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    Clinical Trial Results:
    Evaluation of the effectiveness, safety, and tolerability of tapentadol PR versus oxycodone/naloxone PR in non-opioid pre-treated subjects with uncontrolled severe chronic low back pain with a neuropathic pain component.

    Summary
    EudraCT number
    2012-002943-11
    Trial protocol
    DE   IT   AT   ES  
    Global end of trial date
    28 Jan 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    03 Apr 2016
    First version publication date
    03 Apr 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KF5503/60
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01838616
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    Grünenthal GmbH: 822818
    Sponsors
    Sponsor organisation name
    Grünenthal GmbH
    Sponsor organisation address
    Zieglerstr. 6, Aachen, Germany, 52078
    Public contact
    GRT Trial Information Desk, Grünenthal GmbH, +49 2415693223, Clinical-Trials@grunenthal.com
    Scientific contact
    GRT Trial Information Desk, Grünenthal GmbH, +49 2415693223, 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
    19 Jan 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jan 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to evaluate the effectiveness, safety, and tolerability of tapentadol PR versus oxycodone/naloxone PR in non-opioid pre-treated subjects with uncontrolled severe chronic low back pain with a neuropathic pain component.
    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 and competent authorities were notified of the trial as required by national regulations, and, where necessary, relevant authorization was obtained. This effectiveness trial tried to stay in in close link to clinical practice and has an exploratory character related to highly important scientific questions. Therefore, an open-label setting, which may be questionned with regards to bias for typical regulatory trials, is justified. Relevant parameters related to tolerability (bowel function), safety (hormone blood levels) and neuropathic symptoms were not expected to be impacted by non-blinding in this respect. The pitfalls of a double-dummy regimen imposing further burden on the subjects and their compliance can be avoided. Upon discontinuation access to suitable alternative analgesia outside of the trial were at the discretion of the investigator.
    Background therapy
    Alllowed: Subjects taking NSAIDs (including cyclooxygenase-II inhibitors) and paracetamol continued their pre-treatment regimen without further adjustment of the dose (i.e., on a stable level). Selective serotonin reuptake inhibitors were only allowed for the treatment of uncomplicated depression if taken at a stable dose for at least 30 days before the Randomization Visit and if it was planned that they were to be continued on a stable dose for the duration of the trial. Compounds used to treat subjects with a diagnosis of psychiatric or neurological disorders requiring treatment (other than those listed as prohibited) were allowed provided they had been taken at a controlled, stable dose for at least 3 months prior to the Randomization Visit and if it was planned that they were to be continued on a stable dose for the duration of the trial. Physiotherapy packs and massages could be used during the trial period if their use was at the same frequency as before the trial, and if they were started at least 14 days prior to the Randomization Visit. Prohibited: Monoamine oxidase inhibitors were prohibited within 14 days before the Randomization Visit and during the trial. The use of laxatives and antiemetic medications were prohibited within 14 days before the Enrollment Visit as a prophylaxis prior to starting IMP and, unless medically indicated, during the course of the trial. Any intake of WHO Step II and Step III analgesics (including use of opioids as rescue medication) was prohibited within 30 days prior to enrollment and, except for the IMP, during the trial. The starting of medication with any centrally acting co-analgesics (e.g., anticonvulsants, antidepressants) and starting or changing WHO Step I analgesics (e.g., NSAIDs, paracetamol) was prohibited throughout the entire trial. Interventional adjunctive therapies, acupuncture or transcutaneous electrical nerve stimulation were not allowed during the course of the trial.
    Evidence for comparator
    The prolonged release formulation of oxycodone/naloxone is indicated for severe pain, which can be adequately managed only with opioid analgesics (based on the Summary of Product Characteristics). Oxycodone/naloxone prolonged release is reported to have a better constipation profile compared to oxycodone (Simpson et al. 2008). Further, the incidence of nausea, vomiting, abdominal pain, and dyspepsia was lower in the oxycodone/naloxone prolonged release group versus the oxycodone prolonged release group.
    Actual start date of recruitment
    25 Feb 2013
    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
    Spain: 39
    Country: Number of subjects enrolled
    Austria: 17
    Country: Number of subjects enrolled
    Germany: 202
    Worldwide total number of subjects
    258
    EEA total number of subjects
    258
    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)
    171
    From 65 to 84 years
    83
    85 years and over
    4

    Subject disposition

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    Recruitment
    Recruitment details
    The trial started on 22 Mar 2013 with the enrollment of the first subject and was completed on 28 Jan 2014 when the last subject completed the last follow-up examination according to the protocol. 367 subjects signed informed consent: 89 did not met in/exclusion criteria, 16 withdrew and 4 subjects were not dosed due to other reasons.

    Pre-assignment
    Screening details
    The duration of the washout period depended on previous coanalgesics, the doses & on the subject’s need (3 to 14 days). Analgesics and co-analgesics apart from NSAIDs (including COX-II inhibitors) & paracetamol were washed out prior to the Randomization Visit. Subjects not requiring a washout were randomized after lab results permitted this.

    Period 1
    Period 1 title
    Titration period
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Tapentadol Prolonged Release
    Arm description
    All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose).
    Arm type
    Experimental

    Investigational medicinal product name
    Tapentadol Prolonged Release
    Investigational medicinal product code
    CG5503
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Upward titration occurred at a minimum of 3-day intervals in increments of 50 mg tapentadol prolonged release BID (morning and evening). The minimum target of titration at the end of the titration period was: • NRS-3 ≤4 with acceptable tolerability as reported by the subject or • Subjects with an NRS-3 score of 5, if pain relief and tolerability were reported as satisfactory to continue in the trial by the subject and investigator and subjects were on maximum daily tapentadol PR 250 mg BID, or the maximum daily tapentadol PR dose could not be achieved because of side effects. Up-titration occurred at least until the minimum target of titration was achieved and could be continued to optimize the effectiveness/tolerability ratio for the individual subject. Dose adjustments required by NRS-3 scores was postponed in case of limited tolerability.

    Arm title
    Oxycodone/Naloxone Prolonged Release
    Arm description
    All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily (100 mg/40 mg total daily dose).
    Arm type
    Active comparator

    Investigational medicinal product name
    Oxycodone/Naloxone Prolonged Release
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Upward titration occurred at a minimum of 3-day intervals in increments of 10mg/5mg oxycodone/naloxone prolonged release BID (morning and evening). The minimum target of titration at the end of the titration period was: • NRS-3 ≤4 with acceptable tolerability as reported by the subject or • Subjects with an NRS-3 score of 5, if pain relief and tolerability were reported as satisfactory to continue in the trial by the subject and investigator and subjects were on maximum daily dose of oxycodone/naloxone prolonged release 40mg/20mg BID plus oxycodone prolonged release 10 mg BID, or the maximum daily oxycodone/naloxone dose could not be achieved because of side effects. Up-titration occurred at least until the minimum target of titration was achieved and could be continued to optimize the effectiveness/tolerability ratio for the individual subject. Dose adjustments required by NRS-3 scores were postponed in case of limited tolerability.

