chylothorax
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Hypoxia
         subjects affected / exposed
    3 / 160 (1.88%)
    3 / 108 (2.78%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    3
    3
    0
    0
    0
    0
    Nasal Congestion
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 108 (0.00%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 108 (0.00%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Painful Respiration
         subjects affected / exposed
    1 / 160 (0.63%)
    0 / 108 (0.00%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Pleural Effusion
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Nervous system disorders
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    5 / 160 (3.13%)
    4 / 108 (3.70%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    8
    7
    1
    0
    0
    0
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 160 (3.75%)
    5 / 108 (4.63%)
    1 / 52 (1.92%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    7
    6
    1
    0
    0
    0
    Sedation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 160 (1.25%)
    2 / 108 (1.85%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    2
    2
    0
    0
    0
    0
    Somnolence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    8 / 160 (5.00%)
    6 / 108 (5.56%)
    2 / 52 (3.85%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    8
    6
    2
    0
    0
    0
    Eye disorders
    Eye Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Abdominal distension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Abdominal Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    17 / 160 (10.63%)
    11 / 108 (10.19%)
    6 / 52 (11.54%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    17
    11
    6
    1
    1
    0
    Dysphagia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 160 (0.63%)
    1 / 108 (0.93%)
    0 / 52 (0.00%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    20 / 160 (12.50%)
    16 / 108 (14.81%)
    4 / 52 (7.69%)
    0 / 15 (0.00%)
    0 / 11 (0.00%)
    0 / 4 (0.00%)
         occurrences all number
    27
    22
    5
    0
    0
    0
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    31 / 160 (19.38%)
    25 / 108 (23.15%)
    6 / 52 (11.54%)
    2 / 15 (13.33%)
    2 / 11 (18.18%)
    0 / 4 (0.00%)
         occurrences all number
    44
    36
    8
    2
    2
    0
    Diarrhoea
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 108 (0.00%)
    0 / 52 (0.00%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Flatulence
         subjects affected / exposed
    0 / 160 (0.00%)
    0 / 108 (0.00%)
    0 / 52 (0.00%)
    1 / 15 (6.67%)
    1 / 11 (9.09%)
    0 / 4 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Impaired gastr