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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

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Nov 2018
    First version publication date
    15 Jun 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    R331333PAI3037
    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
    Interim
    Date of interim/final analysis
    26 Apr 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Dec 2016
    Global end of trial reached?
    No
    General information about the trial
    Main objective of the trial
    This trial is performed to meet the 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]). Only the objectives and data for the EU part (subjects aged 2 years to less than 18 years old) are presented in this posting. The recruitment of the remaining subjects aged less than 2 years old for the completion of the US part (subjects from birth to less than 17 years old) is ongoing. Main objectives of the trial for the EU PDCO population: Efficacy and safety of tapentadol oral solution in children and adolescents aged 2 years to less than 18 years 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 following initiation of IMP.
    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 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 has unbearable pain despite using NCA/PCA (Nurse controlled analgesia/Patient controlled analgesia), an additional bolus of morphine or hydromorphone were 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: 30
    Country: Number of subjects enrolled
    Spain: 13
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    Croatia: 11
    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: 7
    Country: Number of subjects enrolled
    United States: 88
    Worldwide total number of subjects
    193
    EEA total number of subjects
    105
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    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. The recruitment of the remaining subjects aged less than 2 years old for the US FDA population is ongoing.

    Pre-assignment
    Screening details
    A total of 193 subjects gave informed consent to participate in the trial, 165 of these subjects were allocated to study drug (investigational medicinal product = IMP) and 160 subjects received IMP (52 subjects on placebo and 108 subjects on tapentadol).

    Pre-assignment period milestones
    Number of subjects started
    193
    Number of subjects completed
    160

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    Consent withdrawn by the parent(s) or subjects: 4
    Reason: Number of subjects
    Adverse event, non-fatal: 1
    Reason: Number of subjects
    Other: 4
    Reason: Number of subjects
    Inclusion criteria not met /exclusion criteria met: 24
    Period 1
    Period 1 title
    12 hours 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 less than 2 year olds in the US FDA set was completed. Subjects less than 2 years old in the US FDA set remain blinded, as independent randomization lists are used for subjects aged less than 2 years old.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    12 hours treatment period - Overall Trial
    Arm description
    All EU PDCO male and female subjects aged 2 years to less than 18 years and received at least one dose of IMP are 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 hours treatment period - Tapentadol
    Arm description
    This arm includes all subjects who received at least one dose of Tapentadol oral solution. 12 hours 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 hours treatment period - Placebo
    Arm description
    This arm includes all subjects who received at least one dose of placebo. 12 hours 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.

    Number of subjects in period 1
    12 hours treatment period - Overall Trial 12 hours treatment period - Tapentadol 12 hours treatment period - Placebo
    Started
    160
    108
    52
    Completed
    136
    90
    46
    Not completed
    24
    18
    6
         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
             -
    Period 2
    Period 2 title
    24 hours treatment and 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 remain blinded, as independent randomization lists are used for subjects aged less than 2 years old.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    24 hours treatment and trial completion - Overall Trial
    Arm description
    All EU PDCO male and female subjects aged 2 years to less than 18 years and received at least one 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 hours treatment and trial completion - Tapentadol
    Arm description
    All EU PDCO male and female subjects aged 2 years to less than 18 years and received at least one 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). 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 hours treatment and trial completion - Placebo
    Arm description
    All EU PDCO male and female subjects aged 2 years to less than 18 years and received at least one 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.

    Number of subjects in period 2
    24 hours treatment and trial completion - Overall Trial 24 hours treatment and trial completion - Tapentadol 24 hours treatment and trial completion - Placebo
    Started
    136
    90
    46
    Completed
    91
    63
    28
    Not completed
    45
    27
    18
         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
         Technical Problems
             2
             1
             1

    Baseline characteristics

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    Baseline characteristics reporting groups [1]
    Reporting group title
    12 hours treatment period - Overall Trial
    Reporting group description
    All EU PDCO male and female subjects aged 2 years to less than 18 years and received at least one dose of IMP are 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 hours treatment period - Tapentadol
    Reporting group description
    This arm includes all subjects who received at least one dose of Tapentadol oral solution. 12 hours treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.

