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    Clinical Trial Results:
    An open label trial, enrolling subjects aged 6 years to less than 18 years suffering from pain requiring prolonged release opioid treatment, to evaluate the safety and efficacy of tapentadol PR versus morphine PR, followed by an open label extension.

    Summary
    EudraCT number
    2012-004360-22
    Trial protocol
    GB   DE   PT   ES   SK   BE   IT   SI   HU   BG   HR   FR  
    Global end of trial date
    15 Oct 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    09 Mar 2019
    First version publication date
    09 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KF5503-66
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02151682
    WHO universal trial number (UTN)
    U1111-1154-4572
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52099
    Public contact
    Grünenthal Trial Information Desk, Grünenthal GmbH, 0049 2415693223, clinical-trials@grunenthal.com
    Scientific contact
    Grünenthal Trial Information Desk, Grünenthal GmbH, 0049 2415693223, 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-000325-PIP01-08
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Dec 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Oct 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Oct 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The trial objectives for Part 1 of the trial were: • To assess the 14-day safety and efficacy of tapentadol prolonged release (PR) in comparison to morphine PR in subjects aged from 6 years to less than 18 years suffering from long-term pain requiring prolonged release opioid treatment. • To evaluate the pharmacokinetic profile of tapentadol and its major metabolite tapentadol-O-glucuronide after multiple doses of tapentadol PR tablets. The trial objective for Part 2 of the trial was: • To describe the long-term safety profile covering up to a 12-month period with treatment of tapentadol PR taken twice daily (Tapentadol Period) in subjects aged 6 years or older suffering from long-term pain requiring prolonged-release opioid treatment, or in subjects without tapentadol treatment (Observation Period) aged 6 years or older who had received at least 1 dose of investigational medicinal product (IMP).
    Protection of trial subjects
    The trial was conducted according to ICH-GCP guidelines, the applicable local laws and regulations, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. The regulatory authorities were notified of the trial as required by national regulations, and where necessary relevant authorizations were obtained.
    Background therapy
    -
    Evidence for comparator
    Morphine is a gold standard in the analgesic management of severe pain (De Conno and Kress. Palliative Medicine 2006; 20: S1) including cancer pain (Broomhead et al. J Pain Symptom Manage 1997; 14: 63-73). Morphine is among the top 10 medications given to children in inpatient settings (Lasky et al. Clin Ther 2012; 34 (3): 720-7). It is one of the World Health Organisation Step III pain medications, authorized for use in children.
    Actual start date of recruitment
    29 Apr 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Portugal: 7
    Country: Number of subjects enrolled
    Spain: 2
    Country: Number of subjects enrolled
    United Kingdom: 8
    Country: Number of subjects enrolled
    Belgium: 1
    Country: Number of subjects enrolled
    Bulgaria: 17
    Country: Number of subjects enrolled
    France: 14
    Country: Number of subjects enrolled
    Germany: 9
    Country: Number of subjects enrolled
    Hungary: 1
    Country: Number of subjects enrolled
    Italy: 3
    Country: Number of subjects enrolled
    Chile: 7
    Worldwide total number of subjects
    69
    EEA total number of subjects
    62
    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)
    19
    Adolescents (12-17 years)
    50
    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 29 Apr 2015 with the enrollment of the first subject in Part 1. Part 1 was completed on 18 Oct 2017 when the last subject completed the last assessment for the primary endpoint. The last subject's last assessment in Part 2 was on 15 Oct 2018.

    Pre-assignment
    Screening details
    73 Subjects signed an informed consent form (assented) for this trial. 1 subject withdrew consent and 2 did not meet in-/exclusion criteria. 70 Subjects were allocated to IMP: 1 of the allocated subjects was not treated, resulting in 69 subjects who were dosed in Part 1.

    Pre-assignment period milestones
    Number of subjects started
    73 [1]
    Number of subjects completed
    69

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    not specified: 1
    Reason: Number of subjects
    Consent withdrawn by subject: 1
    Reason: Number of subjects
    Inclusion criteria not me/exclusion criteria met: 2
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 73 subjects signed an informed consent form (assented). 1 subject withdrew consent and 2 did not meet in-/exclusion criteria. 70 subjects were allocated to investigational medicinal product (IMP). 1 of the allocated subjects was not treated, resulting in 69 subjects who were dosed in Part 1.
    Period 1
    Period 1 title
    Part 1
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Subjects were stratified using interactive response technology: by age group (6 years to less than 12 years and 12 years to less than 18 years, at the second visit [Allocation Visit]) so that at least 25% of subjects were in the younger age group, and by underlying pain condition (cancer/non-cancer-related pain). Randomization was carried out in blocks and in a 2:1 ratio (tapentadol PR to morphine PR). The block size was not disclosed to sites before the conduct of Part 1 was completed.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Morphine prolonged release (Part 1)
    Arm description
    The treatment group comprised 7 subjects aged 6 years to less than 12 years and 17 subjects aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on subject’s weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for subjects weighing 55 kg and more was 200 mg per day.
    Arm type
    Active comparator

    Investigational medicinal product name
    Morphine prolonged release
    Investigational medicinal product code
    Other name
    Morphine sulfate prolonged-release tablets, MST Mundipharma (Trade Mark)
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10 mg or 30 mg tablets were taken orally twice daily. The dose was based on the subject's weight. The dose had not to exceed a total of 200 mg per day for subjects weighing 55 kg or more.

    Arm title
    Tapentadol prolonged release (Part 1)
    Arm description
    The treatment group comprised 12 subjects aged 6 years to less than 12 years and 33 subjects aged 12 years to less than 18 years. Subjects starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on subject’s weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for subjects weighing 55 kg and more was 500 mg per day.
    Arm type
    Experimental

    Investigational medicinal product name
    Tapentadol prolonged release
    Investigational medicinal product code
    Other name
    Tapentadol prolonged-release tablet, Palexia retard, Nucynta, Yantil
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25 mg or 100 mg tablets were taken orally twice daily. The dose was based on the subject's weight. The dose had not to exceed a total of 500 mg per day for subjects weighing 55 kg or more.