    Number of subjects in period 1 [1]
    Tapentadol Prolonged Release Oxycodone/Naloxone Prolonged Release
    Started
    130
    128
    Completed
    100
    62
    Not completed
    30
    66
         Protocol deviation
    -
    1
         Transferred to other arm/group
    -
    43
         Lack of efficacy
    5
    1
         Not specified
    2
    -
         Adverse event, non-fatal
    18
    16
         Consent withdrawn by subject
    5
    5
    Notes
    [1] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: Subjects in the oxycodone/naloxone PR treatment arm that did not reach the minimum target of titration or experiencing intolerable side effects at the end of the Titration Period were switched to the Pick-up Arm. They could also enter the Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment Pick-up Arm at any time during the Titration Period or Continuation Period, via an unscheduled visit, due to lack of tolerability or lack of efficacy under treatment with oxycodone/naloxone PR.
    Period 2
    Period 2 title
    Continuation Period
    Is this the baseline period?
    No
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Tapentadol prolonged release
    Arm description
    In the continuation period, subjects continued their end of titration period tapentadol PR dose (stablized dose); however, it was permitted to make a single titration step (up or down; except for subjects already on the maximum dose of tapentadol PR for whom up-titration was not permitted) using the same titration step as used in the titration period. The continuation period lasted 9 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Tapentadol Prolonged Release
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were suitable to enter the continuation period if the minimum target of titration was reached. In the continuation period, subjects continued their treatment with the tapentadol prolonged release dose achieved at the end of the titration period; however, it was permitted to make a single titration step (up or down; except for subjects already on the maximum dose of tapentadol PR for whom up-titration was not permitted) using the same titration step as used in the titration period. Subjects were permitted a maximum dose of 250 mg tapentadol prolonged release twice a day (500 mg total daily dose).

    Arm title
    Oxycodone/Naloxone Prolonged Release
    Arm description
    In the continuation period, subjects continued their end of titration period tapentadol PR dose (stablized dose); however, it was permitted to make a single titration step (up or down; except for subjects already on the maximum dose of tapentadol PR for whom up-titration was not permitted) using the same titration step as used in the titration period. The continuation period lasted 9 weeks.
    Arm type
    Active comparator

    Investigational medicinal product name
    Oxycodone/Naloxone Prolonged Release
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were suitable to enter the continuation period if the minimum target of titration was reached. Subjects titrated to oxycodone/naloxone PR 40 mg/20 mg BID requiring higher oxycodone doses were supplemented with oxycodone PR 10 mg BID. One titration step with oxycodone PR 10 mg BID was allowed, to be performed at the regular titration dates. Subjects were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily (100 mg/40 mg total daily dose).

    Arm title
    Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment
    Arm description
    Subjects in the oxycodone/naloxone PR treatment arm that did not reach the minimum target of titration or experiencing intolerable side effects at the end of the Titration Period were switched to the Pick-up Arm. They could also enter the Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment Pick-up Arm at any time during the Titration Period, via an unscheduled visit, due to lack of tolerability or lack of efficacy under treatment with oxycodone/naloxone PR.
    Arm type
    Experimental

    Investigational medicinal product name
    Tapentadol Prolonged Release
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All subjects were directly switched from oxycodone/naloxone PR to tapentadol PR using an equianalgesic ratio of 1:5 (oxycodone : tapentadol), together with a down-titration step under tapentadol PR (except for participants on oxycodone/naloxone PR 10 mg/5 mg twice daily).

    Number of subjects in period 2 [2]
    Tapentadol prolonged release Oxycodone/Naloxone Prolonged Release Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment
    Started
    100
    62
    50
    Completed
    86
    48
    35
    Not completed
    14
    14
    15
         Protocol deviation
    2
    -
    -
         Transferred to other arm/group
    -
    7
    -
         Lack of efficacy
    3
    1
    4
         Not specified
    -
    1
    1
         Adverse event, non-fatal
    8
    1
    9
         Consent withdrawn by subject
    -
    4
    1
         Lost to follow-up
    1
    -
    -
    Notes
    [2] - The number of subjects transferring in and out of the arms in the period are not the same. It is expected the net number of transfers in and out of the arms in a period, will be zero.
    Justification: Subjects in the oxycodone/naloxone PR treatment arm that did not reach the minimum target of titration or experiencing intolerable side effects at the end of the Titration Period were switched to the Pick-up Arm. They could also enter the Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment Pick-up Arm at any time during the Titration Period or Continuation Period, via an unscheduled visit, due to lack of tolerability or lack of efficacy under treatment with oxycodone/naloxone PR.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Tapentadol Prolonged Release
    Reporting group description
    All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose).

    Reporting group title
    Oxycodone/Naloxone Prolonged Release
    Reporting group description
    All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily (100 mg/40 mg total daily dose).

