A Study to Evaluate Tapentadol (CG5503) in the Treatment of Chronic Tumor-Related Pain Compared With Placebo and Morphine

A responder is a participant in the study that: 1. completed 28 days of the maintenance phase 2. had a numeric rating scale score below 5 on the 11 point scale (where 0 indicates no pain and 10 indicates worst possible pain. This twice daily current pain score was averaged over Day 18 to Day 43. 3. did not use more than 20 mg of rescue medication per day on average in the 28 day maintenance period (from Day 18 to Day 43). A participant that met all 3 of the above-mentioned criteria is counted as a responder, in other words the participant benefited from the assigned drug treatment. A participant that failed to meet only 1 of the 3 criteria is not counted as a responder.

Time frame: Day 18 through Day 43 (End of Maintenance Phase)

Population: Full Analysis Set (Maintenance Phase).

Participants were asked to record their average pain over the last 24 hours pain intensity each evening. Average pain scores are the averages of all scores recorded during each week. The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine.

Time frame: Day 18 through Day 43 (End of Maintenance Phase)

Population: Full Analysis Set (Maintenance Period). Last observation carried forward.

Participants were asked to record their average pain over the last 24 hours pain intensity each evening. Average pain scores are the averages of all scores recorded during each week. The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine.

Time frame: Day 1 through Day 14 (End of Titration Phase)

Population: Full Analysis Set (Titration Period), observed.

Participants were asked to record their average pain over the last 24 hours pain intensity each evening. Average pain scores are the averages of all scores recorded during each week. The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine.

Time frame: Day 1 through Day 14 (End of Titration Phase)

Population: Full Analysis Set (Titration Period), observed.

The participant scores the EuroQol-5D. The EuroQoL-5D is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1 = no problems, 2 = some problems, 3 = extreme problems). The responses to the five EQ-5D dimensions are scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating full health and 0 representing dead. A positive change in the mean indicates that during this phase the health status improved. A positive change indicates an improvement in health. The minimal important difference is 0.074 (range -0.011 to 0.140).

Time frame: Day 1 (Start of Titration); Day 14 (End of Titration Phase)

Population: Full analysis set (Titration Phase), observed.

The participant scores the EuroQol-5D. The EuroQoL-5D is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1 = no problems, 2 = some problems, 3 = extreme problems). The responses to the five EQ-5D dimensions are scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating full health and 0 representing dead. A negative change in the mean indicates a worsening in health status since the beginning of the maintenance phase. A positive change indicates an improvement in health. The minimal important difference in the Health Status Index is 0.074 (range -0.011 to 0.140).

Time frame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)

Population: Full Analysis Set (Maintenance Phase), observed. Start of Maintenance and Endpoint Maintenance observations. No morphine treatment analysis was planned.

The Constipation Assessment (PAC-SYM) is a 12-item self-report questionnaire that assesses the severity of symptoms of constipation. Participants are asked How severe have each of these symptoms been in the last two weeks? e.g. Pain in your stomach. There are 3 subscales: 4 questions on Abdominal symptoms, 3 questions on rectal symptoms and 5 questions on stool symptoms. Responses are rated on a 5-point Likert Scale ranging from 0 (absence of symptom) to 4 (very severe symptoms). The changes in overall mean and in each of the mean sub-scores vary theoretically from -4 to +4 (where a change of +4 would indicate a change from not present to very severe symptom). If the changes in the overall or subscale mean scores are positive then there is a worsening in symptoms associated with constipation from the start to the end of the maintenance phase. A negative mean change indicates an improvement.

Time frame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)

Population: Safety Analysis Set (Maintenance Phase), observed. Start of Maintenance and Endpoint Maintenance observations.

The Constipation Assessment (PAC-SYM) is a 12-item self-report questionnaire that assesses the severity of symptoms of constipation. Participants are asked How severe have each of these symptoms been in the last two weeks? e.g. Pain in your stomach. There are 3 subscales: 4 questions on Abdominal symptoms, 3 questions on rectal symptoms and 5 questions on stool symptoms. Responses are rated on a 5-point Likert Scale ranging from 0 (absence of symptom) to 4 (very severe symptoms). The changes in overall mean and in each of the mean sub-scores vary theoretically from -4 to +4 (where a change of +4 would indicate a change from not present to very severe symptom). If the changes in the overall or subscale mean scores are positive then there is a worsening in symptoms associated with constipation from the start to the end of the titration phase.

