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    Clinical Trial Results:
    Efficacy, safety, and tolerability of GRT6005 in subjects with moderate to severe chronic low back pain

    Summary
    EudraCT number
    2012-001920-36
    Trial protocol
    AT   DE   BE   GB   ES   SE   DK   HU   FI   NL  
    Global end of trial date
    10 Jul 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    25 Feb 2016
    First version publication date
    26 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KF6005/06
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01725087
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52078
    Public contact
    Grünenthal Clinical Trial Helpdesk, Grünenthal GmbH, +49 241 569 3223, Clinical-Trials@grunenthal.com
    Scientific contact
    Grünenthal Clinical Trial Helpdesk, Grünenthal GmbH, +49 241 569 3223, Clinical-trials@grunenthal.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Jun 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Jul 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Jul 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of this trial is to assess the analgesic efficacy, safety, and tolerability of once daily orally administered GRT6005 in a total of 3 fixed doses (i.e., 200 μg, 400 μg, and 600 μg GRT6005) compared to placebo in subjects with moderate to severe chronic LBP.
    Protection of trial subjects
    The trial was conducted according to ICH-GCP guidelines, the applicable local laws, and in accordance with the ethical principles that have their origins in the Declaration of Helsinki. Regulatory authorities were notified of the trial and amendments as required by national regulations, and where necessary relevant authorization was obtained. Furthermore, the competent authorities were notified of this trial in accordance with national requirements.
    Background therapy
    Other analgesic medications (including non-steroidal anti-inflammatory drugs, cyclooxygenase II inhibitors and opioids, including long-acting formulations and combination products) except for rescue medication, paracetamol/acetaminophen were prohibited during the trial. Paracetamol/acetaminophen (500 mg tablets) was provided as rescue medication for unacceptable pain due to chronic LBP. No rescue medication was allowed during the last 3 days before intake of first IMP. The maximum total daily dose of paracetamol/acetaminophen was 2 g during the washout phase and after allocation to treatment. Paracetamol/acetaminophen was not taken for more than 3 consecutive days at the maximum allowed total daily dose. In addition, the use of rescue medication at the maximum allowed total daily dose was not to exceed 20 days in total during the maintenance phase. Neuroleptics, serotonin norepinephrine re-uptake inhibitors, antidepressants commonly used for the treatment of painful conditions such as tricyclic antidepressants, anticonvulsants (including α2δ-subunit blockers including gabapentin and pregabalin), and monoamine oxidase (MAO) inhibitors were washed out for at least 3 days or 5 times their half-life and were prohibited for the remaining trial duration. Topically applied lidocaine and capsaicin were prohibited.
    Evidence for comparator
    Opioid analgesics, including tapentadol have been shown to be efficacious in chronic non-malignant pain including chronic LBP and can be an important asset in the therapeutic armamentarium. A placebo control was chosen following recommendations of the Note for Guidance on Clinical Investigation of Medicinal Products for Treatment of Nociceptive Pain (CPMP/EWP/612/00) to establish the baseline frequency and magnitude of changes in clinical endpoints that may occur in the absence of treatment with an active drug substance.
    Actual start date of recruitment
    30 Nov 2012
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 24
    Country: Number of subjects enrolled
    Poland: 172
    Country: Number of subjects enrolled
    Spain: 93
    Country: Number of subjects enrolled
    Sweden: 48
    Country: Number of subjects enrolled
    United Kingdom: 19
    Country: Number of subjects enrolled
    Austria: 45
    Country: Number of subjects enrolled
    Belgium: 7
    Country: Number of subjects enrolled
    Denmark: 22
    Country: Number of subjects enrolled
    Finland: 22
    Country: Number of subjects enrolled
    Germany: 120
    Country: Number of subjects enrolled
    Hungary: 65
    Worldwide total number of subjects
    637
    EEA total number of subjects
    637
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    436
    From 65 to 84 years
    201
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    First subject signed informed consent on the 30 November 2012 and the last subject completed the trial on the 10 July 2014.