    Number of subjects in period 1
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Started
    24
    45
    Completed
    22
    40
    Not completed
    2
    5
         Technical problems
             -
             1
         Reason missing
             1
             -
         Adverse event, non-fatal
             -
             2
         Consent withdrawn by subject
             -
             1
         No need for opioid
             1
             1
    Period 2
    Period 2 title
    Part 2
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded
    Blinding implementation details
    Subjects who completed Part 1 (on tapentadol PR or morphine PR) could continue or switch to treatment with tapentadol PR for up to 12 months in Part 2. Subjects who completed Part 1 (on tapentadol PR or morphine PR) or discontinued early from Part 1 could continue directly in the Observation Period in Part 2. Subjects who completed Part 1 (on tapentadol PR or morphine PR) and discontinued from tapentadol PT treatment in Part 2 could enter the Observation Period in Part 2.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Tapentadol prolonged release in Part 2
    Arm description
    36 subjects who completed Part 1 of the trial (26 on tapentadol PR and 10 subjects on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2.
    Arm type
    Experimental

    Investigational medicinal product name
    Tapentadol prolonged release
    Investigational medicinal product code
    Other name
    Tapentadol prolonged-release tablet, Palexia retard; Nucynta, Yantil
    Pharmaceutical forms
    Prolonged-release tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects on tapentadol PR continued on the current dose and if necessary could modify their tapentadol PR dosage. Subjects who were randomized to morphine PR in Part 1 were rotated to tapentadol PR with 70 percent of their current morphine equivalent dose or lower. The dosage could be increased gradually up to approximately 4.5 mg/kg tapentadol PR twice daily.

    Arm title
    Observation Period After Tapentadol in Part 1
    Arm description
    18 Subjects who completed tapentadol PR treatment in Part 1 or discontinued tapentadol treatment early in Part 1 directly entered the Observation Period of Part 2 for up to 12 months.
    Arm type
    Standard of care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Observation Period After Morphine in Part 1
    Arm description
    14 Subjects who completed morphine PR treatment in Part 1 or discontinued morphine treatment early in Part 1 directly entered the Observation Period of Part 2 for up to 12 months.
    Arm type
    Standard of care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    Observation Period After Tapentadol in Part 2
    Arm description
    26 Subjects who completed morphine PR or tapentadol PR treatment in Part 1 of the trial entered the Observation Period in Part 2 for up to 12 months after they had discontinued from tapentadol PR treatment in Part 2.
    Arm type
    Standard of care

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    Tapentadol prolonged release in Part 2 Observation Period After Tapentadol in Part 1 Observation Period After Morphine in Part 1 Observation Period After Tapentadol in Part 2
    Started
    36
    18
    14
    26
    Completed
    8
    14
    14
    19
    Not completed
    28
    4
    0
    7
         Protocol deviation
             1
             -
             -
             -
         Missing
             -
             1
             -
             3
         No need for opioid treatment anymore
             13
             -
             -
             -
         Lack of efficacy
             3
             -
             -
             -
         Adverse event, serious fatal
             -
             2
             -
             1
         Adverse event, non-fatal
             3
             -
             -
             -
         not specified
             6
             -
             -
             2
         Consent withdrawn by subject
             1
             1
             -
             1
         Final post-treatment visit not performed
             1
             -
             -
             -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Morphine prolonged release (Part 1)
    Reporting group description
    The treatment group comprised 7 subjects aged 6 years to less than 12 years and 17 subjects aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on subject’s weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for subjects weighing 55 kg and more was 200 mg per day.

    Reporting group title
    Tapentadol prolonged release (Part 1)
    Reporting group description
    The treatment group comprised 12 subjects aged 6 years to less than 12 years and 33 subjects aged 12 years to less than 18 years. Subjects starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on subject’s weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for subjects weighing 55 kg and more was 500 mg per day.

    Reporting group values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1) Total
    Number of subjects
    24 45 69
    Age categorical
    Units: Subjects
        6 years to less than 12 years
    7 12 19
        12 years to less than 18 years
    17 33 50
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    13.2 ± 2.8 13.2 ± 2.8 -
    Gender categorical
    Units: Subjects
        Female
    10 22 32
        Male
    14 23 37
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    4 7 11
        Not Hispanic or Latino
    20 36 56
        Unknown or Not Reported
    0 2 2
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0 0
        Asian
    0 0 0
        Native Hawaiian or Other Pacific Islander
    0 1 1
        Black or African American
    0 0 0
        White
    24 44 68
        More than one race
    0 0 0
        Unknown or not reported
    0 0 0
    Pain cause
    Units: Subjects
        Cancer-related pain (6 to less than 12 years)
    1 0 1
        Cancer-related pain (12 to less than 18 years)
    4 9 13
        Non-cancer-related pain (6 to less than 12 years)
    6 12 18
        Non-cancer-related pain (12 to less than 18 years)
    13 24 37
    Type of pain
    Units: Subjects
        Neuropathic
    4 9 13
        Nociceptive/somatic
    13 28 41
        Nociceptive/visceral
    0 0 0
        Neuropathic and nociceptive/somatic
    6 6 12
        Neuropathic and nociceptive/visceral
    0 0 0
        Nociceptive/somatic and nociceptive/visceral
    1 1 2
        All of the pain types
    0 1 1
    Height
    Units: meter
        arithmetic mean (standard deviation)
    1.580 ± 0.170 1.557 ± 0.166 -
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    50.13 ± 14.97 49.95 ± 16.98 -
    Body mass index
    Units: kilograms per square meter
        arithmetic mean (standard deviation)
    19.63 ± 4.12 20.07 ± 4.68 -
    Pain intensity (VAS)
    Subjects were asked to indicate the current level of pain intensity at the time of assessment on a validated vertical visual analog scale (VAS). It was scored such that a score of 0 was equivalent to “no pain” and a score of 100 was equivalent to “pain as bad as it could be”. VAS data at baseline were available for 32 subjects on tapentadol PR and for 19 subjects on morphine PR (51 of 69 subjects overall).
    Units: Units on a scale
        arithmetic mean (standard deviation)
    50.8 ± 32.5 47.8 ± 32.4 -
    Pain intensity (FPS-R)
    Pain intensity was assessed on a revised Faces Pain Scale (FPS-R). The FPS-R is a validated self-reported 6-point scale with 0 representing “no pain” and 10 representing “very much pain”. Facial representations were used to indicate how much the pain hurts. FPS-R data at baseline were available for 32 subject on tapentadol PR and for 19 subjects on morphine PR (51 of 69 subjects overall).
    Units: Units on a scale
        arithmetic mean (standard deviation)
    4.2 ± 3.0 4.6 ± 3.3 -

    End points

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    End points reporting groups
    Reporting group title
    Morphine prolonged release (Part 1)
    Reporting group description
    The treatment group comprised 7 subjects aged 6 years to less than 12 years and 17 subjects aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on subject’s weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for subjects weighing 55 kg and more was 200 mg per day.