    Reporting group title
    12 hours treatment period - Placebo
    Reporting group description
    This arm includes all subjects who received at least one dose of placebo. 12 hours 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: The number of subjects reported in the baseline period are based on the number of subjects allocated and treated.
    Reporting group values
    12 hours treatment period - Overall Trial 12 hours treatment period - Tapentadol 12 hours treatment period - Placebo Total
    Number of subjects
    160 108 52 160
    Age categorical
    Units: Subjects
        Children (2-11 years)
    82 55 27 82
        Adolescents (12-17 years)
    78 53 25 78
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.7 ± 4.7 10.8 ± 4.7 10.4 ± 4.8 -
    Gender categorical
    Units: Subjects
        Female
    76 53 23 76
        Male
    84 55 29 84
    Type of opioid analgesia used
    Units: Subjects
        Hydromorphone
    51 33 18 51
        Morphine
    109 75 34 109
    Height
    Units: meter
        arithmetic mean (standard deviation)
    144.4 ± 28.2 145 ± 27.7 143.3 ± 29.5 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    42.8 ± 21.08 43.09 ± 21.72 42.22 ± 19.88 -
    Body Mass index
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    18.92 ± 4.03 18.83 ± 4.13 19.12 ± 3.84 -
    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 -

    End points

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    End points reporting groups
    Reporting group title
    12 hours treatment period - Overall Trial
    Reporting group description
    All EU PDCO male and female subjects aged 2 years to less than 18 years and received at least one dose of IMP are 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 hours treatment period - Tapentadol
    Reporting group description
    This arm includes all subjects who received at least one dose of Tapentadol oral solution. 12 hours treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.

    Reporting group title
    12 hours treatment period - Placebo
    Reporting group description
    This arm includes all subjects who received at least one dose of placebo. 12 hours treatment period completers were defined as subjects who did not discontinue the treatment period before 12 hours.
    Reporting group title
    24 hours treatment and trial completion - Overall Trial
    Reporting group description
    All EU PDCO male and female subjects aged 2 years to less than 18 years and received at least one 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 hours treatment and trial completion - Tapentadol
    Reporting group description
    All EU PDCO male and female subjects aged 2 years to less than 18 years and received at least one 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 hours treatment and trial completion - Placebo
    Reporting group description
    All EU PDCO male and female subjects aged 2 years to less than 18 years and received at least one 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 - Overall Trial
    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 - 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 - 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 - 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 - 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.

    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 was the amount of supplemental opioid analgesic medication used within the first 24 hours after first IMP intake. Supplemental opioid analgesia was expressed in mg/kg of morphine IV equivalents.
    End point type
    Primary
    End point timeframe
    up to 24 hours
    End point values
    FAS - Tapentadol FAS - 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 - Tapentadol v FAS - 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

    Secondary: 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
    Total amount of supplemental opioid analgesic medication used within 12 hours after first IMP. Supplemental opioid analgesia was expressed in mg/kg of morphine IV equivalents.
    End point type
    Secondary
    End point timeframe
    up to 12 hours
    End point values
    FAS - Tapentadol FAS - Placebo
    Number of subjects analysed
    108
    52
    Units: milligram(s)/kilogram
        arithmetic mean (standard deviation)
    0.09 ± 0.11
    0.14 ± 0.19
    No statistical analyses for this end point

    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 IV equivalents
    End point type
    Secondary
    End point timeframe
    24 to 96 hours after IMP
    End point values
    FAS - Tapentadol FAS - 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 Face, Legs, Activity, Cry, Consolability Scale in children from birth to less than 6 years