    Pre-assignment
    Screening details
    1090 subjects signed informed consent in 79 active sites in 11 European countries. The primary reason for subjects not being allocated to treatment were a failure to meet the inclusion criteria/exclusion criteria (347 subjects), withdrawal of informed consent (64 subjects), or the occurrence of non-treatment emergent adverse events (8 subjects)

    Period 1
    Period 1 title
    Overall trial (overall 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
    All IMPs were administered in a double-dummy design to maintain the blind.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo tablets matching cebranopadol film coated tablets were taken once daily for 14 weeks; placebo tablets matching tapentadol PR film-coated tablets were taken twice a day for 14 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Three placebo tablets (2 matching cebranopadol [GRT6005] and 1 matching tapentadol polonged release film-coated tablets) were taken in the morning, 1 placebo tablet matching tapentadol prolonged release film-coated tablets in the evening.

    Arm title
    Cebranopadol 200 µg
    Arm description
    Cebranopadol film-coated tablets were taken once daily at target doses of 200 μg in the maintenance phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Cebranopadol
    Investigational medicinal product code
    GRT6005
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Cebranopadol film-coated tablets were taken once daily at target doses of 200 µg and were maintained at this dose up to the end of the maintenance phase.

    Arm title
    Cebranopadol 400 µg
    Arm description
    Cebranopadol film-coated tablets were taken once daily at target doses of 400 μg in the maintenance phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Cebranopadol
    Investigational medicinal product code
    GRT6005
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects assigned to 400 μg were titrated in increments of 200 μg starting with 200 μg and increasing to the target dose of 400 μg on Day 4. They were then kept on this target dose for the remainder of the 14-day titration phase and the 12-week maintenance phase.

    Arm title
    Cebranopadol 600 µg
    Arm description
    Cebranopadol film-coated tablets were taken once daily at target doses of 600 μg in the maintenance phase.
    Arm type
    Experimental

    Investigational medicinal product name
    Cebranopadol 600 µg
    Investigational medicinal product code
    GRT6005
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects assigned to 600 μg GRT6005 were titrated in increments of 200 μg starting with 200 μg and increasing stepwise to 400 μg on Day 4 and to the target dose of 600 μg on Day 7. They were then kept on this target dose during the remainder of the 14-day titration phase and the 12-week maintenance phase.

    Arm title
    Tapentadol prolonged release
    Arm description
    Tapentadol prolonged release (PR) film-coated tablets at doses of 50 mg, 100 mg, and 150 mg twice daily were used for titration only; the target dose was 200 mg BID.
    Arm type
    Active comparator

    Investigational medicinal product name
    Tapentadol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Tapentadol prolonged release was used with forced titration in increments of 50 mg tapentadol twice daily every 3 days in fixed steps starting with 50 mg tapentadol twice daily on Day 1. The dose was increased to 100 mg twice daily on Day 4, to 150 mg twice daily on Day 7, and to the target dose of 200 mg twice daily on Day 10. The titration phase lasted 14 days, the maintenance phase with tapentadol 200 mg daily lasted 12 weeks. Each morning, all subjects additionally took 2 placebo tablets matching GRT6005 film-coated tablets.

    Number of subjects in period 1 [1]
    Placebo Cebranopadol 200 µg Cebranopadol 400 µg Cebranopadol 600 µg Tapentadol prolonged release
    Started
    126
    129
    127
    127
    126
    Completed
    100
    68
    61
    54
    77
    Not completed
    26
    61
    66
    73
    49
         Inclusion criteria not met/Exclusion criteria met
    1
    1
    1
    -
    -
         Protocol deviation
    -
    -
    1
    -
    -
         Lack of efficacy
    14
    5
    4
    4
    8
         Not specified
    3
    1
    4
    2
    1
         Adverse event, non-fatal
    4
    42
    52
    62
    33
         Consent withdrawn by subject
    3
    10
    4
    5
    6
         Lost to follow-up
    1
    2
    -
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: 1090 subjects signed informed consent. 641 subjects were allocated to IMP. 637 subjects were dosed. 635 subjects were in the Full Analysis Set. 533 subjects were in the Per Protocol Set.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo tablets matching cebranopadol film coated tablets were taken once daily for 14 weeks; placebo tablets matching tapentadol PR film-coated tablets were taken twice a day for 14 weeks.

    Reporting group title
    Cebranopadol 200 µg
    Reporting group description
    Cebranopadol film-coated tablets were taken once daily at target doses of 200 μg in the maintenance phase.

    Reporting group title
    Cebranopadol 400 µg
    Reporting group description
    Cebranopadol film-coated tablets were taken once daily at target doses of 400 μg in the maintenance phase.