    Reporting group title
    Tapentadol prolonged release (Part 1)
    Reporting group description
    The treatment group comprised 12 subjects aged 6 years to less than 12 years and 33 subjects aged 12 years to less than 18 years. Subjects starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on subject’s weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for subjects weighing 55 kg and more was 500 mg per day.
    Reporting group title
    Tapentadol prolonged release in Part 2
    Reporting group description
    36 subjects who completed Part 1 of the trial (26 on tapentadol PR and 10 subjects on morphine PR) continued treatment or switched to treatment with tapentadol PR for up to 12 months in Part 2.

    Reporting group title
    Observation Period After Tapentadol in Part 1
    Reporting group description
    18 Subjects who completed tapentadol PR treatment in Part 1 or discontinued tapentadol treatment early in Part 1 directly entered the Observation Period of Part 2 for up to 12 months.

    Reporting group title
    Observation Period After Morphine in Part 1
    Reporting group description
    14 Subjects who completed morphine PR treatment in Part 1 or discontinued morphine treatment early in Part 1 directly entered the Observation Period of Part 2 for up to 12 months.

    Reporting group title
    Observation Period After Tapentadol in Part 2
    Reporting group description
    26 Subjects who completed morphine PR or tapentadol PR treatment in Part 1 of the trial entered the Observation Period in Part 2 for up to 12 months after they had discontinued from tapentadol PR treatment in Part 2.

    Primary: Number of subjects classified as responder (Part 1)

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    End point title
    Number of subjects classified as responder (Part 1)
    End point description
    A subject was defined as responder if both of the following criteria were met: - Completion of the 14-day Treatment Period (Part 1). - One of the following calculated from the scheduled pain assessments ("pain right now") documented during the last 3 days of the Treatment Period: • Average pain less than 50 on a visual analog scale (VAS, range 0 [no pain] to 100 [pain as bad as it could be]) for subjects aged 12 years to less than 18 years; or less than 5 on the Faces Pain Scale-revised (FPS-R, range 0 [no pain] and 10 [very much pain]) for subjects aged 6 years to less than 12 years. • Average reduction from baseline of pain greater than or equal to 20 on a VAS for subjects aged 12 years to less than 18 years; or greater than or equal to 2 on the FPS-R for subjects aged 6 years to less than 12 years. The proportion of subjects classified as responders was assessed and compared between the treatment groups.
    End point type
    Primary
    End point timeframe
    From Day 1 up to Day 14 (End of Part 1)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24 [1]
    45 [2]
    Units: Number of subjects
        Number of subjects classified as responder
    19
    32
    Notes
    [1] - Full Analysis Set; missing pain assessments (last 3 days) were imputed using multiple imputation.
    [2] - Full Analysis Set; missing pain assessments (last 3 days) were imputed using multiple imputation.
    Statistical analysis title
    Responder analysis
    Statistical analysis description
    A logistic regression model was fitted to the response using baseline pain, age group, treatment and underlying pain condition as explanatory variables, followed by a Farrington-Manning test for non-inferiority, based on Full Analysis Set.
    Comparison groups
    Morphine prolonged release (Part 1) v Tapentadol prolonged release (Part 1)
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    P-value
    = 0.079 [4]
    Method
    Farrington-Manning test
    Parameter type
    Risk difference (RD)
    Point estimate
    -0.06
    Confidence interval
         level
    80%
         sides
    2-sided
         lower limit
    -0.19
         upper limit
    0.06
    Notes
    [3] - A confidence interval for the risk difference (RD) completely above the pre-specified non-inferiority margin of -0.2 represents non-inferiority of tapentadol prolonged-release versus morphine prolonged-release.
    [4] - The p-value is based on Farrington-Manning variance estimator using a pre-specified non-inferiority margin of -0.2. A 1-sided alpha of <0.1 was used. A p-value <0.1 represents non-inferiority.

    Secondary: Extent of constipation (Part 1)

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    End point title
    Extent of constipation (Part 1)
    End point description
    Constipation was assessed using the modified constipation assessment scale (mCAS). This is an 8-item questionnaire where the observer has scored constipation on a nominal scale (no Problem [score 0], some problem [score 1] or severe Problem [score 2]). The response to an item could also be scored as “unable to assess”. The Total Score can vary from 0-16; the higher the Total Score the higher the extent of constipation. A positive change from Day 1 to Day 14 indicates a worsening, a negative change an improvement.
    End point type
    Secondary
    End point timeframe
    From Day 1 to Day 14 (End of Part 1)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24 [5]
    45 [6]
    Units: score on a scale
    arithmetic mean (standard deviation)
        Day 1 (N = 23/40)
    2.7 ± 3.0
    1.5 ± 1.4
        Day 14 (N = 24/41)
    2.7 ± 2.4
    1.8 ± 2.0
        Change from Day 1 (N = 23/39)
    -0.1 ± 1.6
    0.4 ± 2.4
    Notes
    [5] - Safety Set
    [6] - Safety Set
    No statistical analyses for this end point

    Secondary: Tolerability (number of TEAEs per subjects)

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    End point title
    Tolerability (number of TEAEs per subjects)
    End point description
    Tolerability was assessed by the number of subjects with exactly 1 to more than 5 treatment emergent adverse events (TEAE) by treatment group during the different trial periods, on a subject level.
    End point type
    Secondary
    End point timeframe
    Part 1: Day 1 (Start of Part 1) to day 14; Part 2: Day 15 to Day 379 (End of Part 2)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1) Tapentadol prolonged release in Part 2
    Number of subjects analysed
    24 [7]
    45 [8]
    36 [9]
    Units: Number of subjects
        Subjects without any TEAEs
    12
    19
    6
        Subjects with at least 1 TEAE
    12
    26
    30
        Subjects with exactly 1 TEAE
    1
    7
    5
        Subjects with exactly 2 TEAEs
    2
    5
    2
        Subjects with exactly 3 TEAEs
    2
    4
    2
        Subjects with exactly 4 TEAEs
    2
    1
    4
        Subjects with exactly 5 TEAEs
    1
    3
    3
        Subjects with more than 5 TEAEs
    4
    6
    14
    Notes
    [7] - Safety Set
    [8] - Safety Set
    [9] - Safety Set
    No statistical analyses for this end point