    Reporting group values
    Tapentadol Prolonged Release Oxycodone/Naloxone Prolonged Release Total
    Number of subjects
    130 128 258
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    88 83 171
        From 65-84 years
    40 43 83
        85 years and over
    2 2 4
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.1 ± 11.48 58.4 ± 12.23 -
    Gender categorical
    Units: Subjects
        Female
    77 84 161
        Male
    53 44 97
    Dermatol pain present
    Typical dermatol pain radiating beyond the knee towards the foot.
    Units: Subjects
        Yes
    113 103 216
        No
    17 23 40
        Missing
    0 2 2
    Evoked typical dermatol pain
    Typical dermatol pain evoked by stretching of the sciatic nerve.
    Units: Subjects
        Yes
    99 92 191
        No
    31 36 67
        Missing
    0 0 0
    Lumbar radiculopathy
    Lumbar radiculopathy is defined as lumbarspinal nerve or sacralspinal nerve impingement caused by (for example) a herniated disc, resulting in pain and possibly numbness and tingling and/or weakness sensation into one or both legs. A diagnosis of lumbar radiculopathy was assessed according to the following specification: • Typical dermatomal pain: − Radiating beyond the knee towards the foot (sciatica). − Evoked by stretching of the sciatic nerve. and • Signs of root dysfunction.
    Units: Subjects
        Yes
    76 75 151
        No
    54 53 107
    painDetect
    The painDETECT was a participant completed questionnaire. The questionnaire consists of 14 questions in four domains. Based on these questions a final assessment score was calculated. The minimum score ranged from zero to a maximum of 38. Participants with a score between 0 and 12 were scored as being “negative” (had no neuropathic pain component). A value between 19 and 38 was rated as being “positive” (neuropathic component present). Values from 13 to 18 were scored as being “unclear”.
    Units: Subjects
        painDetect positive
    96 97 193
        painDetect unclear
    33 27 60
        missing
    1 4 5
    Sleep Evaluation: Overall Quality of Sleep Last Night
    The sleep evaluation questionnaire was completed by the subject. One of the main concepts is the overall quality of sleep. This was rated as being one of the following: excellent, good, fair or poor.
    Units: Subjects
        excellent
    2 4 6
        good
    37 27 64
        fair
    49 67 116
        poor
    42 27 69
        missing
    0 3 3
    History of low back pain - duration of pain
    Units: months
        arithmetic mean (standard deviation)
    115.8 ± 121.26 102.4 ± 101.44 -
    Height
    Units: centimeters
        arithmetic mean (standard deviation)
    168.9 ± 11 167.1 ± 9.71 -
    Weight
    Units: kilograms
        arithmetic mean (standard deviation)
    85.3 ± 18.23 81.6 ± 18.43 -
    Recalled Average Pain Intensity
    The recalled average pain intensity score on the NRS-3 was assessed using the 11-point NRS. This scale recalled the average pain intensity during the last 3 days.
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.7 ± 1.04 7.6 ± 0.95 -
    Average Pain Intensity Over Three Days for Pain Radiating Towards or Into the Leg
    Typical dermatomal pain was defined as being pain that radiates beyond the knee towards the foot (sciatica) or pain evoked by stretching of the sciatic nerve. The participant was asked to rate their pain intensity over the past 3 days with regards to this particular pain characteristic. The recalled average pain intensity over the past 3 days for the pain radiating towards or into the leg was assessed by using an 11-point Numeric Rating Scale (NRS), where 0 = no pain and 10 = pain as bad as you can imagine.
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.5 ± 1.25 7.6 ± 1.025 -
    Worst Pain Intensity Over the Past 24 Hours
    The recalled worst pain intensity during the last 24 hours was assessed using an 11-point Numeric Rating Scale, where 0 = no pain and 10 = pain as bad as you can imagine. The participant was asked: “Please rate your pain intensity by assessing the one number that best describes your worst pain during the last 24 hours prior to the visit”
    Units: units on a scale
        arithmetic mean (standard deviation)
    8.1 ± 1.03 8 ± 1.06 -
    painDETECT Assessment
    The painDETECT was a participant completed questionnaire. The questionnaire consists of 14 questions in four domains. Based on these questions a final assessment score was calculated. The minimum score ranged from zero to a maximum of 38. Participants with a score between 0 and 12 were scored as being “negative” (had no neuropathic pain component). A value between 19 and 38 was rated as being “positive” (neuropathic component present). Values from 13 to 18 were scored as being “unclear”.
    Units: units on a scale
        arithmetic mean (standard deviation)
    22.3 ± 5.25 22.5 ± 4.79 -
    Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment
    In the NPSI the subject rated their symptoms of neuropathic pain. Ten pain questions were answered on an 11-point scale; from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity, e.g. worst burning imaginable). The overall NPSI score was calculated by the summation of all ten responses and ranges between 0 (absent) and 1 (worst possible intensity).
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.598 ± 0.1769 0.612 ± 0.1445 -
    Neuropathic Pain Symptom Inventory (NPSI) Sub-Score Burning Pain
    The subject rated their symptom of burning pain on an 11-point scale; from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity). The overall sub-score for burning pain was calculated by the summation of all subjects that responded and the response range reported between 0 (absent) and 1 (worst possible intensity).
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.612 ± 0.2652 0.634 ± 0.2279 -
    Neuropathic Pain Symptom Inventory (NPSI) Sub-Score Pressing Pain
    The subject rated their symptom of pressing pain on an 11-point scale; from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity). The overall sub-score for pressing pain was calculated by the summation of all subjects that responded and the response range reported between 0 (absent) and 1 (worst possible intensity).
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.595 ± 0.2523 0.608 ± 0.1848 -
    Neuropathic Pain Symptom Inventory (NPSI) Sub-Score Paroxysmal Pain
    The subject rated their symptom of paroxysmal (pain like electric shocks or stabbing) pain on an 11-point scale; from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity).The overall sub-score for paroxysmal pain was calculated by the summation of all subjects that responded and the response range reported between 0 (absent) and 1 (worst possible intensity).
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.638 ± 0.2312 0.67 ± 0.172 -
    Neuropathic Pain Symptom Inventory (NPSI) Sub-Score Evoked Pain
    The subject rated their symptom of evoked (due to touch) pain on an 11-point scale; from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity). The overall sub-score for evoked pain was calculated by the summation of all subjects that responded and the response range reported between 0 (absent) and 1 (worst possible intensity).
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.555 ± 0.2536 0.548 ± 0.23 -
    Neuropathic Pain Symptom Inventory (NPSI) Sub-Score Paresthesia/Dysesthesia
    The subject rated their symptom of paresthesia (sensation that is not unpleasant) or dysesthesia (unpleasant) on an 11-point scale; from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity). The overall sub-score for paresthesia/dysesthesia was calculated by the summation of all subjects that responded and the response range reported between 0 (absent) and 1 (worst possible intensity).
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.621 ± 0.2292 0.642 ± 0.1809 -
    Short Form Health Survey (SF-12) Physical Component Summary
    The Short Form Health Survey (SF-12) has several brief broad questions on 8 aspects of health that a subjectked to score over the last week. The physical summary scores were calculated from the individual responses to physical functioning, role physical, bodily pain, general health. A higher score indicates a better perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state.
    Units: units on a scale
        arithmetic mean (standard deviation)
    30.319 ± 7.2739 31.684 ± 6.8313 -
    Short Form Health Survey (SF-12) Mental Component Summary
    The Short Form Health Survey (SF-12) has several brief broad questions on 8 aspects of health that a subjectked to score over the last week. The mental summary scores were calculated from the individual responses to vitality, social functioning, role-emotional and mental health. A higher score indicates a better perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state.
    Units: units on a scale
        arithmetic mean (standard deviation)
    48.736 ± 11.5697 45.216 ± 11.7462 -
    EuroQol-5 (EQ-5D) Health Status Index Outcome
    The subject scored the EuroQol-5 questionnaire. The EuroQol-5 questionnaire uses a health state classification with 5 dimensions. Each dimension was assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1 (with 1 indicating "full health" and 0 representing "dead"). The higher the values (the closer the value is to 1) the better the health status in a treatment group.
    Units: units on a scale
        arithmetic mean (standard deviation)
    0.3186 ± 0.29464 0.3392 ± 0.31134 -
    Hospital Anxiety and Depression Scale: Anxiety
    The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe anxiety. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate anxiety. A score of 11 or above is considered to be a case of anxiety.
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.3 ± 4.06 8.2 ± 4.28 -
    Hospital Anxiety and Depression Scale: Depression
    The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe depression. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate depression. A score of 11 or above is considered to be a case of depression. A decrease in values over time indicates that there has been an improvement.
    Units: units on a scale
        arithmetic mean (standard deviation)
    7.4 ± 4.08 8 ± 4.08 -
    Sleep Evaluation: Number of Awakenings
    The participants were requested to answer the following question: How many times did you wake up during the night? The values were calculated from the data that subjects self-reported for the night prior to their Randomization Visit (Baseline).
    Units: Number of Awakenings
        arithmetic mean (standard deviation)
    3 ± 2.8 2.6 ± 1.67 -
    Sleep Evaluation: Number of Hours Slept
    The sleep evaluation questionnaire was completed by the subject. The answer was in response to the question: How long did you sleep last night [hours]?
    Units: hours
        arithmetic mean (standard deviation)
    5.781 ± 1.5908 5.675 ± 1.7118 -
    Sleep Evaluation: Latency (Time Taken to Fall Asleep)
    The sleep evaluation questionnaire was completed by the subject. The subject was asked: How long after bedtime/lights out did you fall asleep last night [hours]? The values are for the night prior to the randomization visit.
    Units: hours
        arithmetic mean (standard deviation)
    1.047 ± 1.1746 1.203 ± 1.3029 -

