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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
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

KF5503/60

ISRCTN number

US NCT number

NCT01838616

WHO universal trial number (UTN)

Other trial identifiers

Grünenthal GmbH: 822818

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

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

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?

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

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Austria: 17

Country: Number of subjects enrolled

Germany: 202

Country: Number of subjects enrolled

Spain: 39

Worldwide total number of subjects

258

EEA total number of subjects

258

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

171

From 65 to 84 years

85 years and over

Subject disposition

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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.

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 title

Titration period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

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.

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
Consent withdrawn by subject	5	5
Adverse event, non-fatal	18	16
Not specified	2	-
Transferred to other arm/group	-	43
Lack of efficacy	5	1
Protocol deviation	-	1

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 title

Continuation Period

Is this the baseline period?

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

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).

Oxycodone/Naloxone Prolonged Release

Arm description

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).

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
Consent withdrawn by subject	-	4	1
Adverse event, non-fatal	8	1	9
Not specified	-	1	1
Transferred to other arm/group	-	7	-
Lost to follow-up	1	-	-
Lack of efficacy	3	1	4
Protocol deviation	2	-	-

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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Reporting group title

Tapentadol Prolonged Release

Reporting group description

Reporting group title

Oxycodone/Naloxone Prolonged Release

Reporting group description

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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Reporting group title

Tapentadol Prolonged Release

Reporting group description

Reporting group title

Oxycodone/Naloxone Prolonged Release

Reporting group description

Reporting group title

Tapentadol prolonged release

Reporting group description

Reporting group title

Oxycodone/Naloxone Prolonged Release

Reporting group description

Reporting group title

Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment

Reporting group description

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

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

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 )

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 )

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 )

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 )

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 )

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 )

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 )

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

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

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

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

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

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 )

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

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

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

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

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

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

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

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

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

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 )

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

Top of page

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 )

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

Top of page

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 )

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

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

Top of page

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

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

Top of page

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 )

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

Top of page

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 )

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)

Top of page

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 )

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

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

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

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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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 name

MedDRA

Dictionary version

16.1

Reporting group title

Tapentadol Prolonged Release FAS

Reporting group description

Reporting group title

Oxycodone/Naloxone Prolonged Release FAS

Reporting group description

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%)
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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
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

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Were there any global substantial amendments to the protocol? No

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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

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Clinical trials

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.

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secondary: Sleep evaluation: Overall quality of sleep last night

Secondary: Sleep evaluation: Overall quality of sleep last night

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

Online references

More information

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.