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    End point title
    Changes from baseline in pain intensity using the Face, Legs, Activity, Cry, Consolability Scale in children from birth to less than 6 years
    End point description
    The 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 five categories (F) Face; (L) Legs; (A) Activity; (C) Cry; (C) Consolabilityis scored from 0-2, which results in a total score between zero and ten. The Pain intensity scores have been obtained before and after first dose of IMP, and before each subsequent dose of IM, 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 - Tapentadol FAS - 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 IM, 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 - Tapentadol FAS - 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 IM, 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 - Tapentadol FAS - 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 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 - Tapentadol FAS - Placebo
    Number of subjects analysed
    108
    52
    Units: category
        Very much improved
    15
    12
        Much improved
    58
    22
        Minimally improved
    18
    8
        No change
    11
    4
        Minimally worse
    3
    2
        Much worse
    1
    1
        Very much worse
    0
    0
        Missing
    2
    3
    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 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 - Tapentadol FAS - Placebo
    Number of subjects analysed
    108
    52
    Units: category
        Very much improved
    16
    11
        Much improved
    53
    23
        Minimally improved
    21
    12
        No change
    13
    3
        Minimally worse
    1
    0
        Much worse
    1
    0
        Very much worse
    0
    0
        Missing
    3
    3
    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 NCA/PCA after the first dose of IMP were summarized descriptively using time-to-event methods and displayed overall and by relevant treatment groups. Subjects who completed the End of Treatment Visit before their first/second use of NCA/PCA or subjects who terminate treatment before their first/second use of NCA/PCA were censored at the End of Treatment Visit.
    End point type
    Secondary
    End point timeframe
    Time to first and second NCA/PCA administration
    End point values
    FAS - Tapentadol FAS - Placebo
    Number of subjects analysed
    108
    52
    Units: minute
    median (confidence interval 95%)
        Time to first NCA/PCA administration
    183 (90 to 446)
    131.5 (74 to 216)
        Time to second NCA/PCA administration
    572 (321 to 1993)
    338 (194 to 820)
    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 hours) were censored at 72 hours 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.
    End point type
    Secondary
    End point timeframe
    up to 72 hours
    End point values
    FAS - Tapentadol FAS - 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 rating 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.
    End point type
    Secondary
    End point timeframe
    After first dose of IMP
    End point values
    FAS - Tapentadol FAS - 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 rating 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.
    End point type
    Secondary
    End point timeframe
    End of Treatment Visit
    End point values
    FAS - Tapentadol FAS - 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 rating 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.
    End point type
    Secondary
    End point timeframe
    After first dose of IMP
    End point values
    FAS - Tapentadol FAS - 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 rating 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.
    End point type
    Secondary
    End point timeframe
    End of Treatment Visit
    End point values
    FAS - Tapentadol FAS - 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

    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 at baseline using the Columbia-Suicide Severity Rating scale; children´s baseline. Suicidal ideation and behavior was assessed at end of treatment using the Columbia-Suicide Severity Rating scale; children´s Since last visit. 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 - Tapentadol SAF - 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 - Tapentadol FAS - Placebo
    Number of subjects analysed
    108
    52
    Units: category
        Awake and alert
    63
    37
        Minimally sedated
    35
    13
        Moderately sedated
    8
    2
        Deeply sedated
    1
    0
        Unarousable
    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 - Tapentadol FAS - Placebo
    Number of subjects analysed
    108
    52
    Units: Subjects
    number (not applicable)
        Awake and alert
    30
    14
        Minimally sedated
    9
    5
        Moderately sedated
    4
    1
        Deeply sedated
    2
    1
        Unarousable
    0
    0
        Missing
    1
    0
    No statistical analyses for this end point

