Comparison of Increasing Doses of Tapentadol Versus a Combination of Tapentadol and Pregabalin

• Sponsor: Grünenthal GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01352741
• Collaborator: (none)
• Enrollment: 622
• Locations: 59
• Arms: 2
• Duration (Months): 10.1
• Patients Per Site: 10.5
• Patients Per Site Per Month: 1

Study Details

Study Description

Brief Summary

The main objective of the study is to evaluate the effectiveness, safety, and tolerability of increasing doses of tapentadol prolonged release (PR) (500 mg per day) versus a combination of tapentadol PR (300 mg per day) and pregabalin (to 300 mg per day) in subjects requiring additional analgesia after titration to tapentadol PR 300 mg per day.

This is a clinical effectiveness trial designed to establish a link between anticipated clinical outcomes and the clinical practice by means of selected measures of clinical and subject reported outcomes. Since, severe low back pain with a neuropathic component, the targeted study population, is frequently treated with a combination therapy (monotherapy is often not effective enough) it is of interest to determine if tapentadol alone (combining 2 mechanisms of action in a single molecule) could be as effective as a combination of tapentadol plus pregabalin. Furthermore, the tolerability profiles of monotherapy versus combination are of interest.

Condition or Disease	Intervention/Treatment	Phase
Low Back Pain; Neuropathic Pain	Drug: Tapentadol Prolonged Release; Drug: Tapentadol Prolonged Release with Pregabalin; Drug: Tapentadol Prolonged Release open label maintenance	Phase 4

Detailed Description

Participants with a diagnosis of chronic low back pain (defined as pain lasting for at least 3 month) and requiring a strong analgesic (World Health Organization [WHO] Step III) as judged by the investigator and having a positive or unclear score using the painDETECT diagnostic screening questionnaire will enter the open-label titration tapentadol prolonged release (PR) period. In total participants will have 11 planned scheduled visits scheduled over 105 days. At the Enrollment Visit [Day -14 (3 to 14 days prior to the Baseline Visit)] the inclusion and exclusion criteria will be checked to evaluate the participant's eligibility for the trial. Participants on previous analgesics will start a washout period three days up to 2 weeks.The duration of the washout period will depend on previous opioid analgesics and co-analgesics and their respective doses, down-tapering steps. Participants who do not need a washout of previous analgesic treatment (e.g. WHO Step I analgesics), a baseline visit can be scheduled as soon as clinical laboratory monitoring results are available.

At the Baseline Visit (Day 1) participants will start the 3 week open-label titration period tapentadol prolonged release (PR) at doses of 2 x 50 mg per day and will be titrated upwards in steps of 100 mg (2 x 50 mg) on a weekly basis.

Participants who do not qualify for randomization may continue the trial in the open-label continuation arm if they have already reached a satisfactory level of pain relief.

Participants qualifying for randomization in the comparative period (Day 22 to 77) will be allocated to 1 of 2 treatment arms and will continue treatment.

Either they continue on tapentadol prolonged release (PR) with increasing doses of tapentadol PR

• After the randomization visit, participants will titrate up to a total daily dose of 400 mg.

• 1 week after the randomization visit, will titrate up to a total daily dose of 500 mg. Participants in this treatment arm will receive a final dose of 500 mg tapentadol PR per day.

Or start on a combination of tapentadol PR 300 mg per day with pregabalin

• After the randomization visit, participants will continue their previous regimen of tapentadol PR 2 x 150 mg per day plus pregabalin 2 x 75 mg (total daily dose of 150 mg pregabalin).

• 1 week after the randomization visit, participants will continue their previous regimen (end of titration period) of tapentadol PR 2 x 150 mg per day plus pregabalin 2 x 150 mg (total daily dose of 300 mg pregabalin). Participants in this treatment arm will receive a final dose of 300 mg tapentadol PR and 300 mg pregabalin.

Participants in the Comparative Period can be assigned to the open-label pick-up arm and will be treated with a stable dose of tapentadol PR 300 mg per day or 400 mg per day if they experience treatment emergent adverse events (at least possibly related to investigational medicinal product).The open-label pick-up period theoretically starts on Day 29, i.e. one week after the Randomization Visit.

The Final Evaluation (Day 77) is planned to take place 8 weeks after randomization.

After the Final Evaluation a Follow-up Period (blinded tapering down/out of IMP in Week 12 and Follow-up Visit (up to Day 91) will take place. Tapering down/out of medication will be performed according to the Summary of Product Characteristics.

Study Design

• Study Type: Interventional
• Actual Enrollment: 622 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Evaluation of the Effectiveness, Safety, and Tolerability of Tapentadol PR Versus a Combination of Tapentadol PR and Pregabalin in Subjects With Severe Chronic Low Back Pain With a Neuropathic Pain Component
• Study Start Date: Mar 1, 2011
• Actual Primary Completion Date: Jan 1, 2012
• Actual Study Completion Date: Jan 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tapentadol Prolonged Release Tapentadol Prolonged Release (100 - 500 mg per day) Oral administration twice daily	Drug: Tapentadol Prolonged Release; 100 - 500 mg per day orally twice daily for a maximum of 12 weeks; Drug: Tapentadol Prolonged Release open label maintenance; 100 - 400 mg per day Tapentadol Prolonged Release orally administered twice daily
Active Comparator: Tapentadol Prolonged Release with Pregabalin Tapentadol Prolonged Release (100 - 300 mg per day) with Pregabalin (150 - 300 mg per day) Both administered orally twice a day.	Drug: Tapentadol Prolonged Release with Pregabalin; Tapentadol Prolonged Release 100 - 300 mg per day with Pregabalin 150 - 300 mg per day orally twice daily for a maximum of 12 weeks; Drug: Tapentadol Prolonged Release open label maintenance; 100 - 400 mg per day Tapentadol Prolonged Release orally administered twice daily

Outcome Measures

Primary Outcome Measures

1. Change in the Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3) [Randomization (Day 22); Final Evaluation Visit (Day 77)]

   The primary endpoint is defined as the comparison of tapentadol prolonged release (PR) 300 mg plus 200 mg per day and the combination of tapentadol PR 300 mg per day and pregabalin 300 mg per day regarding the change in NRS-3 pain intensity scores (recalled average pain intensity score during the last 3 days on 11-point NRS, where 0 is the no pain and 10 is pain as bad as you can imagine) from the randomization visit to the final evaluation visit. Theoretically a maximum decrease of -10 and an increase of +4 in the pain intensity would have been possible. A negative sign indicates a decrease in pain intensity from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (Baseline visit).

Secondary Outcome Measures

1. Open-label Titration Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3) [Enrollment (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)]

   The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS). This scale recalls the average pain intensity during the last 3 days. The participant 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)". Where 0 = no pain and 10 indicates pain as bad as you can imagine. This is the treatment period prior to the primary outcome period.

2. Open-label Continuation Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3) [Enrollment (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)]

   The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS). This scale recalls the average pain intensity during the last 3 days. The participant 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)". Where 0 = no pain and 10 indicates pain as bad as you can imagine.

3. End of Open-label Pick-up Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3) [Final Evaluation Visit (Day 77)]

   The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS). This scale recalls the average pain intensity during the last 3 days. The participant 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)". Where 0 = no pain and 10 indicates pain as bad as you can imagine.

4. Open-label Titration Period: Radiating Pain [Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)]

   The NRS-3 pain intensity score at the visits in the open-label titration period for the two comparative double-blind period treatment groups analyzed is reported. NRS-3 pain intensity score (recalled average pain intensity score during the last 3 days on an 11-point NRS) for radiating pain (pain radiating into or towards the leg, typically of shooting, radiating character, usually radiating below the knee towards the foot) is reported. Where 0 = no pain and 10 indicates pain as bad as you can imagine.

5. Open-label Titration Period: Radiating Mean Pain Intensity Score for the Comparative Period Population [Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)]

   The NRS-3 pain intensity score at the visits in the open-label titration period for the two comparative double-blind period treatment groups analyzed is reported. NRS-3 pain intensity score (recalled average pain intensity score during the last 3 days on an 11-point NRS) for radiating pain (pain radiating into or towards the leg, typically of shooting, radiating character, usually radiating below the knee towards the foot) is reported. Where 0 = no pain and 10 indicates pain as bad as you can imagine.

6. Double-blind Comparative Period: Change in NRS-3 Pain Intensity Score for the Radiating Pain [Randomization Visit (Day 22); End of Evaluation Visit (Day 77)]

   NRS-3 pain intensity score (recalled average pain intensity score during the last 3 days on 11-point NRS, where 0 is the no pain and 10 is pain as bad as you can imagine) for radiating pain (pain radiating into or towards the leg, typically of shooting, radiating character, usually radiating below the knee towards the foot). The value reported represents the change from the randomization visit (i.e., the last 3 days in the titration period) to the end of the double-blind comparative period (i.e., the last 3 days in the comparative period). 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).

7. Open-label Titration Period: Worst Mean Pain Intensity Scores Over the Past 24 Hours [Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)]

   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".

8. Open-label Titration Period: Comparative Double-blind Period Population Worst Mean Pain Intensity Scores Over the Past 24 Hours [Enrollment Visit (Day-12); Baseline Visit (day 1); Randomization Visit (Day 22)]

   The recalled worst pain intensity during the last 24 hours was assessed using an 11-point Numeric Rating Scale (NRS), 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 past 24 hours prior to the visit".