    Secondary: Tolerability (number of subjects with related TEAEs)

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    End point title
    Tolerability (number of subjects with related TEAEs)
    End point description
    Tolerability was assessed by the number of subjects with treatment emergent adverse events (TEAEs) which were considered by the investigator to be at least possibly related to the treatment the subject received.
    End point type
    Secondary
    End point timeframe
    Part 1: Day 1 (Start of Part 1) to day 14; Part 2: Day 15 to Day 379 (End of Part 2)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1) Tapentadol prolonged release in Part 2
    Number of subjects analysed
    24 [10]
    45 [11]
    36 [12]
    Units: Number of subjects
    6
    12
    13
    Notes
    [10] - Safety Set
    [11] - Safety Set
    [12] - Safety Set
    No statistical analyses for this end point

    Other pre-specified: Change in pain intensity in the open-label, active-controlled Treatment Period (Part 1)

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    End point title
    Change in pain intensity in the open-label, active-controlled Treatment Period (Part 1)
    End point description
    Pain intensity was assessed by scoring “pain right now” twice daily up to Day 14 by every subject using the Visual Analog Scale (VAS) as well as the Faces Pain Scale-Revised (FPS-R) in an electronic diary. Pain intensity was first documented using the VAS and directly thereafter the FPS-R. If required, pain intensity diary entry could be assisted by the legal guardian or a health care provider. The VAS is scored from 0, equivalent to “no pain”, to 100, equivalent to “pain as bad as it could be”. The FPS-R is a validated self-reported 6-point scale with 0 representing “no pain” and 10 representing “very much pain”. Facial representations were used to indicate how much the pain hurts. The "pain right now" scores at baseline (last evaluation before starting IMP) and the mean of last 6 assessments collected up to the time point of last IMP intake in Part 1 (i.e., Day 14 or the day of early discontinuation) were used for the calculation of the change in pain intensity from baseline.
    End point type
    Other pre-specified
    End point timeframe
    From baseline up to Day 14 (End of Part 1) or early discontinuation
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24 [13]
    45 [14]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Pain intensity change from Baseline (FPS-R)
    -2.0 ± 3.5
    -1.9 ± 3.4
        Pain intensity change from Baseline (VAS)
    -23.4 ± 36.9
    -18.8 ± 33.5
    Notes
    [13] - Full Analysis Set; results based on FPS-R and VAS results for 17 subjects.
    [14] - Full Analysis Set; results based on FPS-R and VAS results for 29 subjects.
    No statistical analyses for this end point

    Other pre-specified: Change in pain intensity in the tapentadol open-label Extension Period (Part 2)

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    End point title
    Change in pain intensity in the tapentadol open-label Extension Period (Part 2)
    End point description
    Pain intensity was assessed by scoring “Pain right now” using the Visual Analog Scale (VAS) as well as the Faces Pain Scale-Revised (FPS-R) at each visit. The pain intensity was first documented using the VAS and directly thereafter the FPS-R. If required, pain intensity assessments could be assisted by the legal guardian or a health care provider. The VAS is scored from 0, equivalent to “no pain”, to 100, equivalent to “pain as bad as it could be”. The FPS-R is a validated self-reported 6-point scale with 0 representing “no pain” and 10 representing “very much pain”. Facial representations were used to indicate how much the pain hurts. The "pain right now" score at the tapentadol baseline (last evaluation before or at Day 15) and at the last assessment in Part 2 (i.e., 12 months after completion of Part 1 or the day of early discontinuation) were used for the calculation of the change in pain intensity from the tapentadol baseline.
    End point type
    Other pre-specified
    End point timeframe
    From Day 15 to Day 379 (End of Part 2)
    End point values
    Tapentadol prolonged release in Part 2
    Number of subjects analysed
    36 [15]
    Units: Units on scale
    arithmetic mean (standard deviation)
        Pain intensity change (FPR-S) from Day 15
    0 ± 2.8
        Pain intensity change (VAS) from Day 15
    -11.7 ± 29.0
    Notes
    [15] - Full Analysis Set; data from 9 subjects were analyzed, data for 22 subjects were missing.
    No statistical analyses for this end point

    Other pre-specified: Use of rescue medication in the open-label, active-controlled Treatment Period (Part 1)

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    End point title
    Use of rescue medication in the open-label, active-controlled Treatment Period (Part 1)
    End point description
    Due to an overall low intake of rescue medication it was not appropriate to present the number of doses of oral morphine solution used at different dose levels of investigational medicinal product (IMP) but the average daily dose (milligrams per kilogram body weight) for the treatment period and a modified average daily dose. Average daily dose and modified average daily dose were both calculated based on drug accountability. For the modified average daily doses, unplausible values were excluded from the analysis, i.e. the amount of rescue medication that was lost due to a broken bottle was excluded from the analysis and negative amounts of rescue medication intakes due to measurement inaccuracies for bottle weights were considered as no intake.
    End point type
    Other pre-specified
    End point timeframe
    From Day 1 up to Day 14 (End of Part 1)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24
    45 [16]
    Units: milligrams per kilogram per day
    arithmetic mean (standard deviation)
        Average daily dose
    0.07 ± 0.154
    0.46 ± 2.426
        Modified average daily dose
    0.08 ± 0.160
    0.11 ± 0.201
    Notes
    [16] - Full Analysis Set; data from 44 subjects were analyzed.
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic concentrations of tapentadol (Part 1)