Time frame: Day 1 (Start of Titration); Day 14 (End of Titration Phase)

Population: Per Protocol Set (Titration Phase), observed. Start of Titration and Endpoint Titration observations.

EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate a better health state. The values indicated represent the change from Day 15, a negative mean value indicates a worsening of health-related quality of life since the start of the maintenance phase.

Time frame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)

Population: Full Analysis Set (Maintenance Phase), observed. Start of Maintenance and Endpoint Maintenance observations.

The Short Form 36 (SF-36) includes several brief questions on 8 aspects, (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. Low scores on the Physical Component Summary measure indicate limitations in physical functioning, e.g. a high degree of bodily pain and physical limitations etc. For the Mental Component Summary measure, a low score is indicative of frequent psychological distress, social and role disability due to emotional problems etc. The theoretical range for the physical component score is 12.3279 to 59.6503. The theoretical range for the mental component score is 13.5313 to 59.6503. Positive values for changes in the component scores indicate an improvement.

Time frame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)

Population: Full analysis set (Maintenance Phase), observed. Start of Maintenance and Endpoint Maintenance observations.

The Short Form 36 (SF-36) includes several brief questions on 8 aspects, (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. Low scores on the Physical Component Summary measure indicate limitations in physical functioning, e.g. a high degree of bodily pain and physical limitations etc. For the Mental Component Summary measure, a low score is indicative of frequent psychological distress, social and role disability due to emotional problems etc. The theoretical range for the physical component score is 12.3279 to 59.6503. The theoretical range for the mental component score is 13.5313 to 59.6503. Positive values for changes in the component scores indicate an improvement.

Time frame: Day 1 (Start of Titration); Day 14 (End of Titration Phase)

Population: Full analysis set (Titration Period), observed. Start of Titration and Endpoint Titration observations.

This instrument was developed by the National Institute on Drug Abuse. The physical components of withdrawal are primarily evaluated and based on questions and clinical observations. The possible opioid withdrawal effects are assessed using the Clinical Opioid Withdrawal Score (COWS). The COWS is a clinician rated 11-item scale that primarily evaluates the physical components of opioid withdrawal and is based on questions and clinical observations. Responses are rated on a Likert-type scale ranging from 0 to 4 or 5 depending on the item. The total COWS score is the sum of all individual items. The following withdrawal categories are based on the total COWS score: * None: total score below 5; * Mild: total score from 5 to 12; * Moderate: total score 13 to 24; * Moderately Severe: total score 25 to 36; * Severe: total score above 36. The investigator completes the COWS after participants discontinued trial medication 2 to less than 5 days after last intake of trial medication.

Time frame: Day 14 (End of Titration Phase)

Population: Safety Analysis Set (Titration Phase). Participants that took at least one dose of trial medication in the titration phase, and discontinued trial medication at the end or during the titration phase and did not continue on other opioid medication.

This instrument was developed by the National Institute on Drug Abuse. The physical components of withdrawal are primarily evaluated and based on questions and clinical observations. The possible opioid withdrawal effects are assessed using the Clinical Opioid Withdrawal Score (COWS). The COWS is a clinician rated 11-item scale that primarily evaluates the physical components of opioid withdrawal and is based on questions and clinical observations. Responses are rated on a Likert-type scale ranging from 0 to 4 or 5 depending on the item. The total COWS score is the sum of all individual items. The following withdrawal categories are based on the total COWS score: * None: total score below 5; * Mild: total score from 5 to 12; * Moderate: total score 13 to 24; * Moderately Severe: total score 25 to 36; * Severe: total score above 36. The investigator completes the COWS after participants discontinued trial medication 2 to less than 5 days after last intake of trial medication.