    End points

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    End points reporting groups
    Reporting group title
    Tapentadol Prolonged Release
    Reporting group description
    All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose).

    Reporting group title
    Oxycodone/Naloxone Prolonged Release
    Reporting group description
    All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily (100 mg/40 mg total daily dose).
    Reporting group title
    Tapentadol prolonged release
    Reporting group description
    In the continuation period, subjects continued their end of titration period tapentadol PR dose (stablized dose); however, it was permitted to make a single titration step (up or down; except for subjects already on the maximum dose of tapentadol PR for whom up-titration was not permitted) using the same titration step as used in the titration period. The continuation period lasted 9 weeks.

    Reporting group title
    Oxycodone/Naloxone Prolonged Release
    Reporting group description
    In the continuation period, subjects continued their end of titration period tapentadol PR dose (stablized dose); however, it was permitted to make a single titration step (up or down; except for subjects already on the maximum dose of tapentadol PR for whom up-titration was not permitted) using the same titration step as used in the titration period. The continuation period lasted 9 weeks.

    Reporting group title
    Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment
    Reporting group description
    Subjects in the oxycodone/naloxone PR treatment arm that did not reach the minimum target of titration or experiencing intolerable side effects at the end of the Titration Period were switched to the Pick-up Arm. They could also enter the Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment Pick-up Arm at any time during the Titration Period, via an unscheduled visit, due to lack of tolerability or lack of efficacy under treatment with oxycodone/naloxone PR.

    Subject analysis set title
    Tapentadol Prolonged Release PPS
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The Per Protocol Set includes all subjects who are included in the Full Analysis Set and had no major protocol deviations which could impact the primary outcome of this trial. Protocol deviations include the following: • Violation of inclusion/exclusion criteria • Time schedule deviations • Non-compliance regarding intake of IMP • Inappropriate intake of concomitant medication • Missing essential data • Subject not discontinued as per protocol • Other non-compliance The Per Protocol Set is independent of the period of the trial.

    Subject analysis set title
    Oxycodone/Naloxone Prolonged Release PPS
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The Per Protocol Set includes all subjects who are included in the Full Analysis Set and had no major protocol deviations which could impact the primary outcome of this trial. Protocol deviations include the following: • Violation of inclusion/exclusion criteria • Time schedule deviations • Non-compliance regarding intake of IMP • Inappropriate intake of concomitant medication • Missing essential data • Subject not discontinued as per protocol • Other non-compliance The Per Protocol Set is independent of the period of the trial.

    Subject analysis set title
    Tapentadol Prolonged Release FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set includes all randomized subjects who took at least 1 dose of the IMP and had at least one pain intensity assessment (NRS-3) post baseline. The Full Analysis Set is independent of the period of the trial.

    Subject analysis set title
    Oxycodone/Naloxone Prolonged Release FAS
    Subject analysis set type
    Full analysis
    Subject analysis set description
    The Full Analysis Set includes all randomized subjects who took at least 1 dose of the IMP and had at least one pain intensity assessment (NRS-3) post baseline. The Full Analysis Set is independent of the period of the trial.

    Subject analysis set title
    Tapentadol Prolonged Release SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Set includes all randomized subjects who took at least 1 dose of Tapentadol Prolonged Release.

    Subject analysis set title
    Oxycodone/Naloxone Prolonged Release SAF
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The Safety Set includes all randomized subjects who took at least 1 dose of Tapentadol Prolonged Release.

    Primary: Change in the Average Pain Intensity Score on an 11-point Numeric Rating Scale (NRS-3)

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    End point title
    Change in the Average Pain Intensity Score on an 11-point Numeric Rating Scale (NRS-3)
    End point description
    For this pain assessment, the subject indicated the level of average pain experienced over the previous 3 days on an 11-point Numeric Rating Scale (NRS-3) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The value reported represents the change from the randomization visit (i.e., the last 3 days in the washout period prior to Investigational Medicinal Product initiation and titration) to the end of the continuation period (i.e., up to 9 weeks on the stable dose). The theoretical values range from -10 to 10. A negative sign indicates a decrease in pain from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (Baseline Visit).
    End point type
    Primary
    End point timeframe
    Baseline (Randomization Visit) to the end of the Continuation Period (Week 12).
    End point values
    Tapentadol Prolonged Release PPS Oxycodone/Naloxone Prolonged Release PPS
    Number of subjects analysed
    117
    112
    Units: units on a scale
        least squares mean (standard error)
    -3.7 ± 0.25
    -2.7 ± 0.26
    Statistical analysis title
    Change in mean pain intensity (NRS-3, LOCF) - PPS
    Comparison groups
    Tapentadol Prolonged Release PPS v Oxycodone/Naloxone Prolonged Release PPS
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.001 [1]
    Method
    Inverse normal method
    Parameter type
    Repeat Confidence Interval
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -1.82
         upper limit
    -0.184
    Notes
    [1] - p-value for testing the non-inferiority (non-inferiority margin = 1.3) based on the inverse normal method, adjusting for multiplicity caused by the group sequential design.