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    End point title
    Pharmacokinetic concentrations of tapentadol (Part 1) [17]
    End point description
    Tapentadol concentrations were measured in subjects in the tapentadol PR treatment arm (Part 1). All subjects who had quantifiable serum concentrations (i.e., serum concentrations above the lower limit of quantification) during the Treatment Period were included in the descriptive pharmacokinetic analysis. Data from subjects who vomited within 6 hours of administration of IMP during the Treatment Period were carefully assessed to decide if the data should be included in the pharmacokinetic analysis.
    End point type
    Other pre-specified
    End point timeframe
    From Day 1 to Day 14 (End of Part 1)
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Tapentadol serum concentrations were only determined in subjects receiving tapentadol PR and not in the morphine PR comparator arm. So no statistical analysis between the two arms is possible.
    End point values
    Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    44 [18]
    Units: nanograms per millilter
    arithmetic mean (standard deviation)
        Day 1 (6 to less than 12 years, N = 12)
    17.2 ± 7.40
        Day 1 (12 to less than 18 years, N = 28)
    19.9 ± 22.99
        Day 14 (6 to less than 12 years, N = 12)
    35.6 ± 18.14
        Day 14 (12 to less than 18 years, N = 29)
    48.5 ± 38.59
        Day 1 (all subjects, N = 40)
    19.1 ± 19.57
        Day 14 (all subjects, N = 41)
    44.7 ± 34.17
    Notes
    [18] - Pharmacokinetic Analysis Set
    No statistical analyses for this end point

    Other pre-specified: Pharmacokinetic concentrations of tapentadol-O-glucoronide (Part 1)

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    End point title
    Pharmacokinetic concentrations of tapentadol-O-glucoronide (Part 1) [19]
    End point description
    Tapentadol-O-glucuronide is a metabolite of tapentadol. The body transforms tapentadol into its metabolites so that it can be more easily/quickly removed from the body. Tapentadol-O-glucoronide concentrations were measured in subjects who received tapentadol PR in Part 1. All subjects who had quantifiable serum concentrations were included in the descriptive pharmacokinetic analysis. Data from subjects who vomited within 6 hours of administration of IMP during Part 1 were carefully assessed to decide if they should be included in the pharmacokinetic analysis.
    End point type
    Other pre-specified
    End point timeframe
    From Day 1 to Day 14 (End of Part1)
    Notes
    [19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Tapentadol-O-glucuronide serum concentrations were only determined in subjects receiving tapentadol PR and not in the morphine PR comparator arm. So no statistical analysis between the two arms is possible.
    End point values
    Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    44 [20]
    Units: nanograms per milliliter
    arithmetic mean (standard deviation)
        Day 1 (6 to less than 12 years, N = 12)
    603.2 ± 312.11
        Day 1 (12 to less than 18 years, N = 28)
    786.7 ± 984.42
        Day 14 (6 to less than 12 years, N = 12)
    1223.8 ± 511.27
        Day 14 (12 to less than 18 years, N = 28)
    1700.3 ± 1363.41
        Day 1 (all subjects, N = 40)
    731.7 ± 840.02
        Day 14 (all subjects, N = 40)
    1557.3 ± 1187.24
    Notes
    [20] - Pharmacokinetic Set
    No statistical analyses for this end point

    Other pre-specified: Palatability of trial medication (Part 1, Day 14)

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    End point title
    Palatability of trial medication (Part 1, Day 14)
    End point description
    Palatability was determined in Part 1 by asking the subject “How does the medication taste”. The subject was requested to give a score on a 5 point hedonic faces rating scale in combination with a verbal rating. The response can range from really bad to really good.
    End point type
    Other pre-specified
    End point timeframe
    Day 14 (Part 1)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24 [21]
    45 [22]
    Units: Number of subjects
        Really bad
    0
    0
        Bad
    0
    1
        A bit bad/ a bit good
    9
    23
        Good
    9
    11
        Really good
    6
    9
        Missing
    0
    1
    Notes
    [21] - Full Analysis Set
    [22] - Full Analysis Set
    No statistical analyses for this end point

    Other pre-specified: Palatability of trial medication (Part 1, Day 8)

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    End point title
    Palatability of trial medication (Part 1, Day 8)
    End point description
    Palatability was determined in Part 1 by asking the subject “How does the medication taste”. The subject was requested to give a score on a 5 point hedonic faces rating scale in combination with a verbal rating. The response can range from really bad to really good.
    End point type
    Other pre-specified
    End point timeframe
    Day 8 (Part 1)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24 [23]
    45 [24]
    Units: Number of subjects
        Really bad
    0
    0
        Bad
    0
    2
        A bit bad/a bit good
    13
    21
        Good
    7
    12
        Really good
    3
    6
        Missing
    1
    4
    Notes
    [23] - Full Analysis Set
    [24] - Full Analysis Set
    No statistical analyses for this end point

    Other pre-specified: Acceptability of trial medication (Part 1, Day 8)

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    End point title
    Acceptability of trial medication (Part 1, Day 8)
    End point description
    Acceptability of the trial medication was determined in Part 1 by asking the subject “Swallowing the medication is...”. The subject was requested to give a score on a 5-point hedonic faces rating scale in combination with a verbal rating. The response can range from really difficult to really easy.
    End point type
    Other pre-specified
    End point timeframe
    Day 8 (Part 1)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24 [25]
    45 [26]
    Units: Number of subjects
        Really difficult
    0
    0
        Difficult
    0
    3
        A bit difficult/a bit easy
    3
    5
        Easy
    8
    9
        Really easy
    12
    24
        Missing
    1
    4
    Notes
    [25] - Full Analysis Set
    [26] - Full Analysis Set
    No statistical analyses for this end point

    Other pre-specified: Acceptability of trial medication (Part 1, Day 14)

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    End point title
    Acceptability of trial medication (Part 1, Day 14)
    End point description
    Acceptability of the trial medication was determined in Part 1 by asking the subject “Swallowing the medication is...”. The subject was requested to give a score on a 5-point hedonic faces rating scale in combination with a verbal rating. The response can range from really difficult to really easy.
    End point type
    Other pre-specified
    End point timeframe
    Day 14 (End of Part 1)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24 [27]
    45 [28]
    Units: Number of subjects
        Really difficult
    1
    1
        Difficult
    0
    1
        A bit difficult/a bit easy
    2
    7
        Easy
    8
    16
        Really easy
    13
    19
        Missing
    0
    1
    Notes
    [27] - Full Analysis Set
    [28] - Full Analysis Set
    No statistical analyses for this end point

    Other pre-specified: Extent of constipation (Part 2)