9. Double-blind Comparative Period: Change in Worst Pain Intensity Over the Past 24 Hours [Randomization Visit (Day 22); Final Evaluation Visit (Day 77)]

   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". A negative change indicates that the pain intensity decreased from the start of the trial.

10. Open-label Titration Period: painDETECT Assessments [Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    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".

11. Open-label Titration Period: Comparative Double-blind Period Population painDETECT Assessment [Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    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".

12. Double-blind Comparative Period: Change in painDETECT Final Assessment [Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)]

    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". The theoretical range of change in this trial ranged from -38 to 19. A negative change indicated a decrease in their neuropathic component of pain.

13. Open-label Titration Period: Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment [Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)]

    In the Neuropathic Pain Symptom Inventory (NPSI) the participant 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 100. 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 participants that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all participants and all participants rated it at its worst possible intensity if a value is 100.

14. Open-label Titration Period: Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment in the Double-blind Comparative Period Population [Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)]

    In the Neuropathic Pain Symptom Inventory (NPSI) the participant 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 100. 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 participants that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all participants and all participants rated it at its worst possible intensity if a value is 100.

15. Double-blind Comparative Period: Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment [Randomization Visit (Day 22); Final Evaluation Visit (Day 77)]

    In the Neuropathic Pain Symptom Inventory (NPSI) the participant 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. Spontaneous Pressing Pain Subscore). The overall NPSI score was calculated by the summation of all ten responses and ranges between 0 and 100. 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) subscores are reported. The overall values reported for all participants that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all participants and all participants rated it at its worst possible intensity if a value is 10 (100 for the overall score) . A negative change indicates that the intensity of the symptom has decreased since the start of treatment.

16. Open-label Titration Period: Comparative Double-blind Period Population Short Form Health Survey (SF-12) Physical Health Composite Score (PCS) [Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)]

    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 participant 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.

17. Double-blind Comparative Period: Changes in the Short Form Health Survey (SF-12) Physical Health Composite Score (PCS) [Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)]

    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 participant was asked to score over the last week. The physical summary scores were calculated from the individual responses to those questions covering physical health. A higher score indicates a better participant 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.

18. Open-label Titration Period: Comparative Double-blind Period Population Short Form Health Survey (SF-12) Mental Health Composite Score (MCS) [Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)]

    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 participant was asked to score over the last week. The mental health summary scores were calculated from the individual responses to two of the 12 questions. A higher score indicates a better participant 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 mental health.

19. Double-blind Comparative Period: Change in Short Form Health Survey (SF-12) Mental Health Composite Score (MCS) [Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)]

    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 participant was asked to score over the last week. The mental health summary scores were calculated from the individual responses to two of the 12 questions. A higher score indicates a better participant 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 mental health.

20. Open-label Titration Period: EuroQol-5 Dimension (EQ-5D) Health Status Index Score for the Double-blind Comparative Period Population [Enrollment Visit (day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    The participant 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.

21. Double-blind Comparative Period: Change EuroQol-5 Dimension (EQ-5D) Health Status Index [Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    The participant 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.

22. Double-blind Comparative Period: Patient Global Impression of Change (PGIC) [Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)]

    In the Patient Global Impression of Change (PGIC) the participant indicated the perceived change over the treatment period. PGIC is a 7 point scale where the patient's rates overall improvement. Patients rate their change as "very much improved," "much improved," "minimally improved," "no change," "minimally worse," "much worse," or "very much worse."

23. Double-blind Comparative Period: Clinician Global Impression of Change (CGIC) [Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)]

    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 participant. The Clinician rated the participants change as "very much improved," "much improved," "minimally improved," "no change," "minimally worse," "much worse," or "very much worse."

24. Open-label Titration Period: Hospital Anxiety and Depression Scale - Anxiety in the Double-blind Comparative Period Population [Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    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 decrease in values over the trial period indicate that there has been an improvement.

25. Double-blind Comparative Period: Change in Hospital Anxiety and Depression Scale - Anxiety in the Double-blind Comparative Period Population [Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)]

    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.

26. Open-label Titration Period: Hospital Anxiety and Depression Scale - Depression in the Double-blind Comparative Period Population [Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    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.

27. Double-blind Comparative Period: Change in Hospital Anxiety and Depression Scale - Depression in the Double-blind Comparative Period Population [Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)]

    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.

28. Open-label Titration Period: Sleep Evaluation Questionnaire - Latency [Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the sleep latency. To assess latency the participant was asked: How long after bedtime/lights out did you fall asleep last night [hours]?

29. Open-label Titration Period: Sleep Evaluation Questionnaire - Latency in the Double-blind Comparative Period Population [Enrollment Visit (Day -12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    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 Randomization Visit (Baseline) and for the night prior to the Final Evaluation Visit (12 weeks after randomization). The higher the value the longer it took to fall asleep. Sleep evaluation questionnaire (SQ) items

30. Double-blind Comparative Period Sleep Evaluation Questionnaire: Change in Latency [Baseline Visit (Day 1); Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)]

    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.

31. Open-label Titration Period: Sleep Evaluation Questionnaire - Number of Awakenings [Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. How many times did you wake up during the night? The values were calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline), for the night prior to the Baseline Visit (Day 1) and the night prior to the Randomization Visit (Day 22). The participant was asked at each visit: "How many times did you wake up during the night?"

32. Open-label Titration Period: Sleep Evaluation - Number of Awakenings in the Double-blind Comparative Period Population [Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. How many times did you wake up during the night? The values were calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline), for the night prior to the Baseline Visit (Day 1) and the night prior to the Randomization Visit (Day 22). The participant was asked at each visit: "How many times did you wake up during the night?"

33. Double-blind Comparative Period: Change in the Number of Awakenings [Baseline Visit (Day 1); Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)]

    The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. Participants were asked: How many times did you wake up during the night? The change in the Number of Awakenings was calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline), for the night prior to the Baseline Visit (Day 1) and the night prior to the Final Evaluation Visit (Day 77). A negative change indicates that the number of awakenings in a treatment group have gone down since the Baseline or Randomization Visit. In general pain can interfere with sleep, one potential indicator is the number of awakenings.

34. Open-label Titration Period: Sleep Evaluation Questionnaire - Time Slept [Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. The participant was asked: "How long did you sleep last night?" [Answered in hours and minutes].

35. Open-label Titration Period: Sleep Evaluation Questionnaire - Number of Hours Slept in the Double-blind Comparative Period Population [Enrollment Visit (Day -12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    The participants were requested to answer the following question: How long did you sleep last night [hours]? The values were calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline) and for the night prior to the End of the Continuation Visit (12 weeks after randomization).

36. Double-blind Comparative Period: Sleep Evaluation Questionnaire - Change in the Number of Hours Slept [Baseline Visit (Day -12); Randomization Visit (Day 1); Final Evaluation Visit (Day 77)]

    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.

37. Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep [Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)]

    The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The participant rated this categorically as being one of the following: excellent, good, fair or poor.

38. Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep in the Double-blind Comparative Period Population [Enrollment Visit (Day-12)]

    The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The participant rated this categorically as being one of the following: excellent, good, fair or poor.

39. Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep in the Double-blind Comparative Period Population [Baseline Visit (Day 1)]

    The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The participant rated this categorically as being one of the following: excellent, good, fair or poor.

40. Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep in the Double-blind Comparative Period Population [Randomization Visit (Day 22)]

    The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The participant rated this categorically as being one of the following: excellent, good, fair or poor.

41. Double-blind Comparative Period: Change in the Overall Quality of Sleep [Randomization Visit (Day 22) to Final Evaluation (Day 77)]

    The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The improvement, no change or worsening is reported based on the replies scored by the participants given at their End of Continuation Visit.

42. Open-label Titration Period: Subject's Satisfaction With Treatment [End of Open-label Titration Period at Randomization Visit (Day 22)]

    Participants rated their satisfaction with the study drug (IMPs) by answering the following question on a 5-point rating scale: "How would you rate your overall satisfaction with your current pain treatment?": Excellent, Very Good, Good, Fair and Poor.

43. Double-blind Comparative Period: Subject's Satisfaction With Treatment [End of Comparative Period at Final Evaluation Visit (Day 77)]

    Participants rated their satisfaction with the study drug (IMPs) by answering the following question on a 5-point rating scale: "How would you rate your overall satisfaction with your current pain treatment?": Excellent, Very Good, Good, Fair and Poor.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects must have a diagnosis of chronic low back pain; chronic pain defined as pain lasting for at least 3 months.

• Subject's pain must require a strong analgesic (defined as World Health Organization (WHO) step III) as judged by the investigator.

• The painDETECT diagnostic screening questionnaire score must be:

• "positive" or

• "unclear".or If the subject is being treated with a stable regimen of centrally acting analgesics (opioids) and/or co-analgesics, even a "negative" painDETECT score (but of at least 9) at the enrollment visit will be acceptable.

• If under regular daily pretreatment with a WHO step II/step III opioid analgesic and/or a centrally acting co-analgesic:

• Subjects must be taking a WHO step II or step III analgesic or co- analgesic on a daily basis for at least 2 weeks prior to the enrollment visit.

• Subjects pretreated with a WHO step II opioid analgesic and/or a centrally acting co-analgesic must have reported an average pain intensity score of at least 5 points (NRS-3≥5) during the last 3 days prior to the enrollment visit. or If under regular, daily pretreatment with a WHO step I analgesic monotherapy or if no regular analgesic pretreatment is reported:

• Subjects must have an average pain intensity score of at least 6 points NRS-3≥6) in the last 3 days prior to the enrollment visit.