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

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    End point title
    Percentage of subjects discontinuing the trial due to TEAEs and drug-related adverse events
    End point description
    The number of subjects with at least one TEAE leading to discontinuation from the trial (i.e. TEAE with “countermeasures”: “trial discontinuation”) were summarized in one table and respective percentage was calculated.
    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 - Tapentadol FAS - Placebo
    Number of subjects analysed
    108
    52
    Units: Subjects
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    107
    52
    Units: percent
    number (not applicable)
        Non-alert
    75.7
    73.1
        Alert (low/high)
    24.3
    26.9
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    107
    52
    Units: percent
    number (not applicable)
        Non-alert
    70.1
    67.3
        Alert (low/high)
    29.9
    32.7
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    107
    52
    Units: percent
    number (not applicable)
        Non-alert
    34.6
    26.9
        Alert (low/high)
    65.4
    73.1
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    107
    52
    Units: percent
    number (not applicable)
        Non-alert
    42.1
    48.1
        Alert (low/high)
    57.9
    51.9
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    94
    40
    Units: percent
    number (not applicable)
        Non-alert
    69.1
    60
        Alert (low/high)
    30.9
    40
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    91
    39
    Units: percent
    number (not applicable)
        Non-alert
    85.7
    74.4
        Alert (low/high)
    14.3
    25.6
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    91
    39
    Units: percent
    number (not applicable)
        Non-alert
    82.4
    74.4
        Alert (low/high)
    17.6
    25.6
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    94
    40
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
        Alert (low/high)
    0
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    94
    40
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
        Alert (low/high)
    0
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    91
    39
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
        Alert (low/high)
    0
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    92
    39
    Units: percent
    number (not applicable)
        Non-alert
    96.7
    94.9
        Alert (low/high)
    3.3
    5.1
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    94
    40
    Units: percent
    number (not applicable)
        Non-alert
    86.2
    97.5
        Alert (low/high)
    13.8
    2.5
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    97
    42
    Units: percent
    number (not applicable)
        Non-alert
    100
    97.6
        Alert (low/high)
    0
    2.4
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    97
    42
    Units: percent
    number (not applicable)
        Non-alert
    95.9
    100
        Alert (low/high)
    4.1
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    90
    37
    Units: percent
    number (not applicable)
        Non-alert
    95.6
    100
        Alert (low/high)
    4.4
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    97
    42
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
        Alert (low/high)
    0
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    97
    42
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
        Alert (low/high)
    0
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    96
    41
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
        Alert (low/high)
    0
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    96
    41
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
        Alert (low/high)
    0
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    97
    41
    Units: percent
    number (not applicable)
        Non-alert
    97.9
    100
        Alert (low/high)
    2.1
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    97
    41
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
        Alert (low/high)
    0
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    94
    40
    Units: percent
    number (not applicable)
        Non-alert
    80.9
    77.5
        Alert (low/high)
    19.1
    22.5
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    97
    41
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
        Alert (low/high)
    0
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    74
    27
    Units: percent
    number (not applicable)
        Non-alert
    97.3
    100
        Alert (low/high)
    2.7
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    97
    42
    Units: percent
    number (not applicable)
        Non-alert
    99
    97.6
        Alert (low/high)
    1
    2.4
    No statistical analyses for this end point

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

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Alanine transaminase
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    96
    40
    Units: percent
    number (not applicable)
        Non-alert
    96.9
    100
        Alert (low/high)
    3.1
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    97
    42
    Units: percent
    number (not applicable)
        Non-alert
    97.9
    95.2
        Alert (low/high)
    2.1
    4.8
    No statistical analyses for this end point

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

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Aspartate transaminase
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    89
    36
    Units: percent
    number (not applicable)
        Non-alert
    97.8
    100
        Alert (low/high)
    2.2
    0
    No statistical analyses for this end point