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    End point title
    Extent of constipation (Part 2)
    End point description
    Constipation was assessed using the modified constipation assessment scale (mCAS). This is an 8-item questionnaire where the observer has scored constipation on a nominal scale (no Problem [score 0], some problem [score 1] or severe Problem [score 2]). The response to an item could also be scored as “unable to assess”. The Total Score can vary from 0-16; the higher the Total Score the higher the extent of constipation. A positive change from baseline to last assessment indicates a worsening, a negative change an improvement.
    End point type
    Other pre-specified
    End point timeframe
    From baseline (Day 15 or switch) to last assessment (up to Day 379 of Part 2)
    End point values
    Tapentadol prolonged release in Part 2 Observation Period After Tapentadol in Part 1 Observation Period After Morphine in Part 1 Observation Period After Tapentadol in Part 2
    Number of subjects analysed
    36 [29]
    18 [30]
    14 [31]
    26 [32]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Baseline
    2.3 ± 2.4
    1.8 ± 2.3
    2.5 ± 2.5
    1.5 ± 2.5
        Last assessment
    1.8 ± 2.7
    0.4 ± 0.8
    0.4 ± 1.2
    0.8 ± 1.7
        Change from baseline
    -0.7 ± 3.3
    -1.4 ± 2.1
    -1.6 ± 1.7
    -1.4 ± 2.7
    Notes
    [29] - Safety Set; N =35 subjects at baseline, N=32 at last assessment, and N=32 for change from baseline.
    [30] - Safety Set; N=17 subjects at baseline, N=10 at last assessment, and N=9 for change from baseline.
    [31] - Safety Set; N=14 subjects at baseline, N=12 at last assessment, and N=12 for change from baseline.
    [32] - Safety Set; N=25 subjects at baseline, N=16 at last assessment, and N=15 for change from baseline.
    No statistical analyses for this end point

    Other pre-specified: Change from baseline in Subjective Opiate Withdrawal Scale (SOWS)

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    End point title
    Change from baseline in Subjective Opiate Withdrawal Scale (SOWS)
    End point description
    Opiate withdrawal symptoms were assessed using the Subjective Opiate Withdrawal Scale (SOWS) questionnaire. The SOWS is designed to reflect common motoric, autonomic, musculoskeletal and psychic signs and symptoms of opiate withdrawal. Each subject was requested to rate the first 15 items of the 16-item questionnaire for 7 days after discontinuation of treatment. Subjects rated the intensity of specific signs and symptoms on a scale of 0 (not at all) to 4 (extremely). The minimum overall score is 0, the maximum score is 64. SOWS Total Score and changes from baseline are presented.
    End point type
    Other pre-specified
    End point timeframe
    At baseline for Part 1 (i.e., Day 14-17), Part 2 (i.e., Day 352-380), or the day after an early termination visit (Part 1/2), and 2-7 days after last intake of investigational medicinal product (IMP) in Part 1 (up to Day 23) and in Part 2 (up to Day 386).
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1) Tapentadol prolonged release in Part 2
    Number of subjects analysed
    24 [33]
    45 [34]
    36 [35]
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Total score at baseline
    4.0 ± 3.8
    6.9 ± 7.6
    6.1 ± 6.0
        Change Day 2 after last IMP intake
    -0.4 ± 2.0
    -1.7 ± 2.5
    -0.7 ± 2.8
        Change Day 3 after last IMP intake
    -1.6 ± 2.7
    -2.3 ± 4.9
    -0.3 ± 3.1
        Change Day 4 after last IMP intake
    -1.7 ± 4.4
    -3.9 ± 4.7
    -0.1 ± 3.6
        Change Day 5 after last IMP intake
    -1.6 ± 3.6
    -3.8 ± 5.1
    0 ± 5.0
        Change Day 6 after last IMP intake
    -2.3 ± 3.6
    -3.6 ± 4.6
    -0.6 ± 3.1
        Change Day 7 after last IMP intake
    -2.7 ± 3.9
    -5.1 ± 6.3
    -1.4 ± 2.8
    Notes
    [33] - Safety Set; data for 9 subjects (baseline) and for 10/10/10/10/9/7 subjects 2-7 days after last IMP.
    [34] - Safety Set; data for 9 subjects (baseline) and 10/11/12/12/12/12 subjects 2-7 days after last IMP.
    [35] - Safety Set; data for 23 subjects (baseline) and 25/25/27/26/25/18 subjects 2-7 days after last IMP.
    No statistical analyses for this end point

    Other pre-specified: Time to discontinuation (lack of efficacy) in Part 1

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    End point title
    Time to discontinuation (lack of efficacy) in Part 1
    End point description
    The time to discontinuation from IMP due to lack of efficacy was planned to be analyzed for both treatment arms (tapentadol PR and morphine PR) in Part 1 of the trial. However, no subject was reported with early discontinuation from IMP due to lack of efficacy.
    End point type
    Other pre-specified
    End point timeframe
    From first day in Part 1 (Day 1) to last day in Part 1.
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24 [36]
    45 [37]
    Units: Number of subjects
        Early discontinuation due to lack of efficacy
    0
    0
    Notes
    [36] - Safety Set
    [37] - Safety Set
    No statistical analyses for this end point

    Other pre-specified: Time to first intake of rescue medication in the open-label, active-controlled Treatment Period (Part 1)

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    End point title
    Time to first intake of rescue medication in the open-label, active-controlled Treatment Period (Part 1)
    End point description
    Morphine oral solution could be given during Part 1 as rescue medication in both treatment groups. The dose per rescue medication intake was 1/6 of the total daily dose of the scheduled tapentadol PR or morphine PR intakes. Rescue medication administration times and doses were recorded. 18 subjects in the morphine PR group and 27 subjects in the tapentadol PR group had no documented intake of rescue medication between Day 1 and Day 14. Summary statistics were calculated based on subjects with any intake, i.e., those that took at least 1 dose of rescue medication. The mean (standard deviation) time (hours) to first dose of rescue medication following the first dose of the IMP (on Day 1) is presented.
    End point type
    Other pre-specified
    End point timeframe
    From Day 1 up to Day 14 (End of Part 1)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24 [38]
    45 [39]
    Units: hours
        arithmetic mean (standard deviation)
    39.7 ± 63.75
    74.6 ± 94.45
    Notes
    [38] - Full Analysis Set; data for N=6 subjects with any intake analyzed.
    [39] - Full Analysis Set; data for N=18 subjects with any intake analyzed.
    No statistical analyses for this end point

    Other pre-specified: Time to discontinuation (treatment emergent adverse events) in Part 1