    Reporting group title
    Cebranopadol 600 µg
    Reporting group description
    Cebranopadol film-coated tablets were taken once daily at target doses of 600 μg in the maintenance phase.

    Reporting group title
    Tapentadol prolonged release
    Reporting group description
    Tapentadol prolonged release (PR) film-coated tablets at doses of 50 mg, 100 mg, and 150 mg twice daily were used for titration only; the target dose was 200 mg BID.

    Reporting group values
    Placebo Cebranopadol 200 µg Cebranopadol 400 µg Cebranopadol 600 µg Tapentadol prolonged release Total
    Number of subjects
    126 129 127 127 126 635
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    86 85 88 91 85 435
        From 65-84 years
    40 44 39 36 41 200
    Age continuous
    The age range was 18 to 80 years of age for this trial. The ages ranged from 22 to 79 years of age. There were no subjects older than 79 years.
    Units: years
        arithmetic mean (standard deviation)
    56.9 ± 12.46 58 ± 11.48 57.5 ± 11.61 56.9 ± 11.66 58.2 ± 11.43 -
    Gender categorical
    Units: Subjects
        Female
    76 84 80 94 78 412
        Male
    50 45 47 33 48 223
    Race
    Units: Subjects
        Black
    0 0 0 0 1 1
        White
    126 128 127 127 125 633
        Other
    0 1 0 0 0 1
    Treatment with opioids (including tramadol) for LBP during the 3 months prior to enrollment
    Subjects had to be on stable analgesic medications (non-opioid and/or opioid medications) for their chronic LBP with regular intake (i.e., at least 4 days per week) for at least 3 months prior to Visit 1. If subjects required opioid treatment, they must have been taking daily doses of opioid based analgesics equivalent to ≤160 mg of oral morphine.
    Units: Subjects
        No
    81 84 82 71 85 403
        Yes
    45 45 45 56 41 232
    Treatment with non-opioids for LBP during 3 months prior to enrollment
    Subjects had to be on stable analgesic medications (non-opioid and/or opioid medications) for their chronic LBP with regular intake (i.e., at least 4 days per week) for at least 3 months prior to Visit 1.
    Units: Subjects
        No
    9 9 12 12 15 57
        Yes
    117 120 115 115 111 578
    Dissatisfaction with current analgesic treatment
    Subjects must have been dissatisfied with current analgesic treatment to qualify for entry into this trial.
    Units: Subjects
        Due to inadequate analgesia
    122 125 120 122 118 607
        Due to poor tolerability
    4 4 7 5 8 28
    Quebec Task Force Classification on spinal disorders
    Subjects with pain in the lumbar area without radiation and with absence of neurologic signs were classified as QTFC 1. Subjects had pain with radiation proximally (i.e., to a lower limb, but not beyond the knee) and not accompanied by neurologic signs were classified as QTFC 2. Subjects had pain with radiation distally (i.e., beyond the knee) but without neurologic signs were classified as QTFC 3. Subjects with pain in the lumbar area with radiation to a limb and with the presence of neurologic signs were classified as QTFC 4.
    Units: Subjects
        QTF Classification 1
    24 32 32 20 40 148
        QTF Classification 2
    45 44 43 54 38 224
        QTF Classification 3
    42 40 43 35 35 195
        QTF Classification 4
    15 13 9 17 13 67
        Missing
    0 0 0 1 0 1
    Assessment of lumbar radiculopathy
    Subjects with lumbar radiculopathy were identified by an overall positive assessment of the question “The symptoms and signs are those of lumbar radiculopathy?” based on a set of questions to assess specific signs and symptoms.
    Units: Subjects
        No
    51 57 54 46 63 271
        Yes
    70 69 70 77 59 345
        Not Done
    5 3 3 4 4 19
    painDETECT assignment at baseline
    The painDETECT Pain Questionnaire was used to assess the likelihood of a neuropathic pain component.
    Units: Subjects
        positive
    45 39 44 42 43 213
        unclear
    36 40 38 36 35 185
        negative
    42 48 45 47 43 225
        missing
    3 2 0 2 5 12
    Height
    Units: meter
        arithmetic mean (standard deviation)
    1.681 ± 0.1009 1.672 ± 0.0951 1.679 ± 0.1026 1.658 ± 0.0958 1.664 ± 0.1015 -
    Weight
    Units: kilogram(s)
        arithmetic mean (standard deviation)
    80.3 ± 14.49 80.6 ± 14.83 80.9 ± 16.49 76.8 ± 14.15 80.6 ± 15 -
    Body Mass Index
    Units: kilogram(s)/square meter
        arithmetic mean (standard deviation)
    28.37 ± 4.076 28.74 ± 4.341 28.53 ± 4.284 27.9 ± 4.078 28.99 ± 3.862 -
    Baseline 24-hour pain assessment
    Subject’s pain assessments on an 11-point NRS (0 = no pain, 10 = pain as bad as you can imagine) using an e-diary: average pain during the last 24 hours. For allocation to treatment, subjects had to have an average 24-hour baseline pain of ≥5 on an 11-point numeric rating scale (NRS) during the 3 days prior to Visit 3 without the use of rescue medication.
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.3 ± 1.26 7.1 ± 1.17 7 ± 1.15 7.2 ± 1.12 7 ± 1.15 -
    History of low back pain
    Units: Year(s)
        arithmetic mean (standard deviation)
    10 ± 10.3 10.8 ± 10.93 10.6 ± 9.95 10.8 ± 10.82 10.6 ± 9.82 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo tablets matching cebranopadol film coated tablets were taken once daily for 14 weeks; placebo tablets matching tapentadol PR film-coated tablets were taken twice a day for 14 weeks.