Exclusion Criteria:

• Presence of concomitant painful conditions other than low back pain that could confound the subject's trial assessments or self-evaluation of the index pain, e.g., syndromes with widespread pain such as fibromyalgia.

• Low back pain caused by cancer and/or metastatic diseases.

• Any painful procedures planned during the trial period (e.g., major surgery) that may, in the opinion of the investigator, affect the effectiveness or safety assessments of the Investigational Medicinal Product (IMP).

• Pending litigation or application for insurance/governmental benefits due to chronic pain or disability and, if granted, benefits might be influenced by a successful participation in the trial.

• Rare hereditary problems of galactose intolerance, Lapp lactase deficiency, or glucose-galactose malabsorption, lactose intolerance.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 506	Klagenfurt		Austria
2	Site 503	Senftenberg		Austria
3	Site 501	Wien		Austria
4	Site 502	Wien		Austria
5	Site 504	Wien		Austria
6	Site 505	Wien		Austria
7	Site 605	Dour		Belgium
8	Site 602	Genk		Belgium
9	Site 603	Gozee		Belgium
10	Site 604	Ham		Belgium
11	Site 601	Pellenberg		Belgium
12	Site 702	Copenhagen		Denmark
13	Site 704	Frederiksberg		Denmark
14	Site 701	Glostrup		Denmark
15	Site 703	Ringsted		Denmark
16	DE 118	Berlin		Germany	10787
17	Site 107	Berlin		Germany
18	Site 111	Böhlen		Germany
19	Site 115	Cottbus		Germany
20	Site 103	Hamburg		Germany
21	Site 110	Hamburg		Germany
22	Site 101	Kiel		Germany
23	Site 114	Kiel		Germany
24	Site 105	Köln		Germany
25	Site 116	Köln		Germany
26	Site 113	Leipzig		Germany
27	Site 109	Lübeck		Germany
28	Site 106	Rendsburg		Germany
29	Site 108	Schönau		Germany
30	Site 117	Weimar		Germany
31	Site 112	Westerstede		Germany
32	Site 104	Wiesbaden		Germany
33	Site 803	Amsterdam		Netherlands
34	Site 804	Eindhoven		Netherlands
35	Site 805	Enschede		Netherlands
36	Site 802	Heerenveen		Netherlands
37	Site 801	Sliedrecht		Netherlands
38	Site 309	Bydgoszcz		Poland
39	Site 312	Gdansk		Poland
40	Site 303	Katowice		Poland
41	Site 308	Krakow		Poland
42	Site 310	Krakow		Poland
43	Site 311	Krakow		Poland
44	Site 307	Lublin		Poland
45	Site 306	Ostrów Mazowiecka		Poland
46	Site 304	Poznan		Poland
47	Site 301	Warsaw		Poland
48	Site 302	Warszawa		Poland
49	Site 305	Wroclaw		Poland
50	Site 904	A Coruna		Spain
51	Site 908	Alicante		Spain
52	Site 901	Badalona		Spain
53	Site 905	Barcelona		Spain
54	Site 902	Centelles		Spain
55	Site 907	Granada		Spain
56	Site 909	Madrid		Spain
57	Site 910	Madrid		Spain
58	Site 903	Oviedo		Spain
59	Site 911	Valencia		Spain

Sponsors and Collaborators

• Grünenthal GmbH

Investigators

• Principal Investigator: Ralf Baron, Prof. Dr., Neurological pain research and therapy Clinic for Neurology Campus Kiel, University Clinic Schleswig-Holstein, Schittenhelmstr. 10, 24105 Kiel, Germany

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Grünenthal GmbH
• ClinicalTrials.gov Identifier: NCT01352741
• Other Study ID Numbers: 247251; 2010-019998-14; KF5503/58
• First Posted: May 12, 2011
• Last Update Posted: Oct 28, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Grünenthal GmbH: low back pain; neuropathic; pain assessment; centrally acting tapentadol pregabalin; severe chronic
• Additional relevant MeSH terms: Neuralgia; Back Pain; Low Back Pain; Pregabalin; Tapentadol

Study Results

Participant Flow

Recruitment Details	The trial started on 23 Mar 2011 and the last participant completed the last follow-up examination on the 17 Jan 2012.
Pre-assignment Detail	622 participants signed an informed consent. All participants included in the 8 week Double Blind Comparative Period were initially in the open-label titration period. Participants in the open-label tapentadol continuation period were in the open-label titration period but did not enter the comparative period.

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	All participants entered the 3-week Titration Period, Tapentadol Prolonged Release was administered in an open-label fashion. Participants that did not qualify for entry into the Comparative Period were able to enter the open-label Continuation Period. During the double-blind comparator phase the dose was increased to 200 mg twice daily and after a week to 250 mg twice daily. Participants that dropped out due to tolerability issues during the comparative period were able to enter the open-label pick-up arm.	At the end of the Open-label Tapentadol Titration Period participants that qualified were randomized to either tapentadol or tapentadol and pregabalin treatment. In this double-blind period participants started on Tapentadol Prolonged Release 300 mg per day (2 x 150 mg) plus Pregabalin 2 x 75 mg (total daily dose of 150 mg). A week later the dose of Pregabalin was increased to a total daily dose of 300 mg per day (2 x 150 mg), the Tapentadol Prolonged Release dose remained at 300 mg per day.
Period Title: Open-label Tapentadol Titration Period
STARTED	445	0
Switched to Open-label Continuation Arm	59	0
Full Analysis Set	436	0
COMPLETED	372	0
NOT COMPLETED	73	0
Period Title: Open-label Tapentadol Titration Period
STARTED	154	159
Switched to Open-label Pick-up Arm	19	18
No Pain Assessments Available	2	2
Full Analysis Set	152	157
Major Protocol Deviations	13	8
Per Protocol Set	139	149
painDetect Per Protocol Set	109	127
SF-12 Per Protocol Set	131	143
EQ-5D Per Protocol Set	131	143
HADS Per Protocol Set (PPS)	123	137
Sleep Evaluation (Latency) PPS	123	137
Sleep Evaluations (Awakenings) PPS	123	137
Sleep Evaluations (Hours Slept) PPS	123	137
COMPLETED	126	133
NOT COMPLETED	28	26
Period Title: Open-label Tapentadol Titration Period
STARTED	59	0
Major Protocol Deviation	2	0
Full Analysis Set	57	0
COMPLETED	51	0
NOT COMPLETED	8	0
Period Title: Open-label Tapentadol Titration Period
STARTED	37	0
COMPLETED	37	0
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Trial Participants
Arm/Group Description	All participants that received at least one dose of tapentadol prolonged release at baseline, in the open-label titration period.
Overall Participants	445
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.9 (11.30)
Sex: Female, Male (Count of Participants)
Female	262 58.9%
Male	183 41.1%
Race/Ethnicity, Customized (participants) [Number]
White	441 99.1%
Asian	2 0.4%
Other	2 0.4%
Region of Enrollment (participants) [Number]
Spain	54 12.1%
Belgium	45 10.1%
Poland	102 22.9%
Denmark	41 9.2%
Austria	55 12.4%
Netherlands	26 5.8%
Germany	122 27.4%
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	168.2 (9.97)
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	83.61 (17.542)
Body Mass Index (BMI) (kg/m²) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m²]	29.57 (5.616)
Diagnosis of Lumbar Radiculopathy (participants) [Number]
Yes	310 69.7%
No	134 30.1%
Missing	1 0.2%
History of low back pain (years) [Median (Full Range) ]
Median (Full Range) [years]	6.3
Subject's satisfaction with previous treatment (participants) [Number]
Poor	126 28.3%
Fair	233 52.4%
Good	68 15.3%
Very Good	10 2.2%
Excellent	1 0.2%
Missing	7 1.6%

Outcome Measures

1. Primary Outcome

Title	Change in the Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)
Description	The primary endpoint is defined as the comparison of tapentadol prolonged release (PR) 300 mg plus 200 mg per day and the combination of tapentadol PR 300 mg per day and pregabalin 300 mg per day regarding the change in NRS-3 pain intensity scores (recalled average pain intensity score during the last 3 days on 11-point NRS, where 0 is the no pain and 10 is pain as bad as you can imagine) from the randomization visit to the final evaluation visit. Theoretically a maximum decrease of -10 and an increase of +4 in the pain intensity would have been possible. A negative sign indicates a decrease in pain intensity from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (Baseline visit).
Time Frame	Randomization (Day 22); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Mean (Standard Deviation) [units on a scale]	-1.6 (2.52)	-1.7 (2.48)

2. Secondary Outcome

Title	Open-label Titration Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)
Description	The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS). This scale recalls the average pain intensity during the last 3 days. The participant 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)". Where 0 = no pain and 10 indicates pain as bad as you can imagine. This is the treatment period prior to the primary outcome period.
Time Frame	Enrollment (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Observed values.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily. Tapentadol PR was administered in an open-label fashion during the 3-week titration period. All participants started at 2 x 50 mg (100 mg per day) after the baseline visit and titrated upwards on a weekly basis by 2 x 50 mg. Dose adjustment could have taken place after 3 days on a stable dose if the participant's pain required faster titration.
Measure Participants	445
Enrollment Visit (N=438)	7.2 (1.21)
Baseline Visit (N=440)	8.3 (1.14)
Randomization Visit (N=377)	5.4 (1.83)

3. Secondary Outcome

Title	Open-label Continuation Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)
Description	The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS). This scale recalls the average pain intensity during the last 3 days. The participant 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)". Where 0 = no pain and 10 indicates pain as bad as you can imagine.
Time Frame	Enrollment (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Observed values.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	Participants that did not qualify for randomization to the Comparator Period, continued on a stable dose of Tapentadol Prolonged Release 300 mg per day, if they had reached a satisfactory level of pain relief.
Measure Participants	59
Enrollment Visit (N=56)	7.3 (1.30)
Baseline Visit (N=57)	7.9 (1.23)
Randomization Visit (N=57)	2.6 (1.27)
Final Evaluation Visit (N=59)	2.6 (2.09)

4. Secondary Outcome

Title	End of Open-label Pick-up Period: Average Pain Intensity Score for the Overall Low Back Pain on an 11-point Numeric Rating Scale (NRS-3)
Description	The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS). This scale recalls the average pain intensity during the last 3 days. The participant 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)". Where 0 = no pain and 10 indicates pain as bad as you can imagine.
Time Frame	Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Observed.