    Primary: Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) Total Score

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    End point title
    Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) Total Score
    End point description
    The Constipation Assessment (PAC-SYM) is a 12-item self-report questionnaire that assessed the severity of symptoms of constipation. Subjects were asked "How severe have each of these symptoms been in the last two weeks?" e.g. "Pain in your stomach". There are 3 subscales: 4 questions on abdominal symptoms, 3 on rectal symptoms and 5 on stool symptoms. Responses were rated on a 5-point Likert scale ranging from 0 (absence of symptom) to 4 (very severe symptoms). If the changes in the overall or subscale scores are positive then there is a worsening in symptoms associated with constipation. The change in the assessment of constipation symptoms (PAC-SYM) total score from the Randomization Visit to the Final Evaluation Visit. The PAC-SYM overall score is the sum of scores of all non-missing items divided by the number of non-missing items (if at least 6 items were non-missing).
    End point type
    Primary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12).
    End point values
    Tapentadol Prolonged Release PPS Oxycodone/Naloxone Prolonged Release PPS
    Number of subjects analysed
    117
    112
    Units: units on a scale
        least squares mean (standard error)
    0.07 ± 0.06
    0.14 ± 0.062
    Statistical analysis title
    Change in PAC-SYM total score
    Comparison groups
    Tapentadol Prolonged Release PPS v Oxycodone/Naloxone Prolonged Release PPS
    Number of subjects included in analysis
    229
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    < 0.001
    Method
    Inverse normal method
    Parameter type
    Repeat Confidence Interval
    Confidence interval
         level
    97.5%
         sides
    2-sided
         lower limit
    -0.259
         upper limit
    0.121
    Notes
    [2] - p-value for testing the non-inferiority (non-inferiority margin = 0.7) based on the inverse normal method, adjusting for multiplicity caused by the group sequential design.

    Secondary: Change in Recalled Average Pain Intensity at the End of Treatment

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    End point title
    Change in Recalled Average Pain Intensity at the End of Treatment
    End point description
    The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS), on this scale 0 indicated "no pain" and 10 indicated "pain as bad as you can imagine". This scale recorded the average pain intensity recalled by the participant during the previous 3 days. The subject was asked: “Please rate your pain intensity by assessing the one number that best describes your pain on average during the last 3 days (the last 72 hours prior to the visit)”. A negative sign indicates a decrease in pain from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (baseline visit).
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12).
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    130
    126
    Units: units on a scale
        least squares mean (standard error)
    -3.7 ± 0.24
    -2.8 ± 0.24
    Statistical analysis title
    Least Square Means for Treatment Comparison
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    ANCOVA
    Confidence interval

    Secondary: Change of Average Pain Intensity Over Three Days for Pain Radiating Towards or Into the Leg

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    End point title
    Change of Average Pain Intensity Over Three Days for Pain Radiating Towards or Into the Leg
    End point description
    Typical dermatomal pain was defined as being pain that radiates beyond the knee towards the foot (sciatica) or pain evoked by stretching of the sciatic nerve. Therefore, the subject was asked to rate their pain intensity over the past 3 days with regards to this particular pain characteristic. The recalled average pain intensity during the last 24 hours was assessed using an 11-point Numeric rating scale, where 0 = "no pain" and 10 = "pain as bad as you can imagine". A negative sign indicates that there was a decrease in the average pain radiating towards or into the leg.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    129
    125
    Units: units on a scale
        least squares mean (standard error)
    -3.9 ± 0.25
    -2.8 ± 0.25
    Statistical analysis title
    Least Square Means for Treatment Comparison
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    ANCOVA
    Confidence interval

    Secondary: Change in Worst Pain Intensity Over the Past 24 Hours at the End of Treatment

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    End point title
    Change in Worst Pain Intensity Over the Past 24 Hours at the End of Treatment
    End point description
    The recalled worst pain intensity during the last 24 hours was assessed using an 11-point Numeric rating scale, where 0 = "no pain" and 10 = "pain as bad as you can imagine". The subject was asked: “Please rate your pain intensity by assessing the one number that best describes your worst pain during the last 24 hours prior to the visit”. A negative change indicates that the pain intensity decreased from the start of the trial.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12).
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    129
    125
    Units: units on a scale
        least squares mean (standard error)
    -3.7 ± 0.25
    -2.8 ± 0.25
    Statistical analysis title
    Least Square Means for Treatment Comparison
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.003
    Method
    ANCOVA
    Confidence interval

    Secondary: Change in painDETECT Final Assessment at the End of Treatment

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    End point title
    Change in painDETECT Final Assessment at the End of Treatment
    End point description
    The painDETECT was a subject completed questionnaire. The questionnaire consists of 14 questions in four domains. Based on these questions a final assessment score was calculated. The minimum score ranged from zero to a maximum of 38. Subjects with a score between 0 and 12 were scored as being "negative" (had no neuropathic pain component). A value between 19 and 38 was rated as being "positive" (neuropathic component present). Values from 13 to 18 were scored as being "unclear". The theoretical range of change in this trial ranged from -38 to 15. A negative change indicated a decrease in their neuropathic component of pain.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12).
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    124
    126
    Units: units on a scale
        least squares mean (standard error)
    -10.8 ± 0.67
    -7.9 ± 0.69
    Statistical analysis title
    Least Square Means for Treatment Comparison
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    250
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    ANCOVA
    Confidence interval

    Secondary: Change in Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment at the End of Treatment

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    End point title
    Change in Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment at the End of Treatment
    End point description
    In the Neuropathic Pain Symptom Inventory (NPSI) the subject rated their symptoms of neuropathic pain. Ten pain questions were answered on an 11-point scale, from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity, e.g. worst burning imaginable). The overall NPSI score was calculated by the summation of all ten responses and ranges between 0 and 1. For pain descriptions burning, pressing, paroxysmal (pain like electric shocks or stabbing), evoked (due to touch) and paresthesia (sensation that is not unpleasant) or dysesthesia (unpleasant) sub-scores are reported. The overall values reported for all subjects that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all subjects and all participants rated it at its worst possible intensity if a value is 1. A negative change indicates that the intensity of the symptom has decreased since the start of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    129
    125
    Units: units on a scale
    least squares mean (standard error)
        Overall Score
    -0.353 ± 0.0208
    -0.248 ± 0.0211
        Sub-Score Burning Pain
    -0.375 ± 0.0249
    -0.278 ± 0.0252
        Sub-Score Pressing Pain
    -0.331 ± 0.0235
    -0.226 ± 0.0238
        Sub-Score Paroxysmal Pain
    -0.385 ± 0.0246
    -0.283 ± 0.025
        Sub-score Evoked Pain
    -0.334 ± 0.0222
    -0.225 ± 0.0225
        Sub-score Paresthesia/Dysesthsia
    -0.363 ± 0.0229
    -0.252 ± 0.0231
    Statistical analysis title
    Least Square Means - Overall NPSI Score
    Comparison groups
    Oxycodone/Naloxone Prolonged Release FAS v Tapentadol Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - Burning Pain
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - Pressing Pain
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.001
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - Paroxysmal Pain
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.012
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - Evoked Pain
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - Paresthesia/Dysesthesia
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Confidence interval