    Reporting group title
    Cebranopadol 200 µg
    Reporting group description
    Cebranopadol film-coated tablets were taken once daily at target doses of 200 μg in the maintenance phase.

    Reporting group title
    Cebranopadol 400 µg
    Reporting group description
    Cebranopadol film-coated tablets were taken once daily at target doses of 400 μg in the maintenance phase.

    Reporting group title
    Cebranopadol 600 µg
    Reporting group description
    Cebranopadol film-coated tablets were taken once daily at target doses of 600 μg in the maintenance phase.

    Reporting group title
    Tapentadol prolonged release
    Reporting group description
    Tapentadol prolonged release (PR) film-coated tablets at doses of 50 mg, 100 mg, and 150 mg twice daily were used for titration only; the target dose was 200 mg BID.

    Primary: Change from baseline pain to the weekly average 24-hour pain (NRS) during the entire 12 weeks of maintenance phase

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    End point title
    Change from baseline pain to the weekly average 24-hour pain (NRS) during the entire 12 weeks of maintenance phase
    End point description
    For the EU and other non-US marketing authorization region the change from baseline to the weekly average 24-hour pain (NRS) during the entire 12 weeks of the maintenance phase was defined as the primary endpoint. Pain was assessed between 19:00 and 22:00 before IMP intake. The subjects were asked via e-diary to answer the following question: “Please rate your pain by selecting the number that best describes your pain on average during the last 24 hours.” The 11-point NRS (Numeric Rating Scale) was used where subjects rated their average pain intensity from 0 [no pain] to 10 [pain as bad as you can imagine].
    End point type
    Primary
    End point timeframe
    Baseline up to end of Maintenance phase (14 weeks)
    End point values
    Placebo Cebranopadol 200 µg Cebranopadol 400 µg Cebranopadol 600 µg Tapentadol prolonged release
    Number of subjects analysed
    125
    122
    120
    117
    123
    Units: units on the Numeric Rating Scale
        number (confidence interval 95%)
    -1.97 (-2.34 to -1.6)
    -2.52 (-2.9 to -2.13)
    -2.67 (-3.08 to -2.27)
    -2.89 (-3.32 to -2.46)
    -2.71 (-3.09 to -2.33)
    Statistical analysis title
    MMRM 200 µg cebranopadol compared to placebo
    Statistical analysis description
    The primary end point was analysed by means of a mixed-effects model for repeated measures (MMRM) with the fixed effects of pooled sites, treatment, time, treatment-by-time interaction, and baseline pain, and used a random intercept. The primary analysis consisted of the contrasts (i.e. mixed model Wald tests) of the individual cebranopadol doses with placebo. To control the family-wise error rate, a gatekeeping and Hochberg multiple comparison procedure was used.
    Comparison groups
    Cebranopadol 200 µg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0346 [1]
    Method
    MMRM
    Parameter type
    MMRM
    Point estimate
    -0.55
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.05
         upper limit
    -0.04
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.26
    Notes
    [1] - Following the gatekeeping and Hochberg multiple comparison procedure the comparison between Cebranopadol 200 µg and Placebo was performed and considered statistically significant.
    Statistical analysis title
    MMRM 400 µg cebranopadol compared to placebo
    Statistical analysis description
    The primary end point was analysed by means of a mixed-effects model for repeated measures (MMRM) with the fixed effects of pooled sites, treatment, time, treatment-by-time interaction, and baseline pain, and used a random intercept. The primary analysis consisted of the contrasts (i.e. mixed model Wald tests) of the individual cebranopadol doses with placebo. To control the family-wise error rate, a gatekeeping and Hochberg multiple comparison procedure was used.
    Comparison groups
    Cebranopadol 400 µg v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0084 [2]
    Method
    MMRM
    Parameter type
    MMRM
    Point estimate
    -0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.23
         upper limit
    -0.18
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.27
    Notes
    [2] - Following the gatekeeping and Hochberg multiple comparison procedure the comparison between Cebranopadol 400 µg and Placebo was performed and considered statistically significant.
    Statistical analysis title
    MMRM 600 µg cebranopadol compared to placebo
    Statistical analysis description
    The primary end point was analysed by means of a mixed-effects model for repeated measures (MMRM) with the fixed effects of pooled sites, treatment, time, treatment-by-time interaction, and baseline pain, and used a random intercept. The primary analysis consisted of the contrasts (i.e. mixed model Wald tests) of the individual cebranopadol doses with placebo. To control the family-wise error rate, a gatekeeping and Hochberg multiple comparison procedure was used
    Comparison groups
    Cebranopadol 600 µg v Placebo
    Number of subjects included in analysis
    242
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001 [3]
    Method
    MMRM
    Parameter type
    MMRM
    Point estimate
    -0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.46
         upper limit
    -0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.28
    Notes
    [3] - Following the gatekeeping and Hochberg multiple comparison procedure the comparison between Cebranopadol 600 µg and Placebo was performed and considered statistically significant.