Arm/Group Title	Tapentadol Prolonged Release After Tapentadol	Tapentadol Prolonged Release After Tapentadol and Pregabalin
Arm/Group Description	Participants that drop-out of the double-blind tapentadol prolonged release treatment in the Comparative Period, due to tolerability issues, continued on Tapentadol Prolonged Release at either 300 mg per day or 400 mg per day in this Open-Label Pick-up arm.	Participants that dropped-out of the Tapentadol Prolonged Release and Pregabalin in the double-blind Comparative Period continued with Tapentadol Prolonged Release at either 300 or 400 mg per day in this Open-Label Pick-up arm.
Measure Participants	19	18
Mean (Standard Deviation) [units on a scale]	4.4 (2.83)	4.5 (1.96)

5. Secondary Outcome

Title	Open-label Titration Period: Radiating Pain
Description	The NRS-3 pain intensity score at the visits in the open-label titration period for the two comparative double-blind period treatment groups analyzed is reported. NRS-3 pain intensity score (recalled average pain intensity score during the last 3 days on an 11-point NRS) for radiating pain (pain radiating into or towards the leg, typically of shooting, radiating character, usually radiating below the knee towards the foot) is reported. Where 0 = no pain and 10 indicates pain as bad as you can imagine.
Time Frame	Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Observed.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily. Tapentadol PR was administered in an open-label fashion during the 3-week titration period. All participants started at 2 x 50 mg (100 mg per day) after the baseline visit and titrated upwards on a weekly basis by 2 x 50 mg. Dose adjustment could have taken place after 3 days on a stable dose if the participant's pain required faster titration
Measure Participants	445
Enrollment Visit (N=438)	7.0 (1.64)
Baseline Visit (N=440)	8.0 (1.60)
Randomization Visit (N=377)	5.3 (2.16)

6. Secondary Outcome

Title	Open-label Titration Period: Radiating Mean Pain Intensity Score for the Comparative Period Population
Description	The NRS-3 pain intensity score at the visits in the open-label titration period for the two comparative double-blind period treatment groups analyzed is reported. NRS-3 pain intensity score (recalled average pain intensity score during the last 3 days on an 11-point NRS) for radiating pain (pain radiating into or towards the leg, typically of shooting, radiating character, usually radiating below the knee towards the foot) is reported. Where 0 = no pain and 10 indicates pain as bad as you can imagine.
Time Frame	Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138; N=149)	7.1 (1.75)	6.9 (1.49)
Baseline Visit (N=139; N=149)	8.1 (1.84)	8.1 (1.37)
Randomization Visit (N=139; N=149)	5.6 (1.87)	5.7 (1.86)

7. Secondary Outcome

Title	Double-blind Comparative Period: Change in NRS-3 Pain Intensity Score for the Radiating Pain
Description	NRS-3 pain intensity score (recalled average pain intensity score during the last 3 days on 11-point NRS, where 0 is the no pain and 10 is pain as bad as you can imagine) for radiating pain (pain radiating into or towards the leg, typically of shooting, radiating character, usually radiating below the knee towards the foot). The value reported represents the change from the randomization visit (i.e., the last 3 days in the titration period) to the end of the double-blind comparative period (i.e., the last 3 days in the comparative period). 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).
Time Frame	Randomization Visit (Day 22); End of Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-blind comparative population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Mean (Standard Deviation) [units on a scale]	-1.5 (2.61)	-1.9 (2.60)

8. Secondary Outcome

Title	Open-label Titration Period: Worst Mean Pain Intensity Scores Over the Past 24 Hours
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 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".
Time Frame	Enrollment Visit (Day -14); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Observed.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily. Tapentadol PR was administered in an open-label fashion during the 3-week titration period. All participants started at 2 x 50 mg (100 mg per day) after the baseline visit and titrated upwards on a weekly basis by 2 x 50 mg. Dose adjustment could have taken place after 3 days on a stable dose if the participant's pain required faster titration.
Measure Participants	445
Enrollment Visit (N=438)	7.6 (1.32)
Baseline Visit (N=440)	8.5 (1.11)
Randomization Visit (N=377)	5.8 (1.98)

9. Secondary Outcome

Title	Open-label Titration Period: Comparative Double-blind Period Population Worst Mean Pain Intensity Scores Over the Past 24 Hours
Description	The recalled worst pain intensity during the last 24 hours was assessed using an 11-point Numeric Rating Scale (NRS), 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 past 24 hours prior to the visit".
Time Frame	Enrollment Visit (Day-12); Baseline Visit (day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-blind comparative population. Per Protocol Set (PPS)

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138; N=149)	7.8 (1.21)	7.5 (1.27)
Baseline Visit (N=139; N=149)	8.5 (1.07)	8.7 (0.97)
Randomization Visit (N=139; N=149)	6.3 (1.52)	6.4 (1.4)

10. Secondary Outcome

Title	Double-blind Comparative Period: Change in Worst Pain Intensity Over the Past 24 Hours
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 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". A negative change indicates that the pain intensity decreased from the start of the trial.
Time Frame	Randomization Visit (Day 22); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-blind comparative population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Mean (Standard Deviation) [units on a scale]	-1.7 (2.67)	-1.8 (2.58)

11. Secondary Outcome

Title	Open-label Titration Period: painDETECT Assessments
Description	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".
Time Frame	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Observed.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily. Tapentadol PR was administered in an open-label fashion during the 3-week titration period. All participants started at 2 x 50 mg (100 mg per day) after the baseline visit and titrated upwards on a weekly basis by 2 x 50 mg. Dose adjustment could have taken place after 3 days on a stable dose if the participant's pain required faster titration.
Measure Participants	445
Enrollment Visit (N=438)	21.4 (5.46)
Baseline Visit (N=440)	22.7 (5.74)
Randomization Visit (N=377)	16.9 (6.57)

12. Secondary Outcome

Title	Open-label Titration Period: Comparative Double-blind Period Population painDETECT Assessment
Description	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".
Time Frame	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-blind comparative population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138; N=149)	21.6 (5.23)	21.7 (5.17)
Baseline Visit (N=139; N=149)	22.4 (5.21)	23.8 (5.51)
Randomization Visit (N=138; N=149)	17.6 (5.93)	18.4 (5.90)

13. Secondary Outcome

Title	Double-blind Comparative Period: Change in painDETECT Final Assessment
Description	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". The theoretical range of change in this trial ranged from -38 to 19. A negative change indicated a decrease in their neuropathic component of pain.
Time Frame	Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-blind comparative population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	109	127
Change from Baseline	-10.2 (8.57)	-11.0 (7.73)
Change from Randomization	-6.0 (8.99)	-5.9 (7.22)

14. Secondary Outcome

Title	Open-label Titration Period: Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment
Description	In the Neuropathic Pain Symptom Inventory (NPSI) the participant 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 100. 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 participants that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all participants and all participants rated it at its worst possible intensity if a value is 100.
Time Frame	Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Observed.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily. Tapentadol PR was administered in an open-label fashion during the 3-week titration period. All participants started at 2 x 50 mg (100 mg per day) after the baseline visit and titrated upwards on a weekly basis by 2 x 50 mg. Dose adjustment could have taken place after 3 days on a stable dose if the participant's pain required faster titration.
Measure Participants	445
Overall Score Enrollment Visit (N=438)	55.2 (16.86)
Overall Score Baseline Visit (N=440)	62.7 (18.41)
Overall Score Randomization Visit (N=377)	42.0 (20.29)

15. Secondary Outcome

Title	Open-label Titration Period: Neuropathic Pain Symptom Inventory (NPSI) Overall Score Assessment in the Double-blind Comparative Period Population
Description	In the Neuropathic Pain Symptom Inventory (NPSI) the participant 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 100. 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 participants that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all participants and all participants rated it at its worst possible intensity if a value is 100.
Time Frame	Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-blind comparative population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Overall Score Enrollment Visit (N=138, N=149)	54.8 (15.12)	57.6 (16.07)
Overall Score Baseline Visit (N=139, N=149)	62.8 (17.13)	65.4 (18.29)
Overall Score Randomization Visit (N=139, N=149)	45.2 (17.99)	46.5 (18.57)
Overall Score Final Evaluation Visit(N=131, N=143)	28.9 (21.78)	30.5 (22.38)