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    End point title
    Time to discontinuation (treatment emergent adverse events) in Part 1
    End point description
    The time to discontinuation from IMP due to treatment emergent adverse events (TEAEs) was analyzed for both treatment arms (tapentadol PR and morphine PR) in Part 1 of the trial. Note that no subject discontinued due to treatment emergent adverse events in the morphine PR arm.
    End point type
    Other pre-specified
    End point timeframe
    From first day in Part 1 (Day 1) to last day in Part 1 (Day 14)
    End point values
    Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1)
    Number of subjects analysed
    24 [40]
    45 [41]
    Units: Days
        median (full range (min-max))
    0 (0 to 0)
    3.0 (2 to 4)
    Notes
    [40] - Safety Set; no subject discontinued due to treatment emergent adverse events.
    [41] - Safety Set; N=2 subjects discontinued due to treatment emergent adverse events
    No statistical analyses for this end point

    Other pre-specified: Time to discontinuation (lack of efficacy) in Part 2

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    End point title
    Time to discontinuation (lack of efficacy) in Part 2
    End point description
    The time to discontinuation from IMP due to lack of efficacy was analyzed for tapentadol PR treatment in Part 2 of the trial.
    End point type
    Other pre-specified
    End point timeframe
    From first day in Part 2 (Day 15) to last day in Part 2 (Day 379)
    End point values
    Tapentadol prolonged release in Part 2
    Number of subjects analysed
    36 [42]
    Units: Weeks
        median (full range (min-max))
    30.9 (9 to 36)
    Notes
    [42] - Safety Set; 3 subjects with early discontinuation from IMP due to lack of efficacy.
    No statistical analyses for this end point

    Other pre-specified: Time to discontinuation (treatment emergent adverse events) in Part 2

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    End point title
    Time to discontinuation (treatment emergent adverse events) in Part 2
    End point description
    The time to discontinuation from IMP due to treatment emergent adverse events (TEAEs) was analyzed for tapentadol PR treatment in Part 2 of the trial.
    End point type
    Other pre-specified
    End point timeframe
    From first day in Part 2 (Day 15) to last day in Part 2 (Day 379)
    End point values
    Tapentadol prolonged release in Part 2
    Number of subjects analysed
    36 [43]
    Units: Weeks
        median (full range (min-max))
    5.3 (3 to 24)
    Notes
    [43] - Safety Set; N=3 subjects discontinued due to treatment emergent adverse events.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were regularly assessed by the investigator using a standard set of questions. Treatment emergent adverse events (TEAEs) were collected from first dose (on Day 1) to last intake of IMP plus 72 hours (therapeutic reach).
    Adverse event reporting additional description
    Part 1: TEAEs from first to last dose in Part 1 if subject continued on tapentadol PR in Part 2; from first to last dose in Part 1 + 72 hours if subject did not continue on tapentadol PR in Part 2. Part 2: TEAEs from start of Tapentadol Period to the last IMP intake in Part 2 + 72 hours (therapeutic reach).
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Overall (Part 1)
    Reporting group description
    Overall (Part 1) includes all subjects with a 2-week treatment with tapentadol PR or morphine PR tablets. One subject who completed the tapentadol PR treatment in Part 1 died in the Observation Period (Part 2; standard-of-care treatment, no IMP) due to progression of Ewing’s sarcoma, which started progressing in Part 1. A second subject died in the Observation Period after Tapentadol in Part 1 due to serious progression of osteosarcoma with fatal outcome. The progression started in the Observation Period.

    Reporting group title
    Morphine prolonged release (Part 1)
    Reporting group description
    The treatment group comprised 7 subjects aged 6 years to less than 12 years and 17 subjects aged 12 years to less than 18 years. Starting doses varied from 10 to 40 milligrams (mg) morphine PR twice daily depending on subject’s weight; if necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for subjects weighing 55 kg and more was 200 mg per day.

    Reporting group title
    Tapentadol prolonged release (Part 1)
    Reporting group description
    The treatment group comprised 12 subjects aged 6 years to less than 12 years and 33 subjects aged 12 years to less than 18 years. Subjects starting doses varied from 25 to 100 mg tapentadol PR twice daily depending on subject’s weight. If necessary, doses were gradually increased up to a maximum dose defined per weight group. The highest dose defined for subjects weighing 55 kg and more was 500 mg per day.

    Reporting group title
    Tapentadol prolonged release in Part 2
    Reporting group description
    Tapentadol prolonged release in Part 2 comprises all subjects who completed Part 1 (on tapentadol PR or morphine PR) and continued on or switched to an extended treatment with tapentadol PR for up to 12 months. No deaths were reported during treatment with tapentadol PR in Part 2. Following tapentadol PR treatment in Part 2, 1 subject died during the Observation Period (under standard-of-care treatment, no IMP) due to malignant neoplasm progression (sarcoma). The progression started in the Observation Period.