    Secondary: Changes in the Short Form Health Survey (SF-12) at the End of Treatment

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    End point title
    Changes in the Short Form Health Survey (SF-12) at the End of Treatment
    End point description
    The Short Form Health Survey (SF-12) has several brief broad questions on 8 aspects of health (physical functioning, role physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health) that a subject was asked to score over the last week. The physical and mental summary scores were calculated from the individual responses. A higher score indicates a better perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state. The change in the SF-12 score shows an improvement in health from baseline if the values are positive. The higher the value the greater the improvement since starting the trial.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    129
    125
    Units: units on a scale
    least squares mean (standard error)
        Physical Functioning
    8.358 ± 0.8262
    5.073 ± 0.8361
        Role-Physical
    7.26 ± 0.7115
    4.668 ± 0.7224
        Bodily Pain
    10.99 ± 0.9462
    7.458 ± 0.957
        General Health
    8.447 ± 0.8702
    4.309 ± 0.8818
        Vitality
    4.943 ± 0.8062
    1.468 ± 0.8179
        Social Functioning
    5.246 ± 0.887
    2.286 ± 0.8997
        Role-Emotional
    4.764 ± 0.9472
    2.587 ± 0.9807
        Mental Health
    5.158 ± 0.8386
    2.973 ± 0.8575
        Physical Component Summary
    9.735 ± 0.7948
    6.202 ± 0.8058
        Mental Component Summary
    3.077 ± 0.8457
    1.146 ± 0.8679
    Statistical analysis title
    Least Square Means - SF-12 Physical functioning
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.004
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - SF-12 Role-physical
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.009
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - SF-12 Bodily pain
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.007
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - SF-12 General health
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - SF-12 Vitality
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - SF-12 Social functioning
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.017
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - SF-12 Role-emotional
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.103
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - SF-12 Mental health
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.063
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - Physical Component Summary
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.002
    Method
    ANCOVA
    Confidence interval
    Statistical analysis title
    Least Square Means - Mental Component Summary
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.104
    Method
    ANCOVA
    Confidence interval

    Secondary: Change in EuroQol-5 (EQ-5D) Health Status Index Outcome at the End of Treatment

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    End point title
    Change in EuroQol-5 (EQ-5D) Health Status Index Outcome at the End of Treatment
    End point description
    The subject scored the EuroQol-5 questionnaire. The EuroQol-5 questionnaire uses a health state classification with 5 dimensions. Each dimension was assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1 (with 1 indicating "full health" and 0 representing "dead"). The higher the values (the closer the value is to 1) the better the health status in a treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    129
    125
    Units: units on a scale
        least squares mean (standard error)
    0.3395 ± 0.02785
    0.2398 ± 0.02811
    Statistical analysis title
    Least Square Means for Treatment Comparison
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.01
    Method
    ANCOVA
    Confidence interval

    Secondary: Change in Hospital Anxiety and Depression Scale at the End of Treatment: Anxiety

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    End point title
    Change in Hospital Anxiety and Depression Scale at the End of Treatment: Anxiety
    End point description
    The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe anxiety. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate anxiety. A score of 11 or above is considered to be a case of anxiety. A negative sign indicates that there has been a decrease in anxiety since the start of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    130
    126
    Units: units on a scale
        least squares mean (standard error)
    -2.1 ± 0.34
    -1.1 ± 0.35
    Statistical analysis title
    Least Square Means for Treatment Comparison
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    256
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.032
    Method
    ANCOVA
    Confidence interval

    Secondary: Change in Hospital Anxiety and Depression Scale at the End of Treatment: Depression

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    End point title
    Change in Hospital Anxiety and Depression Scale at the End of Treatment: Depression
    End point description
    The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe depression. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate depression. A score of 11 or above is considered to be a case of depression. A decrease in values over time indicates that there has been an improvement. A negative change value indicates a decrease in the depression score since the start of treatment.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    124
    114
    Units: units on a scale
        least squares mean (standard error)
    -2.4 ± 0.34
    -1.1 ± 0.36
    Statistical analysis title
    Least Square Means for Treatment Comparison
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.011
    Method
    ANCOVA
    Confidence interval

    Secondary: Patient Global Impression of Change at the End of Treatment

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    End point title
    Patient Global Impression of Change at the End of Treatment
    End point description
    In the Patient Global Impression of Change (PGIC) the subject indicated the perceived change over the treatment period. PGIC is a 7 point scale depicting a patient's rating of overall improvement. Patients rate their change as “very much improved,” “much improved,” “minimally improved,” “no change,” “minimally worse,” “much worse,” or “very much worse.”
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    129
    125
    Units: subjects
        Very Much Improved
    27
    18
        Much Improved
    43
    19
        Minimally Improved
    32
    46
        No Change
    21
    29
        Minimally Worse
    3
    6
        Much Worse
    2
    4
        Very Much Worse
    1
    3
    Statistical analysis title
    Fisher’s exact test (α = 0.05, two-sided)
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    254
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005
    Method
    Fisher exact
    Confidence interval

    Secondary: Clinician Global Impression of Change at the End of Treatment

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    End point title
    Clinician Global Impression of Change at the End of Treatment
    End point description
    In the Clinician Global Impression of Change (CGIC) the clinician indicated the perceived change over the treatment period. The clinician was requested to choose one of seven categories for each subject. The Clinician rated the subjcect's change as “very much improved,” “much improved,” “minimally improved,” “no change,” “minimally worse,” “much worse,” or “very much worse.”
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    128
    123
    Units: subjects
        Very Much Improved
    32
    18
        Much Improved
    44
    25
        Minimally Improved
    22
    37
        No Change
    21
    26
        Minimally Worse
    6
    7
        Much Worse
    3
    9
        Very Much Worse
    0
    1
    Statistical analysis title
    Fisher’s exact test (α = 0.05, two-sided)
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.005
    Method
    Fisher exact
    Confidence interval

    Secondary: Sleep Evaluation at the End of Treatment: Change in the Number of Awakenings