Time frame: Day 43 (End of Maintenance Phase)

Population: Safety Analysis Set. Participants that did not discontinue due to adverse event during the first week of the maintenance phase and started opioid after last study medication.

Participants were asked to record their current pain intensity in the morning and evening. Average pain scores are the averages of all scores recorded during the 3 days prior to re-randomization or during each week. The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine.

Time frame: Day 15 through Day 43 (End of Maintenance Phase)

Population: Full Analysis Set (Maintenance Period). Last observation carried forward.

Participants were asked to record their current pain intensity in the morning and evening. Average pain scores are the averages of all scores recorded during the during each week. The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine.

Time frame: Day 1 through Day 14 (End of Titration Phase)

Population: Observed, i.e. participants contributing data via their electronic diary.

Participants were asked to record their current pain intensity in the morning and evening. Average pain scores are the averages of all scores recorded during each week. The participant scored their pain intensity on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated no pain and a score of 10 indicated pain as bad as you can imagine.

Time frame: Day 1 through Day 14 (End of Titration Phase)

Population: Full Analysis Set (Titration Phase), observed.

EuroQoL-5D Health State Visual Analog Scale (VAS) is a participant rated questionnaire to assess health-related quality of life in terms of a single index value. The VAS component rates current health state on a scale from 0 (worst imaginable health state) to 100 (best imaginable health state); higher scores indicate better health. The values indicated represent the change from Day 1, a positive value indicates an improvement since the start of treatment.

Time frame: Day 1 (Start of Titration); Day 14 (End of Titration Phase)

Population: Full analysis set (Titration Phase), observed.

Participants were issued morphine 10 mg immediate release medication. The number of participants using rescue medication morphine sulfate immediate release 10 mg tablets in the maintenance phase were counted. This use of morphine immediate release was captured in each participant's electronic diary.

Time frame: Day 15 through Day 43 (End of Maintenance Phase)

Population: Full Analysis Set (Maintenance phase), observed.

In the Patient Global Impression of Change (PGIC) the participant is asked Since I began study treatment, my overall status is. The participant is asked to circle one of seven categories. Scores range from very much improved to very much worse. The question was asked at the end of the maintenance phase with reference to the start of the maintenance phase where the participant continued at the dose that was effective at the end of the Titration Phase.

Time frame: Day 43 (End of Maintenance Phase)

Population: Full Analysis Set, observed.

Participants were asked the following question: Please rate the overall quality of your sleep last night? The quality of sleep from the start of maintenance to the completion of treatment is reported. The participant could choose one of the following options: Excellent, good, fair and poor.

Time frame: Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)

Population: FAS (Maintenance Phase) Last Observation Carried Forward for participants re-randomized.~Tapentadol: 105 participants responded at the start and 103 participants at the end.~Morphine: 108 participants responded at the start and 107 participants at the end.~Placebo: 110 participants responded at the start and 107 participants at the end.

Participants were asked the following question: Please rate the overall quality of your sleep last night? The quality of sleep from the start of the titration phase to the end of the titration phase was measured. The participant could choose one of the following options: Excellent, good, fair and poor.

Time frame: Day 1 (Start of Titration); Day 14 (end of Titration Phase)

Population: Full Analysis Set (Titration Phase), observed. Tapentadol: 302 participants dosed gave a response at the start of titration and from 309 participants at the end of titration.~Morphine: 143 participants dosed gave a response at the start of titration and from 142 participants at the end of titration.

Mean total daily dose of rescue medication morphine sulphate immediate release tablets in milligrams per day (mg/day).

Time frame: Day 1 (Start of Titration Phase) through Day 43 (End of Maintenance Phase)

Population: Full analysis set for each phase of the trial, observed.

The number of participants using rescue medication morphine sulfate immediate release 10 mg tablets in the titration phase were counted. This data was captured in an electronic diary. During the trial, morphine immediate release 10 mg was allowed as required without a maximum dose defined. However, participants were only re-randomized if their mean consumption of rescue medication was less or equal to 2 doses (20 mg) per day during the last 3 days of the titration phase).

Time frame: Day 1 through Day 14 (End of Titration Phase)

Population: Full Analysis Set (Titration phase), observed.