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

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    End point title
    Percentage of subjects who develop abnormal laboratory parameter - Phosphorus
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    92
    37
    Units: percent
    number (not applicable)
        Non-alert
    98.9
    97.3
        Alert (low/high)
    1.1
    2.7
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    92
    37
    Units: percent
    number (not applicable)
        Non-alert
    98.9
    100
        Alert (low/high)
    1.1
    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.
    End point type
    Other pre-specified
    End point timeframe
    until end of treatment
    End point values
    SAF - Tapentadol SAF - Placebo
    Number of subjects analysed
    97
    42
    Units: percent
    number (not applicable)
        Non-alert
    100
    100
        Alert (low/high)
    0
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    95
    40
    Units: percent
    number (not applicable)
        Non-alert
    97.9
    100
        Alert (low/high)
    2.1
    0
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    101
    48
    Units: percent
    number (not applicable)
        Non-alert
    58.4
    45.8
        Alert (low/high)
    41.6
    54.2
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    100
    48
    Units: percent
    number (not applicable)
        Non-alert
    97
    100
        Alert (low/high)
    3
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    101
    48
    Units: percent
    number (not applicable)
        Non-alert
    75.2
    79.2
        Alert (low/high)
    24.8
    20.8
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    101
    48
    Units: percent
    number (not applicable)
        Non-alert
    69.3
    66.7
        Alert (low/high)
    30.7
    33.3
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    101
    48
    Units: percent
    number (not applicable)
        Non-alert
    95
    100
        Alert (low/high)
    5
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    101
    48
    Units: percent
    number (not applicable)
        Non-alert
    96
    97.9
        Alert (low/high)
    4
    2.1
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    43
    21
    Units: mm/Hg
        arithmetic mean (standard deviation)
    1 ± 11.74
    4.7 ± 11.66
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    43
    21
    Units: mm/Hg
        arithmetic mean (standard deviation)
    -3.7 ± 11.72
    0 ± 9.84
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    43
    21
    Units: beats per minute
        arithmetic mean (standard deviation)
    -3.5 ± 18.83
    -3.4 ± 17.41
    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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    43
    21
    Units: breaths per minute
        arithmetic mean (standard deviation)
    -0.3 ± 6.33
    2.8 ± 4.55
    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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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 - Tapentadol SAF - 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.
    End point type
    Other pre-specified
    End point timeframe
    baseline to end to treatment
    End point values
    SAF - Tapentadol SAF - 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

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    End point title
    Changes from baseline in 12-lead ECG parameters
    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 - Tapentadol SAF - 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 - Tapentadol SAF - Placebo
    Number of subjects analysed
    98
    46
    Units: beats per minute
        arithmetic mean (standard deviation)
    -3.9 ± 22.6
    -0.6 ± 19.5
    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
    Placebo - Safety set
    Reporting group description
    All subjects who received at least one dose of placebo.

    Reporting group title
    Tapentadol - Safety set
    Reporting group description
    All subjects who received at least one dose of Tapentadol oral solution.

    Reporting group title
    Overall – Safety Set
    Reporting group description
    All subjects who received at least one dose of IMP.