    Primary: Change from baseline to the average 24-hour pain (NRS) during Week 12 of the maintenance phase

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    End point title
    Change from baseline to the average 24-hour pain (NRS) during Week 12 of the maintenance phase
    End point description
    For the US marketing authorization region the change from baseline to the weekly average 24-hour pain (NRS) during week 12 of the maintenance phase was defined as the primary endpoint. Pain was assessed between 19:00 and 22:00 before IMP intake. The subjects were asked via e-diary to answer the following question: “Please rate your pain by selecting the number that best describes your pain on average during the last 24 hours.” The 11-point NRS (Numeric Rating Scale) was used where subjects rated their average pain intensity from 0 [no pain] to 10 [pain as bad as you can imagine].
    End point type
    Primary
    End point timeframe
    Baseline up to end of maintenance phase (14 weeks)
    End point values
    Placebo Cebranopadol 200 µg Cebranopadol 400 µg Cebranopadol 600 µg Tapentadol prolonged release
    Number of subjects analysed
    125
    122
    120
    117
    123
    Units: units on the Numeric Rating Scale
        number (confidence interval 95%)
    -2.16 (-2.58 to -1.74)
    -2.95 (-3.41 to -2.5)
    -2.95 (-3.44 to -2.47)
    -3.18 (-3.7 to -2.66)
    -3.05 (-3.5 to -2.6)
    Statistical analysis title
    MMRM cebranopadol 200 µg compared to placebo
    Statistical analysis description
    The primary end point was analysed by means of a mixed-effects model for repeated measures (MMRM) with the fixed effects of pooled sites, treatment, time, treatment-by-time interaction, and baseline pain, and used a random intercept. The primary analysis consisted of the contrasts (i.e. mixed model Wald tests) of the individual cebranopadol doses with placebo. To control the family-wise error rate, a gatekeeping and Hochberg multiple comparison procedure was used.
    Comparison groups
    Cebranopadol 200 µg v Placebo
    Number of subjects included in analysis
    247
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0095 [4]
    Method
    MMRM
    Parameter type
    MMRM
    Point estimate
    -0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.39
         upper limit
    -0.19
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.3
    Notes
    [4] - Following the gatekeeping and Hochberg multiple comparison procedure the comparison between Cebranopadol 200 µg and Placebo was performed and considered statistically significant.
    Statistical analysis title
    MMRM cebranopadol 400 µg compared to placebo
    Statistical analysis description
    The primary end point was analysed by means of a mixed-effects model for repeated measures (MMRM) with the fixed effects of pooled sites, treatment, time, treatment-by-time interaction, and baseline pain, and used a random intercept. The primary analysis consisted of the contrasts (i.e. mixed model Wald tests) of the individual cebranopadol doses with placebo. To control the family-wise error rate, a gatekeeping and Hochberg multiple comparison procedure was used.
    Comparison groups
    Cebranopadol 400 µg v Placebo
    Number of subjects included in analysis
    245
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.0122 [5]
    Method
    MMRM
    Parameter type
    MMRM
    Point estimate
    -0.79
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.41
         upper limit
    -0.17
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.32
    Notes
    [5] - Following the gatekeeping and Hochberg multiple comparison procedure the comparison between Cebranopadol 400 µg and Placebo was performed and considered statistically significant.
    Statistical analysis title
    MMRM cebranopadol 600 µg compared to placebo
    Comparison groups
    Cebranopadol 600 µg v Placebo
    Number of subjects included in analysis
    242
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0021 [6]
    Method
    MMRM
    Parameter type
    MMRM
    Point estimate
    -1.02
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.67
         upper limit
    -0.37
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.33
    Notes
    [6] - Following the gatekeeping and Hochberg multiple comparison procedure the comparison between Cebranopadol 600 µg and Placebo was performed and considered statistically significant.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Treatment Emergent Adverse Events (TEAEs) are defined as any Adverse Event that occurred after first intake of Investigational Medicinal Product (IMP) up to the last follow-up contact/visit (i.e. up to 14 days after last IMP intake).
    Adverse event reporting additional description
    A TEAE is defined as any AE that occurred on or after the first intake of IMP. In addition, pre-treatment AEs which worsen during the treatment period are also considered TEAEs. Investigator rated causalities reported: Certain, Probable/Likely, Possible reported as being causally related to treatment.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Cebranopadol 200 µg
    Reporting group description
    -