16. Secondary Outcome

Title	Double-blind Comparative Period: Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment
Description	In the Neuropathic Pain Symptom Inventory (NPSI) the participant 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. Spontaneous Pressing Pain Subscore). The overall NPSI score was calculated by the summation of all ten responses and ranges between 0 and 100. 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) subscores are reported. The overall values reported for all participants that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all participants and all participants rated it at its worst possible intensity if a value is 10 (100 for the overall score) . A negative change indicates that the intensity of the symptom has decreased since the start of treatment.
Time Frame	Randomization Visit (Day 22); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-blind comparative population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	131	143
Overall Score	-16.8 (18.95)	-16.6 (20.04)
Subscore: Superficial Spontaneous Burning	-1.9 (2.75)	-2.3 (2.65)
Subscore: Deep Sponatenous Pressing Pain	-1.4 (2.26)	-1.4 (2.58)
Subscore: Paroxysmal Pain	-2.0 (2.39)	-1.6 (2.44)
Subscore: Evoked Pain	-1.8 (2.28)	-1.7 (2.32)
Subscore: Parasthesia/Dysesthesia	-1.4 (2.44)	-1.5 (2.49)

17. Secondary Outcome

Title	Open-label Titration Period: Comparative Double-blind Period Population Short Form Health Survey (SF-12) Physical Health Composite Score (PCS)
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 participant 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.
Time Frame	Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138; N=149)	29.9 (8.55)	29.8 (7.56)
Baseline Visit (N=139; N=149)	28.2 (8.17)	28.5 (7.68)
Randomization Visit (N=139; N=149)	34.1 (9.36)	34.1 (8.45)

18. Secondary Outcome

Title	Double-blind Comparative Period: Changes in the Short Form Health Survey (SF-12) Physical Health Composite Score (PCS)
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 participant was asked to score over the last week. The physical summary scores were calculated from the individual responses to those questions covering physical health. A higher score indicates a better participant 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.
Time Frame	Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	131	143
Change from Baseline Visit	12.3 (12.98)	11.1 (11.36)
Change from Randomization Visit	6.2 (13.04)	5.6 (10.88)

19. Secondary Outcome

Title	Open-label Titration Period: Comparative Double-blind Period Population Short Form Health Survey (SF-12) Mental Health Composite Score (MCS)
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 participant was asked to score over the last week. The mental health summary scores were calculated from the individual responses to two of the 12 questions. A higher score indicates a better participant 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 mental health.
Time Frame	Enrollment Visit; Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138; N=149)	46.1 (11.84)	44.8 (12.24)
Baseline Visit (N=139; N=149)	45.4 (12.43)	43.2 (13.32)
Randomization Visit (N=139; N=149)	49.2 (11.64)	47.3 (11.80)

20. Secondary Outcome

Title	Double-blind Comparative Period: Change in Short Form Health Survey (SF-12) Mental Health Composite Score (MCS)
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 participant was asked to score over the last week. The mental health summary scores were calculated from the individual responses to two of the 12 questions. A higher score indicates a better participant 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 mental health.
Time Frame	Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	131	143
Change from Baseline Visit (N=131; N=143)	3.9 (10.59)	6.5 (11.62)
Change from Randomization Visit (N=131; N=143)	0.1 (8.42)	2.5 (9.77)

21. Secondary Outcome

Title	Open-label Titration Period: EuroQol-5 Dimension (EQ-5D) Health Status Index Score for the Double-blind Comparative Period Population
Description	The participant 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.
Time Frame	Enrollment Visit (day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138; N=149)	0.32 (0.304)	0.33 (0.313)
Baseline Visit (N=139; N=149)	0.29 (0.306)	0.18 (0.316)
Randomization Visit (N=139; N=149)	0.55 (0.254)	0.52 (0.237)

22. Secondary Outcome

Title	Double-blind Comparative Period: Change EuroQol-5 Dimension (EQ-5D) Health Status Index
Description	The participant 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.
Time Frame	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	131	143
Change from Baseline Visit	0.34 (0.358)	0.43 (0.386)
Change from Randomization Visit	0.09 (0.317)	0.09 (0.254)

23. Secondary Outcome

Title	Double-blind Comparative Period: Patient Global Impression of Change (PGIC)
Description	In the Patient Global Impression of Change (PGIC) the participant indicated the perceived change over the treatment period. PGIC is a 7 point scale where the patient's rates overall improvement. Patients rate their change as "very much improved," "much improved," "minimally improved," "no change," "minimally worse," "much worse," or "very much worse."
Time Frame	Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-blind comparative population. Full Analysis Set (FAS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	152	157
Very much improved	28 6.3%	32 NaN
Much improved	44 9.9%	66 NaN
Minimally improved	51 11.5%	31 NaN
No change	10 2.2%	10 NaN
Minimally worse	5 1.1%	5 NaN
Much worse	4 0.9%	5 NaN
Very much worse	0 0%	1 NaN
Missing	10 2.2%	7 NaN

24. Secondary Outcome

Title	Double-blind Comparative Period: Clinician Global Impression of Change (CGIC)
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 participant. The Clinician rated the participants change as "very much improved," "much improved," "minimally improved," "no change," "minimally worse," "much worse," or "very much worse."
Time Frame	Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Full Analysis Set (FAS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	142	150
Very much improved	26 5.8%	30 NaN
Much improved	54 12.1%	82 NaN
Minimally improved	46 10.3%	19 NaN
No change	8 1.8%	10 NaN
Minimally worse	3 0.7%	2 NaN
Much worse	5 1.1%	5 NaN
Very much worse	0 0%	2 NaN
Missing	10 2.2%	7 NaN

25. Secondary Outcome

Title	Open-label Titration Period: Hospital Anxiety and Depression Scale - Anxiety in the Double-blind Comparative Period Population
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 decrease in values over the trial period indicate that there has been an improvement.
Time Frame	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138; N=149)	7.4 (4.51)	8.6 (4.94)
Baseline Visit (N=139; N=149)	7.7 (4.52)	9.0 (5.15)
Randomization Visit (N=139; N=149)	5.8 (3.77)	7.1 (4.39)

26. Secondary Outcome

Title	Double-blind Comparative Period: Change in Hospital Anxiety and Depression Scale - Anxiety in the Double-blind Comparative Period Population
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.
Time Frame	Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	123	137
Change from Baseline Visit	-2.2 (3.70)	-3.1 (4.28)
Change from Randomization Visit	-0.3 (2.93)	-1.2 (3.38)

27. Secondary Outcome

Title	Open-label Titration Period: Hospital Anxiety and Depression Scale - Depression in the Double-blind Comparative Period Population
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.
Time Frame	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-blind Comparative Population; Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138; N=149)	6.9 (4.18)	7.8 (4.43)
Baseline Visit (N=139; N=149)	7.6 (4.66)	8.6 (4.81)
Randomization Visit (N=139; N=149)	6.0 (3.96)	6.8 (4.24)

28. Secondary Outcome

Title	Double-blind Comparative Period: Change in Hospital Anxiety and Depression Scale - Depression in the Double-blind Comparative Period Population
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.
Time Frame	Baseline Visit (Day 1); Randomization Visit (Day 22); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	123	137
Change from Baseline Visit	-2.0 (3.56)	-3.1 (3.99)
Change from Randomization Visit	-0.4 (3.06)	-1.3 (2.94)

29. Secondary Outcome

Title	Open-label Titration Period: Sleep Evaluation Questionnaire - Latency
Description	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the sleep latency. To assess latency the participant was asked: How long after bedtime/lights out did you fall asleep last night [hours]?
Time Frame	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Observed.

Arm/Group Title	Enrollment Visit (Day -12)	Baseline Visit (Day 1)	Randomization Visit (Day 22)
Arm/Group Description	Participant feedback at the Enrollment Visit; on previous analgesic medication prior to study drug start.	At the end of the washout period prior to starting 100 mg/day tapentadol prolonged release.	End of open-label titration period. Participants with 100 to 300 mg/day tapentadol.
Measure Participants	438	440	377
Mean (Standard Deviation) [hours]	1.2 (1.50)	1.5 (1.56)	1.3 (1.67)

30. Secondary Outcome

Title	Open-label Titration Period: Sleep Evaluation Questionnaire - Latency in the Double-blind Comparative Period Population
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 Randomization Visit (Baseline) and for the night prior to the Final Evaluation Visit (12 weeks after randomization). The higher the value the longer it took to fall asleep. Sleep evaluation questionnaire (SQ) items
Time Frame	Enrollment Visit (Day -12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138, N=149)	1.3 (1.70)	1.3 (1.52)
Baseline Visit (N=139, N=149)	1.5 (1.65)	1.5 (1.54)
Randomization Visit (N=139, N=149)	1.1 (1.45)	1.4 (1.78)

31. Secondary Outcome

Title	Double-blind Comparative Period Sleep Evaluation Questionnaire: Change in Latency
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.
Time Frame	Baseline Visit (Day 1); Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	123	137
Change from baseline visit	-0.3 (2.30)	-0.3 (2.10)
Change from randomization visit	0.2 (1.88)	-0.2 (2.04)

32. Secondary Outcome

Title	Open-label Titration Period: Sleep Evaluation Questionnaire - Number of Awakenings
Description	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. How many times did you wake up during the night? The values were calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline), for the night prior to the Baseline Visit (Day 1) and the night prior to the Randomization Visit (Day 22). The participant was asked at each visit: "How many times did you wake up during the night?"
Time Frame	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Observed.