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    End point title
    Sleep Evaluation at the End of Treatment: Change in the Number of Awakenings
    End point description
    The participants were requested to answer the question: How many times did you wake up during the night? The values were calculated from the data that participants self-reported. The change from baseline in the number of times of waking up during the night in a treatment group is reported. A negative symbol indicates that there was a reduction in the number of awakenings.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    128
    123
    Units: number of awakenings
        least squares mean (standard error)
    -0.8 ± 0.15
    -0.5 ± 0.16
    Statistical analysis title
    Least Square Means for Treatment Comparison
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    251
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.084
    Method
    ANCOVA
    Confidence interval

    Secondary: Sleep Evaluation at the End of Treatment: Change in the Number of Hours Slept

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    End point title
    Sleep Evaluation at the End of Treatment: Change in the Number of Hours Slept
    End point description
    The sleep evaluation questionnaire was completed by the participant. The answer was in response to the question: Sleep evaluation: How long did you sleep last night [hours]? The value reported is the change in the number of hours of sleep from baseline. The positive value indicates that there was an increase in the number of hours of sleep in a treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    124
    114
    Units: hours
        least squares mean (standard error)
    0.46 ± 0.1714
    0.412 ± 0.1763
    Statistical analysis title
    Least Square Means for Treatment Comparison
    Comparison groups
    Oxycodone/Naloxone Prolonged Release FAS v Tapentadol Prolonged Release FAS
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.84
    Method
    ANCOVA
    Confidence interval

    Secondary: Sleep Evaluation at the End of Treatment: Change in Latency (Change in the Time Taken to Fall Asleep)

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    End point title
    Sleep Evaluation at the End of Treatment: Change in Latency (Change in the Time Taken to Fall Asleep)
    End point description
    The sleep evaluation questionnaire was completed by the participant. The participant was asked: How long after bedtime/lights out did you fall asleep last night [hours]? The values are for the night prior to the visits. The negative change from baseline indicates that the time to falling asleep decreased from baseline in a treatment group.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Visit (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    124
    114
    Units: hours
        least squares mean (standard error)
    -0.3 ± 0.1
    -0.177 ± 0.1025
    Statistical analysis title
    Least Square Means for Treatment Comparison
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.378
    Method
    ANCOVA
    Confidence interval

    Secondary: Comparison of the Number of Participants Affected by Gastrointestinal Treatment Emergent Adverse Events (TEAEs) Typical for Opioids

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    End point title
    Comparison of the Number of Participants Affected by Gastrointestinal Treatment Emergent Adverse Events (TEAEs) Typical for Opioids
    End point description
    In this outcome measure the number of participants affected by early gastrointestinal-related treatment emergent adverse events (TEAEs). As the trial population was opioid-naïve this was considered of interest. The composition score from participant who reported: Mild, moderate to severe nausea and/or Mild, moderate to severe vomiting and/or Mild, moderate to severe constipation was evaluated.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit) to End of Titration Period (End of Week 3)
    End point values
    Tapentadol Prolonged Release Oxycodone/Naloxone Prolonged Release
    Number of subjects analysed
    130
    128
    Units: subjects
    42
    59
    Statistical analysis title
    Fisher’s exact test (α = 0.05, two-sided)
    Comparison groups
    Tapentadol Prolonged Release v Oxycodone/Naloxone Prolonged Release
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.03
    Method
    Fisher exact
    Confidence interval

    Secondary: Composite Event Based Comparison of Gastrointestinal Treatment Emergent Adverse Events (TEAEs) Typical for Opioids

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    End point title
    Composite Event Based Comparison of Gastrointestinal Treatment Emergent Adverse Events (TEAEs) Typical for Opioids
    End point description
    In this outcome measure the early gastrointestinal-related treatment emergent events (TEAEs) were evaluated. As the trial population was opioid-naïve this was considered of interest. The composition score of reported events of Mild, moderate to severe nausea and/or Mild, moderate to severe vomiting and/or Mild, moderate to severe constipation was evaluated.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Week 3 (End of Titration Period)
    End point values
    Tapentadol Prolonged Release Oxycodone/Naloxone Prolonged Release
    Number of subjects analysed
    130
    128
    Units: number of events
    56
    81
    Statistical analysis title
    Fisher’s exact test (α = 0.05, two-sided)
    Comparison groups
    Tapentadol Prolonged Release v Oxycodone/Naloxone Prolonged Release
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.07
    Method
    Fisher exact
    Confidence interval

    Secondary: Sleep evaluation: Overall quality of sleep last night

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    End point title
    Sleep evaluation: Overall quality of sleep last night
    End point description
    The sleep evaluation questionnaire was completed by the subject. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The subject rated this categorically as being one of the following: excellent, good, fair or poor. The improvement, no change or worsening is reported based on the replies scored by the subject given at their End of Continuation Visit.
    End point type
    Secondary
    End point timeframe
    Baseline (Randomization Visit); End of Continuation Period (Week 12)
    End point values
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects analysed
    124
    114
    Units: subjects
        Improvement
    62
    43
        No change
    46
    56
        Worsening
    16
    15
    Statistical analysis title
    Fisher’s exact test (α = 0.05, two-sided)
    Comparison groups
    Tapentadol Prolonged Release FAS v Oxycodone/Naloxone Prolonged Release FAS
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.132
    Method
    Fisher exact
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Tapentadol Prolonged Release FAS
    Reporting group description
    All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.

    Reporting group title
    Oxycodone/Naloxone Prolonged Release FAS
    Reporting group description
    All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.

    Reporting group title
    Tapentadol (PR) after Oxycodone/Naloxone (PR) treatment
    Reporting group description
    Subjects in the oxycodone/naloxone PR treatment arm experiencing lack of efficacy, intolerable side effects, or not reaching the minimum target of titration at the end of the Titration Period could be switched to tapentadol PR in the Pick-up Arm.