    Reporting group title
    Cebranopadol 400 µg
    Reporting group description
    -

    Reporting group title
    Cebranopadol 600 µg
    Reporting group description
    -

    Reporting group title
    Tapentadol prolonged release
    Reporting group description
    -

    Serious adverse events
    Placebo Cebranopadol 200 µg Cebranopadol 400 µg Cebranopadol 600 µg Tapentadol prolonged release
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 126 (1.59%)
    3 / 130 (2.31%)
    4 / 127 (3.15%)
    2 / 128 (1.56%)
    3 / 126 (2.38%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    Pelvic fracture
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 130 (0.00%)
    1 / 127 (0.79%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 130 (0.77%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 130 (0.77%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lentigo maligna
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 130 (0.00%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial flutter
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 130 (0.00%)
    0 / 127 (0.00%)
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 130 (0.77%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Transient ischaemic attack
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 130 (0.00%)
    0 / 127 (0.00%)
    1 / 128 (0.78%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Oedema peripheral
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 130 (0.00%)
    1 / 127 (0.79%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral arterial occlusive disease
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 130 (0.00%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chest discomfort
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 130 (0.77%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 130 (0.00%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Dyspepsia
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 130 (0.77%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Faeces discoloured
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 130 (0.00%)
    1 / 127 (0.79%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salivary gland calculus
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 130 (0.00%)
    1 / 127 (0.79%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 126 (0.79%)
    0 / 130 (0.00%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 130 (0.00%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    1 / 126 (0.79%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hepatic steatosis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 130 (0.77%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 126 (0.00%)
    1 / 130 (0.77%)
    0 / 127 (0.00%)
    0 / 128 (0.00%)
    0 / 126 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Cebranopadol 200 µg Cebranopadol 400 µg Cebranopadol 600 µg Tapentadol prolonged release
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    80 / 126 (63.49%)
    107 / 130 (82.31%)
    105 / 127 (82.68%)
    115 / 128 (89.84%)
    98 / 126 (77.78%)
    Vascular disorders
    Chills
         subjects affected / exposed
    0 / 126 (0.00%)
    0 / 130 (0.00%)
    0 / 127 (0.00%)
    2 / 128 (1.56%)
    9 / 126 (7.14%)
         occurrences all number
    0
    0
    0
    2
    9
    Respiratory, thoracic and mediastinal disorders
    Nasopharyngitis
         subjects affected / exposed
    12 / 126 (9.52%)
    8 / 130 (6.15%)
    3 / 127 (2.36%)
    6 / 128 (4.69%)
    12 / 126 (9.52%)
         occurrences all number
    12
    8
    3
    6
    13
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    11 / 126 (8.73%)
    34 / 130 (26.15%)
    42 / 127 (33.07%)
    62 / 128 (48.44%)
    36 / 126 (28.57%)
         occurrences all number
    11
    39
    48
    69
    45
    Somnolence
         subjects affected / exposed
    6 / 126 (4.76%)
    24 / 130 (18.46%)