Arm/Group Title	Enrollment Visit (Day -12)	Baseline Visit (Day 1)	Randomization Visit (Day 22)
Arm/Group Description	Participant feedback at the Enrollment Visit; on previous analgesic medication prior to study drug start.	At the end of the washout period prior to starting 100 mg/day tapentadol prolonged release.	End of open-label titration period. Participants with 100 to 300 mg/day tapentadol.
Measure Participants	438	440	377
Mean (Standard Deviation) [Number of Awakenings]	3.3 (2.64)	3.9 (3.11)	2.5 (1.87)

33. Secondary Outcome

Title	Open-label Titration Period: Sleep Evaluation - Number of Awakenings in the Double-blind Comparative Period Population
Description	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. How many times did you wake up during the night? The values were calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline), for the night prior to the Baseline Visit (Day 1) and the night prior to the Randomization Visit (Day 22). The participant was asked at each visit: "How many times did you wake up during the night?"
Time Frame	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138; N=149)	3.2 (2.84)	3.4 (2.36)
Baseline Visit (N=139; N=149)	3.6 (2.47)	4.6 (4.01)
Randomization Visit (N=139; N=149)	2.5 (1.76)	2.7 (2.00)

34. Secondary Outcome

Title	Double-blind Comparative Period: Change in the Number of Awakenings
Description	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. Participants were asked: How many times did you wake up during the night? The change in the Number of Awakenings was calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline), for the night prior to the Baseline Visit (Day 1) and the night prior to the Final Evaluation Visit (Day 77). A negative change indicates that the number of awakenings in a treatment group have gone down since the Baseline or Randomization Visit. In general pain can interfere with sleep, one potential indicator is the number of awakenings.
Time Frame	Baseline Visit (Day 1); Randomization Visit (Day 22) to Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	123	137
Change from Baseline Visit	-1.4 (2.57)	-2.5 (3.11)
Change from Randomization Visit	-0.2 (2.01)	-0.8 (1.78)

35. Secondary Outcome

Title	Open-label Titration Period: Sleep Evaluation Questionnaire - Time Slept
Description	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the number of awakenings. The participant was asked: "How long did you sleep last night?" [Answered in hours and minutes].
Time Frame	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Observed.

Arm/Group Title	Enrollment Visit (Day -12)	Baseline Visit (Day 1)	Randomization Visit (Day 22)
Arm/Group Description	Participant feedback at the Enrollment Visit; on previous analgesic medication prior to study drug start.	At the end of the washout period prior to starting 100 mg/day tapentadol prolonged release.	End of open-label titration period. Participants with 100 to 300 mg/day tapentadol.
Measure Participants	438	440	377
Mean (Standard Deviation) [hours]	5.8 (1.69)	5.3 (1.79)	6.4 (1.41)

36. Secondary Outcome

Title	Open-label Titration Period: Sleep Evaluation Questionnaire - Number of Hours Slept in the Double-blind Comparative Period Population
Description	The participants were requested to answer the following question: How long did you sleep last night [hours]? The values were calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline) and for the night prior to the End of the Continuation Visit (12 weeks after randomization).
Time Frame	Enrollment Visit (Day -12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Enrollment Visit (N=138, N=149)	5.8 (1.66)	5.7 (1.70)
Baseline Visit (N=139, N=149)	5.3 (1.67)	5.2 (1.70)
Randomization Visit (N=139, N=149)	6.2 (1.30)	6.4 (1.59)

37. Secondary Outcome

Title	Double-blind Comparative Period: Sleep Evaluation Questionnaire - Change in the Number of Hours Slept
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.
Time Frame	Baseline Visit (Day -12); Randomization Visit (Day 1); Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Per Protocol Set.

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	123	137
Change from baseline visit	1.2 (1.89)	1.6 (1.84)
Change from randomization visit	0.3 (1.71)	0.3 (1.70)

38. Secondary Outcome

Title	Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep
Description	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The participant rated this categorically as being one of the following: excellent, good, fair or poor.
Time Frame	Enrollment Visit (Day-12); Baseline Visit (Day 1); Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Observed.

Arm/Group Title	Enrollment Visit (Day -12)	Baseline Visit (Day 1)	Randomization Visit (Day 22)
Arm/Group Description	Participant feedback at the Enrollment Visit; on previous analgesic medication prior to study drug start.	At the end of the washout period prior to starting 100 mg/day tapentadol prolonged release.	End of open-label titration period. Participants with 100 to 300 mg/day tapentadol.
Measure Participants	445	445	445
Excellent	9 2%	5 NaN	21 NaN
Good	110 24.7%	76 NaN	173 NaN
Fair	171 38.4%	149 NaN	127 NaN
Poor	148 33.3%	210 NaN	56 NaN
Missing	7 1.6%	5 NaN	68 NaN

39. Secondary Outcome

Title	Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep in the Double-blind Comparative Period Population
Description	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The participant rated this categorically as being one of the following: excellent, good, fair or poor.
Time Frame	Enrollment Visit (Day-12)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Excellent	1 0.2%	5 NaN
Good	37 8.3%	30 NaN
Fair	42 9.4%	61 NaN
Poor	58 13%	53 NaN
Missing	1 0.2%	0 NaN

40. Secondary Outcome

Title	Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep in the Double-blind Comparative Period Population
Description	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The participant rated this categorically as being one of the following: excellent, good, fair or poor.
Time Frame	Baseline Visit (Day 1)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Excellent	2 0.4%	1 NaN
Good	23 5.2%	17 NaN
Fair	42 9.4%	49 NaN
Poor	72 16.2%	82 NaN

41. Secondary Outcome

Title	Open-label Titration Period: Sleep Evaluation Questionnaire - Overall Quality of Sleep in the Double-blind Comparative Period Population
Description	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The participant rated this categorically as being one of the following: excellent, good, fair or poor.
Time Frame	Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Excellent	7 1.6%	8 NaN
Good	62 13.9%	59 NaN
Fair	48 10.8%	56 NaN
Poor	22 4.9%	26 NaN

42. Secondary Outcome

Title	Double-blind Comparative Period: Change in the Overall Quality of Sleep
Description	The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep. The improvement, no change or worsening is reported based on the replies scored by the participants given at their End of Continuation Visit.
Time Frame	Randomization Visit (Day 22) to Final Evaluation (Day 77)

Outcome Measure Data

Analysis Population Description

Double-Blind Comparative Population. Per Protocol Set (PPS).

Arm/Group Title	Tapentadol Prolonged Release	Tapentadol Prolonged Release and Pregabalin
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period. Subsequently increased in the comparative period to Tapentadol Prolonged Release to 500 mg per day.	Tapentadol Prolonged Release (100 - 300 mg per day) in the open-label titration period. Subsequently Tapentadol 300 mg per day was combined with Pregabalin at a daily dose of 300 mg per day.
Measure Participants	139	149
Improvement	39 8.8%	58 NaN
No change	63 14.2%	59 NaN
Worsening	21 4.7%	20 NaN
Missing	16 3.6%	12 NaN

43. Secondary Outcome

Title	Open-label Titration Period: Subject's Satisfaction With Treatment
Description	Participants rated their satisfaction with the study drug (IMPs) by answering the following question on a 5-point rating scale: "How would you rate your overall satisfaction with your current pain treatment?": Excellent, Very Good, Good, Fair and Poor.
Time Frame	End of Open-label Titration Period at Randomization Visit (Day 22)

Outcome Measure Data

Analysis Population Description

Last Observation Carried Forward (LOCF); Per Protocol Set

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	Tapentadol PR (100 - 300 mg per day) oral administration twice daily in the open-label titration period.
Measure Participants	445
Poor	12 2.7%
Fair	119 26.7%
Good	178 40%
Very Good	58 13%
Excellent	11 2.5%
Missing	67 15.1%

44. Secondary Outcome

Title	Double-blind Comparative Period: Subject's Satisfaction With Treatment
Description	Participants rated their satisfaction with the study drug (IMPs) by answering the following question on a 5-point rating scale: "How would you rate your overall satisfaction with your current pain treatment?": Excellent, Very Good, Good, Fair and Poor.
Time Frame	End of Comparative Period at Final Evaluation Visit (Day 77)

Outcome Measure Data

Analysis Population Description

Last Observation Carried Forward (LOCF); Per Protocol Set

Arm/Group Title	Tapentadol in the Comparative Period	Tapentadol and Pregabalin in the Comparative Period
Arm/Group Description	The dose of Tapentadol Prolonged Release was increased to 400 mg (2 x 200mg) and a week later to 500 mg (2 x 250 mg) per day and maintained at 500 mg per day.	Tapentadol Prolonged Release 300 mg per day (2 x 150 mg) plus Pregabalin 2 x 75 mg (total daily dose of 150 mg). A week later the dose of Pregabalin was increased to a total daily dose of 300 mg per day (2 x 150 mg), the Tapentadol Prolonged Release dose remained at 300 mg per day.
Measure Participants	139	149
Poor	3 0.7%	6 NaN
Fair	32 7.2%	28 NaN
Good	43 9.7%	43 NaN
Very Good	32 7.2%	43 NaN
Excellent	21 4.7%	23 NaN
Missing	8 1.8%	6 NaN