    Serious adverse events
    Overall (Part 1) Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1) Tapentadol prolonged release in Part 2
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 69 (5.80%)
    1 / 24 (4.17%)
    3 / 45 (6.67%)
    13 / 36 (36.11%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Vascular disorders
    Thrombophlebitis superficial
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Limb operation
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Malignant neoplasm progression
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 24 (0.00%)
    1 / 45 (2.22%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Mucosal inflammation
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 24 (4.17%)
    0 / 45 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Breakthrough pain
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Malaise
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Dissociation
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    White blood cell count decreased
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Lymphopenia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sickle cell anaemia with crisis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Movement disorder
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neuralgia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 24 (4.17%)
    0 / 45 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 24 (4.17%)
    0 / 45 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 24 (0.00%)
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Cutaneous lupus erythematosus
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Clostridium difficile infection
         subjects affected / exposed
    1 / 69 (1.45%)
    1 / 24 (4.17%)
    0 / 45 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 69 (1.45%)
    0 / 24 (0.00%)
    1 / 45 (2.22%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Application site infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Herpes zoster
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infection
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Overall (Part 1) Morphine prolonged release (Part 1) Tapentadol prolonged release (Part 1) Tapentadol prolonged release in Part 2
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 69 (53.62%)
    11 / 24 (45.83%)
    26 / 45 (57.78%)
    30 / 36 (83.33%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    4 / 36 (11.11%)
         occurrences all number
    0
    0
    0
    4
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    0
    3
    Neutropenia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    2
    Thrombocytopenia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    0
    4
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    4 / 69 (5.80%)
    0 / 24 (0.00%)
    4 / 45 (8.89%)
    2 / 36 (5.56%)
         occurrences all number
    4
    0
    4
    2
    Dysarthria
         subjects affected / exposed
    2 / 69 (2.90%)
    2 / 24 (8.33%)
    0 / 45 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Headache
         subjects affected / exposed
    9 / 69 (13.04%)
    3 / 24 (12.50%)
    6 / 45 (13.33%)
    10 / 36 (27.78%)
         occurrences all number
    12
    3
    9
    24
    Somnolence
         subjects affected / exposed
    2 / 69 (2.90%)
    2 / 24 (8.33%)
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    2
    2
    0
    2
    Paraesthesia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    2
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    5 / 69 (7.25%)
    3 / 24 (12.50%)
    2 / 45 (4.44%)
    2 / 36 (5.56%)
         occurrences all number
    5
    3
    2
    3
    Pyrexia
         subjects affected / exposed
    4 / 69 (5.80%)
    1 / 24 (4.17%)
    3 / 45 (6.67%)
    2 / 36 (5.56%)
         occurrences all number
    6
    1
    5
    4
    Psychiatric disorders
    Nightmare
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    3
    Sleep disorder
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    2
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    6 / 69 (8.70%)
    0 / 24 (0.00%)
    6 / 45 (13.33%)
    3 / 36 (8.33%)
         occurrences all number
    7
    0
    7
    6
    Abdominal pain upper
         subjects affected / exposed
    2 / 69 (2.90%)
    2 / 24 (8.33%)
    0 / 45 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    2
    2
    0
    3
    Constipation
         subjects affected / exposed
    11 / 69 (15.94%)
    4 / 24 (16.67%)
    7 / 45 (15.56%)
    5 / 36 (13.89%)
         occurrences all number
    11
    4
    7
    6
    Diarrhoea
         subjects affected / exposed
    3 / 69 (4.35%)
    0 / 24 (0.00%)
    3 / 45 (6.67%)
    3 / 36 (8.33%)
         occurrences all number
    3
    0
    3
    3
    Nausea
         subjects affected / exposed
    14 / 69 (20.29%)
    4 / 24 (16.67%)
    10 / 45 (22.22%)
    11 / 36 (30.56%)
         occurrences all number
    15
    5
    10
    18
    Vomiting
         subjects affected / exposed
    13 / 69 (18.84%)
    7 / 24 (29.17%)
    6 / 45 (13.33%)
    5 / 36 (13.89%)
         occurrences all number
    15
    9
    6
    5
    Toothache
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    3
    Renal and urinary disorders
    Dysuria
         subjects affected / exposed
    2 / 69 (2.90%)
    2 / 24 (8.33%)
    0 / 45 (0.00%)
    0 / 36 (0.00%)
         occurrences all number
    2
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 69 (5.80%)
    3 / 24 (12.50%)
    1 / 45 (2.22%)
    2 / 36 (5.56%)
         occurrences all number
    4
    3
    1
    2
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 69 (4.35%)
    0 / 24 (0.00%)
    3 / 45 (6.67%)
    5 / 36 (13.89%)
         occurrences all number
    3
    0
    3
    5
    Pain in extremity
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    3 / 36 (8.33%)
         occurrences all number
    0
    0
    0
    9
    Metabolism and nutrition disorders
    Hypokalaemia
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    0
    0
    0
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    0 / 69 (0.00%)
    0 / 24 (0.00%)
    0 / 45 (0.00%)
    5 / 36 (13.89%)
         occurrences all number
    0
    0
    0
    7

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Aug 2015
    The amendment was enacted to: • Explicitly allow a home visit to take place instead of a site visit after a case-by-case approval by the sponsor. • Allow more flexibility in selecting the supplier of the rescue medication by allowing both morphine sulfate and morphine hydrochloride to be used, and by using an interactive response technology system (voice and web based) to assign subjects to rescue medication. • Allow the results of a non-protocol blood sample taken within 14 days of Visit 2 to be used for assessing the exclusion criteria and for baseline values without the need to repeat the sample at the Enrollment Visit. This was done to potentially reduce the volume of blood taken from the subject. • Clarify and correct the definitions of the endpoints, populations, and statistical analyses. • Clarify and correct the days on which the SOWS questionnaire is completed, and the questions to be assessed. • Add the measurement of height for the calculation of the glomerular clearance at 3 monthly intervals in the Tapentadol Period (Part 2). • Specify that if a subject turns 18 years old before Visit VE, an additional subject would be allocated to IMP. • Specify that subjects who vomit after IMP intake must not take additional IMP until the time of their next scheduled IMP dose. • Correct the labeling specification for the pharmacokinetic samples. • Add an additional exclusion criterion to exclude female subjects who are breast-feeding a child. Although there is no information on the excretion of tapentadol in human milk, there are pre-clinical data indicating that tapentadol is excreted in animal milk. Morphine is known to be excreted in breast milk, and may thus cause respiratory depression in the newborn.
    25 Sep 2017
    This amendment introduced the following changes: • The alpha for the primary endpoint analysis was updated based on the methodology proposed by Hlavin et al. (2016). As a consequence of the alpha adjustment, the sample size was reduced. • A definition of long-term pain was added. • Specifications of the trial population were modified, requiring the inclusion of fewer subjects in the lower age group. The expectation that at least 15 subjects would be treated with tapentadol PR for a minimum of 12 weeks was added. • The estimated dates of last subject out for Part 1 and Part 2 were updated. • The main analysis was rescheduled such that it will be performed after all subjects complete the first 12 weeks of Part 2. • The interim analysis for the sample size re-assessment was removed due to the reduced sample size. The adaptive 2-stage design of the trial was simplified to a fixed 1-stage design. • Instructions pertaining to ECG-related discontinuation were added. • The timing of the Early Termination Visit was explicitly defined. • History of CRPS and history of a pain indication that is unlikely to respond to opioids was added to the exclusion criteria. • Safety experience from post-marketing data was updated. • Instructions for calculating the starting dose in Part 1 and Part 2 were revised. Hlavin G, Koenig F, Male C, Posch M, Bauer P. Evidence, eminence and extrapolation. Stat Med 2016; 35 (13): 2117-32.

    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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