The purpose of this study will be to determine whether tapentadol (CG5503) is effective and safe in the treatment of chronic tumor related pain compared to placebo. In addition tapentadol (CG5503) will also be compared to morphine controlled release, also referred to as slow release (SR). \*Tapentadol prolonged-release (PR) is the term used in the European Union and is referred to as extended release (ER) in the United States.
Normally chronic tumor related pain is controlled when participants receive repeated doses of opioid analgesics. However, opioid therapy is commonly associated with side effects such as nausea, vomiting, sedation, constipation, addiction, tolerance, and respiratory depression. Tapentadol (CG5503), a newly synthesized drug with an prolonged release (PR) formulation, also acts as a centrally acting pain reliever but has 2 mechanisms of action. The aim of this trial is to investigate the effectiveness (level of pain control) and safety (side effects) of tapentadol (CG5503) PR compared with no drug (placebo) and corresponding dose of morphine (an opioid commonly used to treat tumor related pain). This trial is a randomized, double-blind (neither investigator nor patient will know which treatment was received), active- and placebo-controlled, parallel-group, randomized withdrawal design, multicenter trial. The trial includes a 2 week titration phase starting with either 40 mg morphine (PR) bid (bid = twice daily dosing, one dose in the morning and one dose in the evening) or 100 mg tapentadol (CG5503) PR bid. Based on effectiveness and side effects subjects can up-titrate in steps of 50 mg tapentadol (CG5503 PR) to a maximal dose of 250 mg tapentadol (CG5503) PR bid or 100 mg morphine PR bid. If participants meet the stabilisation criteria at the end of the titration phase they will be re-randomized to either placebo or active treatment and will continue 4 weeks at the last dose level in the maintenance phase. Only participants on tapentadol in the titration phase will be re-randomized to either matching placebo or to tapentadol. To maintain the blinding nature of the trial participants in the morphine arm during the titration phase will also be re-randomized however they will all remain on morphine controlled release in the maintenance phase. Placebo to match tapentadol tablets, as well as placebo to match morphine capsules, will be used to mask the treatment allocation. Participants will be issued with an electronic diary (eDiary) to capture Numeric Rating Scale (NRS) pain intensities. Assessments of pain relief include the pain intensity numeric rating scale (NRS) and patient global impression of change (PGIC). Safety evaluations include monitoring of adverse events, physical examinations, clinical laboratory tests and electrocardiograms. Venous blood samples will be collected for the determination of serum concentrations of tapentadol (CG5503).
Tablet taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. Titration phase: Starting at 100 mg, increasing at a minimum of 3 day intervals by 50 mg, with a maximum dose of 250 mg.
Tablet taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. In the maintenance phase only to participants that were randomized to tapentadol in the titration phase.
Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. Titration phase: Starting at 40 mg, increasing at a minimum of 3 days intervals by 20 mg, with a maximum dose of 100 mg. Maintenance phase: continuing on dose level established in titration phase.
Number of Participants Scored as Responder in Maintenance Phase.
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)
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Tapentadol Treatment Arm.
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)
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Morphine Treatment Arm.
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)
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase.
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Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
622
Site 043004
Klagenfurt, Austria
Site 043002
Vienna, Austria
Site 043001
Vienna, Austria
Site 043005
Vienna, Austria
Site 359013
Gabrovo, Bulgaria
Site 359011
Pleven, Bulgaria
Site 359014
Plovdiv, Bulgaria
Site 359004
Shumen, Bulgaria
Site 359008
Sofia, Bulgaria
Site 359012
Varna, Bulgaria
...and 61 more locations
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)
Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Tapentadol Arm.
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)
Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Morphine Arm.
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)
Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase.
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)
Use of Rescue Medication in the Titration Phase.
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)
Number of Participants Using Immediate Release Morphine Rescue Medication in the Maintenance Phase
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)
The Average Mean Total Daily Dose of Rescue Medication.
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)
Changes in the Short Form 36® Health Survey (SF-36®) During the Titration Phase.
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)
Changes in the Short Form 36® Health Survey (SF-36®) During the Maintenance Phase.
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)
Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Change From Start of Titration to Endpoint Titration.
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)
Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Titration Phase.
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)
Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Over Time in the Maintenance Phase for Tapentadol and the Placebo Randomized Withdrawal Treatment Arms.
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)
Changes in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Maintenance Phase.
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)
Patient Global Impression of Change
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)
Quality of Sleep (Sleep Questionnaire) in the Titration Phase.
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)
Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial.
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)
Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase.
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)
Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase.
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)
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Titration Phase
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)
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Maintenance Phase
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)