    25 / 127 (19.69%)
    21 / 128 (16.41%)
    18 / 126 (14.29%)
         occurrences all number
    6
    26
    27
    23
    18
    Disturbance in attention
         subjects affected / exposed
    0 / 126 (0.00%)
    4 / 130 (3.08%)
    5 / 127 (3.94%)
    5 / 128 (3.91%)
    7 / 126 (5.56%)
         occurrences all number
    0
    4
    5
    6
    7
    Headache
         subjects affected / exposed
    11 / 126 (8.73%)
    14 / 130 (10.77%)
    15 / 127 (11.81%)
    11 / 128 (8.59%)
    10 / 126 (7.94%)
         occurrences all number
    17
    14
    21
    16
    12
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 126 (2.38%)
    13 / 130 (10.00%)
    21 / 127 (16.54%)
    21 / 128 (16.41%)
    18 / 126 (14.29%)
         occurrences all number
    3
    15
    22
    21
    22
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    8 / 126 (6.35%)
    29 / 130 (22.31%)
    38 / 127 (29.92%)
    46 / 128 (35.94%)
    33 / 126 (26.19%)
         occurrences all number
    8
    36
    47
    48
    44
    Vomiting
         subjects affected / exposed
    5 / 126 (3.97%)
    19 / 130 (14.62%)
    19 / 127 (14.96%)
    31 / 128 (24.22%)
    15 / 126 (11.90%)
         occurrences all number
    5
    23
    24
    35
    16
    Constipation
         subjects affected / exposed
    5 / 126 (3.97%)
    18 / 130 (13.85%)
    21 / 127 (16.54%)
    23 / 128 (17.97%)
    22 / 126 (17.46%)
         occurrences all number
    6
    18
    22
    24
    23
    Abdominal pain upper
         subjects affected / exposed
    7 / 126 (5.56%)
    8 / 130 (6.15%)
    6 / 127 (4.72%)
    4 / 128 (3.13%)
    7 / 126 (5.56%)
         occurrences all number
    7
    8
    7
    4
    7
    Dry mouth
         subjects affected / exposed
    3 / 126 (2.38%)
    3 / 130 (2.31%)
    7 / 127 (5.51%)
    3 / 128 (2.34%)
    14 / 126 (11.11%)
         occurrences all number
    3
    3
    7
    4
    14
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    2 / 126 (1.59%)
    11 / 130 (8.46%)
    17 / 127 (13.39%)
    10 / 128 (7.81%)
    12 / 126 (9.52%)
         occurrences all number
    2
    13
    18
    11
    13
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 126 (0.00%)
    6 / 130 (4.62%)
    4 / 127 (3.15%)
    6 / 128 (4.69%)
    8 / 126 (6.35%)
         occurrences all number
    0
    6
    4
    6
    8

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 May 2013
    • Discontinuation criterion “Subject did not meet inclusion/exclusion criteria”: Criterion was changed from compulsory to optional discontinuation, to allow case-by-case decisions and avoid compulsory withdrawal of subjects when there is no impact on safety and tolerability and on integrity and reliability of data. • Specificiation of individual exclusion criteria and discontinuation criteria for: hepatic impairment, hepatitis, QT prolongation and ECG reading, previous invasive procedures aimed at reducing low back pain. • painDETECT exclusion criterion wording was changed to better explain that this only applies when the maximum number of subjects in the stratification subgroup has been reached. • Inconsistencies and errors were corrected and clarifications or references added that did not change the content of the original protocol.
    15 Nov 2013
    Based on the availability of new data on GRT6005 regarding subjects with impaired renal function, the exclusion criterion was adapted to lower the cut-off value for creatinine clearance. Additionally, it was allowed to re-enroll subjects who failed enrollment in this trial only because of the exclusion criteria that were changed in Amendment 01 and Amendment 02, but for no other reason, and who may be eligible after the implementation of these amendments. Further changes were implemented in order to correct or clarify statements in the protocol.

    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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