    Serious adverse events
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS Tapentadol (PR) after Oxycodone/Naloxone (PR) treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 130 (2.31%)
    2 / 128 (1.56%)
    0 / 50 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Tracheobronchitis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Tapentadol Prolonged Release FAS Oxycodone/Naloxone Prolonged Release FAS Tapentadol (PR) after Oxycodone/Naloxone (PR) treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    100 / 130 (76.92%)
    106 / 128 (82.81%)
    29 / 50 (58.00%)
    Vascular disorders
    Hot flush
         subjects affected / exposed
    7 / 130 (5.38%)
    4 / 128 (3.13%)
    0 / 50 (0.00%)
         occurrences all number
    7
    4
    0
    Hypertension
         subjects affected / exposed
    3 / 130 (2.31%)
    1 / 128 (0.78%)
    2 / 50 (4.00%)
         occurrences all number
    3
    1
    2
    Hypertensive crisis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Hypotension
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Surgical and medical procedures
    Vocal cord polypectomy
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Melanocytic naevus
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 128 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Chills
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Drug withdrawal syndrome
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    39 / 130 (30.00%)
    31 / 128 (24.22%)
    2 / 50 (4.00%)
         occurrences all number
    42
    32
    2
    Influenza like illness
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Irritability
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Local swelling
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 128 (1.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Malaise
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Oedema peripheral
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Pain
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Thirst
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Psychiatric disorders
    Apathy
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Claustrophobia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Drug dependence
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Euphoric mood
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Insomnia
         subjects affected / exposed
    4 / 130 (3.08%)
    2 / 128 (1.56%)
    0 / 50 (0.00%)
         occurrences all number
    4
    2
    0
    Restlessness
         subjects affected / exposed
    2 / 130 (1.54%)
    2 / 128 (1.56%)
    0 / 50 (0.00%)
         occurrences all number
    2
    2
    0
    Sleep disorder
         subjects affected / exposed
    1 / 130 (0.77%)
    2 / 128 (1.56%)
    0 / 50 (0.00%)
         occurrences all number
    2
    2
    0
    Tic
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Withdrawal syndrome
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Nervousness
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Fall
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Injury
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Ligament sprain
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 128 (1.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Thermal burn
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Traumatic haematoma
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Investigations
    Biopsy chest wall
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 128 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Blood phosphorus decreased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Blood testosterone decreased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Creatinine renal clearance decreased
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Tachycardia paroxysmal
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 128 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Dry throat
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Epistaxis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory distress
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Dizziness
         subjects affected / exposed
    24 / 130 (18.46%)
    22 / 128 (17.19%)
    6 / 50 (12.00%)
         occurrences all number
    26
    22
    6
    Headache
         subjects affected / exposed
    10 / 130 (7.69%)
    5 / 128 (3.91%)
    1 / 50 (2.00%)
         occurrences all number
    10
    5
    1
    Hypoaesthesia
         subjects affected / exposed
    3 / 130 (2.31%)
    5 / 128 (3.91%)
    1 / 50 (2.00%)
         occurrences all number
    3
    6
    1
    Neuromuscular blockade
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Orthostatic intolerance
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Paraesthesia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Sciatica
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Somnolence
         subjects affected / exposed
    3 / 130 (2.31%)
    3 / 128 (2.34%)
    0 / 50 (0.00%)
         occurrences all number
    4
    3
    0
    Speech disorder
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Syncope
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 128 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Tremor
         subjects affected / exposed
    1 / 130 (0.77%)
    2 / 128 (1.56%)
    1 / 50 (2.00%)
         occurrences all number
    1
    2
    1
    Vertigo CNS origin
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Cervicobrachial syndrome
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    2
    1
    0
    Eye disorders
    Ocular hyperaemia
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Vision blurred
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Visual impairment
         subjects affected / exposed
    0 / 130 (0.00%)
    2 / 128 (1.56%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    0
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Vertigo
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 128 (0.78%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Abdominal pain lower
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    5 / 130 (3.85%)
    5 / 128 (3.91%)
    1 / 50 (2.00%)
         occurrences all number
    5
    6
    1
    Bowel movement irregularity
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Colitis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Constipation
         subjects affected / exposed
    20 / 130 (15.38%)
    33 / 128 (25.78%)
    1 / 50 (2.00%)
         occurrences all number
    20
    34
    1
    Diarrhoea
         subjects affected / exposed
    6 / 130 (4.62%)
    0 / 128 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    6
    0
    3
    Dry mouth
         subjects affected / exposed
    9 / 130 (6.92%)
    7 / 128 (5.47%)
    0 / 50 (0.00%)
         occurrences all number
    9
    8
    0
    Dyspepsia
         subjects affected / exposed
    2 / 130 (1.54%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    2
    1
    0
    Eructation
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Flatulence
         subjects affected / exposed
    1 / 130 (0.77%)
    3 / 128 (2.34%)
    0 / 50 (0.00%)
         occurrences all number
    1
    3
    0
    Gastritis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Nausea
         subjects affected / exposed
    29 / 130 (22.31%)
    23 / 128 (17.97%)
    7 / 50 (14.00%)
         occurrences all number
    31
    23
    7
    Paraesthesia oral
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Saliva altered
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    10 / 130 (7.69%)
    21 / 128 (16.41%)
    4 / 50 (8.00%)
         occurrences all number
    11
    24
    4
    Renal and urinary disorders
    Renal impairment
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 128 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Urinary retention
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Renal pain
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Hepatobiliary disorders
    Biliary colic
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Cold sweat
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Eczema
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Erythema
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    Haematidrosis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Hyperhidrosis
         subjects affected / exposed
    8 / 130 (6.15%)
    13 / 128 (10.16%)
    4 / 50 (8.00%)
         occurrences all number
    8
    13
    4
    Pruritus
         subjects affected / exposed
    8 / 130 (6.15%)
    11 / 128 (8.59%)
    0 / 50 (0.00%)
         occurrences all number
    9
    12
    0
    Rash
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    1
    1
    0
    Rash pruritic
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Skin irritation
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Urticaria
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Muscle spasms
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    1
    Myosclerosis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Osteoporosis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Pain in extremity
         subjects affected / exposed
    1 / 130 (0.77%)
    2 / 128 (1.56%)
    0 / 50 (0.00%)
         occurrences all number
    1
    2
    0
    Plantar fasciitis
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Spinal pain
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Tendon pain
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    4 / 130 (3.08%)
    5 / 128 (3.91%)
    0 / 50 (0.00%)
         occurrences all number
    5
    5
    0
    Fluid retention
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Exostosis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Flank pain
         subjects affected / exposed
    0 / 130 (0.00%)
    0 / 128 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 130 (0.77%)
    1 / 128 (0.78%)
    1 / 50 (2.00%)
         occurrences all number
    3
    1
    1
    Cystitis
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Furuncle
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    3 / 130 (2.31%)
    3 / 128 (2.34%)
    0 / 50 (0.00%)
         occurrences all number
    3
    3
    0
    Gastrointestinal infection
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0
    Influenza
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Nasopharyngitis
         subjects affected / exposed
    8 / 130 (6.15%)
    5 / 128 (3.91%)
    2 / 50 (4.00%)
         occurrences all number
    8
    5
    2
    Oral herpes
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Otitis media
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Pulpitis dental
         subjects affected / exposed
    2 / 130 (1.54%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory tract infection
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    0
    Tooth abscess
         subjects affected / exposed
    0 / 130 (0.00%)
    1 / 128 (0.78%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    0
    Urinary tract infection
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 130 (0.77%)
    0 / 128 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? No

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26095455
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