Adverse Events

Time Frame	Baseline Visit; up to end of Week 11.
Adverse Event Reporting Description	Treatment Emergent Adverse Events are reported, starting with the first dose in the open-label titration period on Day 1 up to Day 77. TEAEs are reported up to Day 91 at the End of the Follow-Up visit. One participant died, before the baseline visit, during the washout phase of the clinical trial.
Arm/Group Title	Open-Label Tapentadol Titration Period		Tapentadol in the Comparative Period		Tapentadol and Pregabalin in the Comparative Period		Open-Label Tapentadol Pick-Up Arm		Open-Label Tapentadol Continuation Period
Arm/Group Description	During the 3-week Titration Period, Tapentadol Prolonged Release was administered in an open-label fashion. Titration dose steps on a weekly basis: First 50 mg administered twice daily, then 100 mg administered twice daily and then 150 mg administered twice daily. The titration period could be shortened to 10 days, with a participant at a predefined dose level for at least 3 days. The dose of 300 mg Tapentadol per day was maintained until the Randomization Visit.		The dose of Tapentadol Prolonged Release was increased to 400 mg (2 x 200mg) and a week later to 500 mg (2 x 250 mg) per day and maintained at 500 mg per day.		Tapentadol Prolonged Release 300 mg per day (2 x 150 mg) plus Pregabalin 2 x 75 mg (total daily dose of 150 mg). A week later the dose of Pregabalin was increased to a total daily dose of 300 mg per day (2 x 150 mg), the Tapentadol Prolonged Release dose remained at 300 mg per day.		Participants that drop-out of the Comparative Period, due to tolerability issues, were permitted to continue on Tapentadol Prolonged Release at either 300 mg per day or 400 mg per day.		Participants who did not qualify for randomization to the Comparator Period, continued on a stable dose of Tapentadol Prolonged Release 300 mg per day if they had reached a satisfactory level of pain relief.
All Cause Mortality
	Open-Label Tapentadol Titration Period		Tapentadol in the Comparative Period		Tapentadol and Pregabalin in the Comparative Period		Open-Label Tapentadol Pick-Up Arm		Open-Label Tapentadol Continuation Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Open-Label Tapentadol Titration Period		Tapentadol in the Comparative Period		Tapentadol and Pregabalin in the Comparative Period		Open-Label Tapentadol Pick-Up Arm		Open-Label Tapentadol Continuation Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/445 (0.7%)		5/154 (3.2%)		3/159 (1.9%)		2/37 (5.4%)		2/59 (3.4%)
Cardiac disorders
Cardiac arrest	0/445 (0%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Cardiac failure	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Tachycardia	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Ear and labyrinth disorders
Vertigo	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Endocrine disorders
Goitre	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Gastrointestinal disorders
Abdominal pain	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Abdominal pain upper	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Constipation	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Nausea	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
General disorders
Chest pain	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Device dislocation	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Drug withdrawal syndrome	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Injury, poisoning and procedural complications
Chest injury	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Fall	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Musculoskeletal and connective tissue disorders
Flank pain	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Nervous system disorders
Muscle contractions involuntary	0/445 (0%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism	0/445 (0%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Vascular disorders
Thrombosis	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Other (Not Including Serious) Adverse Events
	Open-Label Tapentadol Titration Period		Tapentadol in the Comparative Period		Tapentadol and Pregabalin in the Comparative Period		Open-Label Tapentadol Pick-Up Arm		Open-Label Tapentadol Continuation Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	227/445 (51%)		98/154 (63.6%)		103/159 (64.8%)		37/37 (100%)		36/59 (61%)
Blood and lymphatic system disorders
Anaemia	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Cardiac disorders
Atrial Fibrillation	0/445 (0%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Brachycardia	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Cardiac Failure	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Cardiovascular Disorder	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Palpitation	1/445 (0.2%)		1/154 (0.6%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Ear and labyrinth disorders
Cupulolithiasis	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Ear Discomfort	1/445 (0.2%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Ear pain	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
External Ear Disorder	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Inner Ear Disorder	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Motion Sickness	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Tinnitus	1/445 (0.2%)		1/154 (0.6%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Vertigo	0/445 (0%)		1/154 (0.6%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Eye disorders
Accommodation Disorder	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Atrial Fibrillation	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Dry Eye	1/445 (0.2%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Eye Irritation	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Eye pruritis	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Vision Blurred	1/445 (0.2%)		2/154 (1.3%)		0/159 (0%)		3/37 (8.1%)		0/59 (0%)
Visual Acuity Reduced	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Visual Impairment	0/445 (0%)		1/154 (0.6%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Gastrointestinal disorders
Abdominal Discomfort	2/445 (0.4%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Abdominal Distension	2/445 (0.4%)		0/154 (0%)		2/159 (1.3%)		2/37 (5.4%)		0/59 (0%)
Abdominal Pain	3/445 (0.7%)		2/154 (1.3%)		0/159 (0%)		1/37 (2.7%)		1/59 (1.7%)
Abdominal Pain Lower	0/445 (0%)		0/154 (0%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Abdominal Pain Upper	7/445 (1.6%)		2/154 (1.3%)		2/159 (1.3%)		1/37 (2.7%)		1/59 (1.7%)
Abdominal Symptom	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Abnormal Faeces	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Colitis	0/445 (0%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Colonic Polyp	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Constipation	25/445 (5.6%)		11/154 (7.1%)		8/159 (5%)		9/37 (24.3%)		10/59 (16.9%)
Diarrhoea	14/445 (3.1%)		6/154 (3.9%)		3/159 (1.9%)		3/37 (8.1%)		2/59 (3.4%)
Dry Mouth	35/445 (7.9%)		6/154 (3.9%)		8/159 (5%)		6/37 (16.2%)		6/59 (10.2%)
Dyspepsia	6/445 (1.3%)		1/154 (0.6%)		2/159 (1.3%)		1/37 (2.7%)		1/59 (1.7%)
Dysphagia	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Enteritis	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Faeces hard	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Flatuence	2/445 (0.4%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Frequent Bowel Movements	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Gastritis	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Gastrointestinal Disorder	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Glossodynia	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Haematochezia	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Haemorrhoids	0/445 (0%)		1/154 (0.6%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Hyperchlorhydria	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Inflammatory Bowel Disease	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Nausea	58/445 (13%)		16/154 (10.4%)		14/159 (8.8%)		12/37 (32.4%)		11/59 (18.6%)
Oesophagitis	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Uvulitis	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Vomiting	20/445 (4.5%)		9/154 (5.8%)		5/159 (3.1%)		5/37 (13.5%)		4/59 (6.8%)
General disorders
Asthenia	6/445 (1.3%)		4/154 (2.6%)		0/159 (0%)		2/37 (5.4%)		2/59 (3.4%)
Chest Discomfort	2/445 (0.4%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Chills	2/445 (0.4%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Discomfort	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Drug Withdrawal Syndrome	2/445 (0.4%)		0/154 (0%)		1/159 (0.6%)		1/37 (2.7%)		1/59 (1.7%)
Fatigue	25/445 (5.6%)		13/154 (8.4%)		16/159 (10.1%)		10/37 (27%)		5/59 (8.5%)
Feeling Abnormal	2/445 (0.4%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Feeling Cold	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Feeling Drunk	1/445 (0.2%)		1/154 (0.6%)		2/159 (1.3%)		1/37 (2.7%)		0/59 (0%)
Feeling Hot	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Gait Disturbance	0/445 (0%)		0/154 (0%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Generalised Oedema	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Hyperplasia	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Inflammation	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Influenza Like Illness	4/445 (0.9%)		2/154 (1.3%)		3/159 (1.9%)		1/37 (2.7%)		0/59 (0%)
Irritability	3/445 (0.7%)		0/154 (0%)		3/159 (1.9%)		0/37 (0%)		0/59 (0%)
Malaise	1/445 (0.2%)		0/154 (0%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Oedema Peripheral	6/445 (1.3%)		0/154 (0%)		3/159 (1.9%)		0/37 (0%)		1/59 (1.7%)
Pain	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Pyrexia	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Thirst	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Immune system disorders
Seasonal Allergy	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Infections and infestations
Abdominal Abscess	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Acute Tonsillitis	1/445 (0.2%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Bacterial Infection	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Bronchitis	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Cystitis	0/445 (0%)		2/154 (1.3%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Diverticulitis	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Ear Infection	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Gastroenteritis	1/445 (0.2%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		1/59 (1.7%)
Gastroenteritis Viral	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Gastrointestinal Infection	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Herpes Zoster Oticus	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Infection	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Influenza	0/445 (0%)		2/154 (1.3%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Laryngitis	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Localised Infection	1/445 (0.2%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Nasopharyngitis	7/445 (1.6%)		2/154 (1.3%)		5/159 (3.1%)		2/37 (5.4%)		3/59 (5.1%)
Oral Herpes	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Otitis Media Acute	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Pharyngitis	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Pneumonia	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Rhinitis	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Sinusitis	0/445 (0%)		2/154 (1.3%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Upper Respiratory Tract Infection	1/445 (0.2%)		0/154 (0%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Urinary Tract Infection	2/445 (0.4%)		1/154 (0.6%)		1/159 (0.6%)		1/37 (2.7%)		2/59 (3.4%)
Vaginal Infection	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Injury, poisoning and procedural complications
Ankle Fracture	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Contusion	0/445 (0%)		1/154 (0.6%)		1/159 (0.6%)		0/37 (0%)		1/59 (1.7%)