    Serious adverse events
    Placebo - Safety set Tapentadol - Safety set Overall – Safety Set
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 108 (1.85%)
    2 / 160 (1.25%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Seizure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abdominal Abscess
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo - Safety set Tapentadol - Safety set Overall – Safety Set
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 52 (50.00%)
    62 / 108 (57.41%)
    88 / 160 (55.00%)
    General disorders and administration site conditions
    Chest Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Face Oedema
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Infusion Site Pruritus
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 108 (0.00%)
    1 / 160 (0.63%)
         occurrences all number
    1
    0
    1
    Pyrexia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    10 / 108 (9.26%)
    11 / 160 (6.88%)
         occurrences all number
    1
    19
    20
    Psychiatric disorders
    Agitation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Anxiety
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 108 (0.00%)
    2 / 160 (1.25%)
         occurrences all number
    2
    0
    2
    Hallucinations, Mixed
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Initial Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Insomnia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 52 (3.85%)
    0 / 108 (0.00%)
    2 / 160 (1.25%)
         occurrences all number
    2
    0
    2
    Withdrawal syndrome
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 108 (0.00%)
    1 / 160 (0.63%)
         occurrences all number
    1
    0
    1
    Injury, poisoning and procedural complications
    Anaemia Postoperative
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 108 (0.93%)
    2 / 160 (1.25%)
         occurrences all number
    1
    1
    2
    Transfusion Reaction
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Investigations
    Alanine Aminotransferase Increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Aspartate aminotransferase increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Blood Urea Decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Haematocrit Decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 108 (0.00%)
    1 / 160 (0.63%)
         occurrences all number
    1
    0
    1
    Haemoglobin Decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 108 (0.93%)
    2 / 160 (1.25%)
         occurrences all number
    1
    1
    2
    Hepatic Enzyme Increased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Oxygen saturation decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 108 (2.78%)
    4 / 160 (2.50%)
         occurrences all number
    1
    4
    5
    Po2 Decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    2
    2
    Red blood cell count decreased
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 108 (0.00%)
    1 / 160 (0.63%)
         occurrences all number
    1
    0
    1
    Cardiac disorders
    Sinus Tachycardia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    2 / 108 (1.85%)
    3 / 160 (1.88%)
         occurrences all number
    1
    2
    3
    Blood and lymphatic system disorders
    Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Haemorrhagic Anaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Thrombocytopenia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Bradypnoea
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 108 (0.00%)
    1 / 160 (0.63%)
         occurrences all number
    1
    0
    1
    Chylothorax
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Hypoxia
         subjects affected / exposed
    0 / 52 (0.00%)
    3 / 108 (2.78%)
    3 / 160 (1.88%)
         occurrences all number
    0
    3
    3
    Nasal Congestion
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 108 (0.00%)
    1 / 160 (0.63%)
         occurrences all number
    1
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 108 (0.00%)
    1 / 160 (0.63%)
         occurrences all number
    1
    0
    1
    Painful Respiration
         subjects affected / exposed
    1 / 52 (1.92%)
    0 / 108 (0.00%)
    1 / 160 (0.63%)
         occurrences all number
    1
    0
    1
    Pleural Effusion
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Nervous system disorders
    Dizziness
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    4 / 108 (3.70%)
    5 / 160 (3.13%)
         occurrences all number
    1
    7
    8
    Headache
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    5 / 108 (4.63%)
    6 / 160 (3.75%)
         occurrences all number
    1
    6
    7
    Sedation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    2 / 108 (1.85%)
    2 / 160 (1.25%)
         occurrences all number
    0
    2
    2
    Seizure
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Somnolence
    alternative assessment type: Non-systematic
         subjects affected / exposed
    2 / 52 (3.85%)
    6 / 108 (5.56%)
    8 / 160 (5.00%)
         occurrences all number
    2
    6
    8
    Eye disorders
    Eye Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Gastrointestinal disorders
    Abdominal Distension
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Abdominal Pain
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Constipation
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 52 (11.54%)
    11 / 108 (10.19%)
    17 / 160 (10.63%)
         occurrences all number
    6
    11
    17
    Dysphagia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Nausea
    alternative assessment type: Non-systematic
         subjects affected / exposed
    4 / 52 (7.69%)
    16 / 108 (14.81%)
    20 / 160 (12.50%)
         occurrences all number
    5
    22
    27
    Vomiting
    alternative assessment type: Non-systematic
         subjects affected / exposed
    6 / 52 (11.54%)
    25 / 108 (23.15%)
    31 / 160 (19.38%)
         occurrences all number
    8
    36
    44
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    1 / 52 (1.92%)
    3 / 108 (2.78%)
    4 / 160 (2.50%)
         occurrences all number
    1
    3
    4
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Pruritus
         subjects affected / exposed
    3 / 52 (5.77%)
    4 / 108 (3.70%)
    7 / 160 (4.38%)
         occurrences all number
    3
    4
    7
    Rash
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Rash macular
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    3
    3
    Urticaria
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Metabolism and nutrition disorders
    Decreased Appetite
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 108 (0.93%)
    2 / 160 (1.25%)
         occurrences all number
    1
    1
    2
    Hyperglycaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Hypomagnesaemia
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 52 (1.92%)
    1 / 108 (0.93%)
    2 / 160 (1.25%)
         occurrences all number
    1
    1
    2
    Lactic Acidosis
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Abdominal Abscess
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1
    Pneumonia mycoplasmal
    alternative assessment type: Non-systematic
         subjects affected / exposed
    0 / 52 (0.00%)
    1 / 108 (0.93%)
    1 / 160 (0.63%)
         occurrences all number
    0
    1
    1

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    27 Nov 2013
    Amendment 01 was implemented to change the site of manufacture of the IMP for logistic reasons.
    14 Oct 2014
    Amendment 02 was implemented for clarification and to comply with US FDA requirements: • The definition of completers has been amended. • Subjects who are cognitively impaired in the investigator’s judgment such that they cannot comply with the protocol are now excluded from participation in the trial. • The age range of the palatability and taste questionnaire has been extended downwards from 3 years to 2 years. • The dose of tapentadol oral solution for subjects between 2 years and less than 6 years has now been defined. • The list of prohibited medication taken within 14 days of allocation to IMP has been extended to include all serotonergic drugs, including selective serotonin/norepinephrine reuptake inhibitors, tricyclic antidepressants, linezolid, triptans, and St. John’s Wort (hypericum perforatum) for safety reasons. The time medication for sedation is prohibited has been extended to 6 hours before allocation to IMP. The use of benzodiazepines for muscle cramps and anxiety has been explicitly allowed. • The use of IMP after 24 hours has been modified to reflect medical practice by allowing its use every 4 hours to 6 hours, and by extending use up to 72 hours to comply with a requirement to assess for at least 48 hours. • The use of the University of Michigan Sedation Scale has been added for assessing sedation. • The primary endpoint will also be evaluated using Bayesian statistics as a supportive analysis. The methodology will be described in the statistical analysis plan.
    16 Apr 2015
    Amendment 03 was implemented to change the sponsor from Janssen Research & Development, LLC to Grünenthal GmbH. As a consequence, the functions of the sponsor and the operational lead were merged.
    23 Jun 2015
    Amendment 04 was implemented to: • Clarify the definition for stopping IMP. • Allow a clinician bolus of morphine or hydromorphone if the subject had unbearable pain in exceptional cases. This has been enacted to ensure that the subjects are not exposed to more pain than would normally be the case. • Add peri- or post-operative analgesia supplied by a continuous regional technique (e.g., nerve block, wound infiltration catheter) or subject controlled epidural analgesia to the prohibited medication from 6 hours prior to time of allocation to IMP until 4 hours after the last administration of IMP. • Exclude continuous positive airway pressure or mechanical ventilation from time of allocation to IMP until 4 hours after the last administration of IMP. • Modify 2 exclusion criteria to: − 8. Subject is obese in the investigator’s judgment. Obesity can be determined based on appropriate body mass index (BMI) charts or tables; e.g., a BMI above the 97th percentile for children based on the World Health Organization growth charts (see Section 19.9). − 16. Peri- or post-operative analgesia supplied by a continuous regional technique (e.g., nerve block, wound infiltration catheter) or subject controlled epidural analgesia that was terminated less than 6 hours before allocation to IMP. • Add an exclusion criteria of: Subject requires continuous positive airway pressure or mechanical ventilation, at the time of allocation to IMP. • Allow the use of non-sponsor supplied dosing syringes. This has been enacted for logistical reasons and does not affect the outcome parameters. • Specify that the administration of IMP must not be repeated if the subject vomits or regurgitates a complete dose. • Allow the pregnancy test to be done on either a urine sample or a serum sample. • Restrict CGIC and PGIC data to a descriptive analysis in the final report.
    27 Oct 2015
    Amendment 05 was implemented to: • Define the dosing for subjects aged 6 months to <2 years old. • Provide restrictions for the medication that can be taken by mothers of a newborn or breastfeeding mother. • Allow the safety laboratory blood sample analysis to be performed at a local laboratory for subjects <2 years old to limit the amount of blood taken.
    19 Aug 2016
    Amendment 06 was implemented to: • Enable the EU PDCO data set to be analyzed for regulatory requirements prior to completion of the US FDA data set. • Remove the analysis of non-opioid analgesic medication as a secondary endpoint for logistical reasons. • Clarify an inconsistency with regard to the start of continuous oxygen saturation monitoring. • Update information on post-marketing experience. • Update the collaborator’s signatories.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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