Epicondylitis	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Excoriation	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Fall	1/445 (0.2%)		3/154 (1.9%)		4/159 (2.5%)		1/37 (2.7%)		0/59 (0%)
Hand Fracture	0/445 (0%)		1/154 (0.6%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Laceration	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Ligament Sprain	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Muscle Rupture	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Post Procedural Complication	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Procedural Pain	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Investigations
Alanine Aminotransferase Increased	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Aspartate Aminotransferase Increased	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Blood Creatinine Decreased	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Blood Pressure Increased	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Blood Triglycerides Increased	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Gamma-Glutamyltransferase Increased	0/445 (0%)		2/154 (1.3%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Haemoglobin Decreased	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Lasegue's Test Positive	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		1/59 (1.7%)
Lipase Increased	0/445 (0%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Neurological Examination Abnormal	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Nitrite Urine Present	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Prostatic Specifc Antigen Increased	0/445 (0%)		0/154 (0%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Protein Urine Present	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Weight Decreased	0/445 (0%)		3/154 (1.9%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
White Blood Cell Count Increased	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Metabolism and nutrition disorders
Decreased Appetite	12/445 (2.7%)		2/154 (1.3%)		1/159 (0.6%)		3/37 (8.1%)		0/59 (0%)
Diabetes Mellitus	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Dyslipidaemia	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		2/37 (5.4%)		0/59 (0%)
Hypercholesterolaemia	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Increased Appetite	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/445 (0.2%)		0/154 (0%)		2/159 (1.3%)		0/37 (0%)		1/59 (1.7%)
Back Pain	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Bursitis	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Flank Pain	1/445 (0.2%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Groin Pain	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Intervertebral Disc Protusion	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Joint Swelling	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Muscle Fatigue	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Muscle Spasms	4/445 (0.9%)		0/154 (0%)		1/159 (0.6%)		3/37 (8.1%)		0/59 (0%)
Muscle Twitching	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Musculoskeletal Pain	1/445 (0.2%)		2/154 (1.3%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Musculoskeletal Stiffness	2/445 (0.4%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Neck Pain	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Osteoarthritis	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Pain in Extremity	2/445 (0.4%)		4/154 (2.6%)		3/159 (1.9%)		0/37 (0%)		1/59 (1.7%)
Sensation of Heaviness	1/445 (0.2%)		1/154 (0.6%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Tendonitis	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Nervous system disorders
Allodynia	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Aphasia	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Balance Disorder	2/445 (0.4%)		2/154 (1.3%)		2/159 (1.3%)		3/37 (8.1%)		0/59 (0%)
Carotid Arteriosclerosis	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Disturbance in Attention	2/445 (0.4%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Dizziness	51/445 (11.5%)		17/154 (11%)		28/159 (17.6%)		11/37 (29.7%)		9/59 (15.3%)
Dysaesthesia	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Dysarthria	0/445 (0%)		0/154 (0%)		2/159 (1.3%)		1/37 (2.7%)		0/59 (0%)
Dysgeusia	2/445 (0.4%)		1/154 (0.6%)		3/159 (1.9%)		0/37 (0%)		0/59 (0%)
Dyskinesia	3/445 (0.7%)		0/154 (0%)		0/159 (0%)		2/37 (5.4%)		0/59 (0%)
Headache	40/445 (9%)		10/154 (6.5%)		13/159 (8.2%)		5/37 (13.5%)		7/59 (11.9%)
Hypoaesthesia	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Hyporeflexia	0/445 (0%)		0/154 (0%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Hypotonia	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Lethargy	3/445 (0.7%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Memory Impairment	2/445 (0.4%)		1/154 (0.6%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Mental Impairment	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Movement Disorder	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Muscle Contraction Involuntary	0/445 (0%)		1/154 (0.6%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Paraesthesia	5/445 (1.1%)		1/154 (0.6%)		0/159 (0%)		2/37 (5.4%)		0/59 (0%)
Restless Leg Syndrome	1/445 (0.2%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Sciatica	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Sedation	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Sensory Loss	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Somnolence	29/445 (6.5%)		13/154 (8.4%)		19/159 (11.9%)		11/37 (29.7%)		4/59 (6.8%)
Speech Disorder	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Syncope	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Tension Headache	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Tremor	3/445 (0.7%)		2/154 (1.3%)		2/159 (1.3%)		0/37 (0%)		2/59 (3.4%)
Psychiatric disorders
Abnormal Dreams	3/445 (0.7%)		0/154 (0%)		2/159 (1.3%)		1/37 (2.7%)		1/59 (1.7%)
Aggression	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Agitation	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Anxiety	4/445 (0.9%)		4/154 (2.6%)		3/159 (1.9%)		3/37 (8.1%)		1/59 (1.7%)
Apathy	2/445 (0.4%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		2/59 (3.4%)
Confusional State	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Depressed Mood	4/445 (0.9%)		3/154 (1.9%)		3/159 (1.9%)		1/37 (2.7%)		0/59 (0%)
Depression	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Disorientation	0/445 (0%)		1/154 (0.6%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Drug Dependence	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Emotional Disorder	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Fear	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Food Aversion	1/445 (0.2%)		1/154 (0.6%)		0/159 (0%)		2/37 (5.4%)		0/59 (0%)
Hallucination, Visual	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Initial Insomnia	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Insomnia	8/445 (1.8%)		3/154 (1.9%)		5/159 (3.1%)		3/37 (8.1%)		3/59 (5.1%)
Libido decreased	1/445 (0.2%)		0/154 (0%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Listless	0/445 (0%)		1/154 (0.6%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Middle Insomnia	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Mood Swings	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Mood Altered	2/445 (0.4%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Nervousness	1/445 (0.2%)		1/154 (0.6%)		2/159 (1.3%)		1/37 (2.7%)		2/59 (3.4%)
Nightmare	1/445 (0.2%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		3/59 (5.1%)
Restlessness	5/445 (1.1%)		1/154 (0.6%)		1/159 (0.6%)		1/37 (2.7%)		2/59 (3.4%)
Sleep Disorder Due To General Medical Condition, Insomnia Type	0/445 (0%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Sleep Talking	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Sleep disorder	4/445 (0.9%)		2/154 (1.3%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Suicidal Ideation	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Tic	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Renal and urinary disorders
Bladder Discomfort	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Dysuria	2/445 (0.4%)		1/154 (0.6%)		3/159 (1.9%)		1/37 (2.7%)		0/59 (0%)
Glycosuria	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Micturition Disorder	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Nephrolithiasis	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		1/59 (1.7%)
Oliguria	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Pollakiuria	1/445 (0.2%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Renal Colic	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Renal Cyst	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Reproductive system and breast disorders
Breast Swelling	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Erectile Dysfunction	1/445 (0.2%)		0/154 (0%)		2/159 (1.3%)		1/37 (2.7%)		0/59 (0%)
Sexual Dysfunctio	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Respiratory, thoracic and mediastinal disorders
Apnoea	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Cough	2/445 (0.4%)		4/154 (2.6%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Dry Throat	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Dysphonia	3/445 (0.7%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Dyspnoea	5/445 (1.1%)		1/154 (0.6%)		0/159 (0%)		2/37 (5.4%)		0/59 (0%)
Hiccups	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Nasal Congestion	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Oropharyngeal Pain	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Respiratory Distress	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Skin and subcutaneous tissue disorders
Acne	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Alopecia	0/445 (0%)		0/154 (0%)		2/159 (1.3%)		0/37 (0%)		0/59 (0%)
Angioedema	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Dry Skin	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Erythema	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Hyperhidrosis	21/445 (4.7%)		18/154 (11.7%)		10/159 (6.3%)		10/37 (27%)		5/59 (8.5%)
Night Sweats	0/445 (0%)		1/154 (0.6%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Onychoclasis	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Pain of Skin	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Petechiae	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Pruritus	10/445 (2.2%)		6/154 (3.9%)		1/159 (0.6%)		4/37 (10.8%)		2/59 (3.4%)
Pruritus Generalised	4/445 (0.9%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Rash	2/445 (0.4%)		2/154 (1.3%)		1/159 (0.6%)		0/37 (0%)		1/59 (1.7%)
Rash Pruritic	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)
Skin Discolouration	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Skin Tightness	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Urticaria	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Surgical and medical procedures
Tooth Extraction	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Vascular disorders
Blood Pressure Fluctuation	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		1/37 (2.7%)		0/59 (0%)
Flushing	2/445 (0.4%)		1/154 (0.6%)		0/159 (0%)		1/37 (2.7%)		0/59 (0%)
Haematoma	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Hot Flush	10/445 (2.2%)		0/154 (0%)		0/159 (0%)		3/37 (8.1%)		1/59 (1.7%)
Hypertension	3/445 (0.7%)		1/154 (0.6%)		5/159 (3.1%)		0/37 (0%)		1/59 (1.7%)
Hypertensive crisis	1/445 (0.2%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Hypotension	2/445 (0.4%)		0/154 (0%)		2/159 (1.3%)		1/37 (2.7%)		1/59 (1.7%)
Thrombophlebitis	0/445 (0%)		1/154 (0.6%)		0/159 (0%)		0/37 (0%)		0/59 (0%)
Thrombosis	0/445 (0%)		0/154 (0%)		1/159 (0.6%)		0/37 (0%)		0/59 (0%)
Venous Thrombosis Limb	0/445 (0%)		0/154 (0%)		0/159 (0%)		0/37 (0%)		1/59 (1.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The sponsor reserves the right to review any publication pertaining to the trial before it is submitted for publication. Neither party has the right to prohibit publication unless publication can be shown to affect possible patent rights.