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Oral Tapentadol 100 mg to 250 mg twice daily. Participants randomized to placebo in the maintenance phase received 100 mg tapentadol prolonged release twice daily for 3 days to taper them off the tapentadol dose they had received in the Titration Phase. From the 4th day (Day 18) all participants received matching placebo in the maintenance (i.e. randomized withdrawal) phase.

Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. Maintenance phase: continuing on dose level established in titration phase.

Oral Tapentadol 100 mg to 250 mg twice daily. Tablet taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses.

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.

Tapentadol Extended Release

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.

Matching Placebo after 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.

Morphine Sulphate Controlled Release

Hans Georg Kress, Dr.

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).

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

A Randomized Withdrawal, Active- and Placebo-controlled, Double-blind, Multi-center Phase III Trial Assessing Safety and Efficacy of Oral CG5503 (Tapentadol) PR* in Subjects With Moderate to Severe Chronic Malignant Tumor-related Pain

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.

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".

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".

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".

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".

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).

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.

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

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.

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).

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.

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).

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.

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.

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.

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.

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.

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.

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.

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Grünenthal GmbH

Tapentadol Prolonged Release (Titration Phase)

Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses.

Morphine Controlled Release (Titration Phase)

Oral Tapentadol 100 mg to 250 mg twice daily. The participant continued at the dose that was effective at the end of the Titration Phase.

Tapentadol Prolonged Release (Maintenance Phase)

Matching Placebo After Tapentadol in Titration Phase

Oral Morphine 40 mg to 100 mg twice daily. The dose that was effective at the end of the Titration Phase.

Morphine Controlled Release (Maintenance Phase)

Tapentadol Prolonged Release

Morphine Controlled Release

Total

Age, Categorical

Age, Continuous

Sex: Female, Male

Austria

Bulgaria

Croatia

Czech Republic

France

Germany

Hungary

Italy

Moldova, Republic of

Poland

Romania

Russian Federation

Serbia

Slovakia

Spain

Sweden

Region of Enrollment

Titration Phase:

Safety Analysis Set (N = 496) Full Analysis Set (N = 492)

Maintenance Phase:

Safety Analysis Set (N = 327) Full Analysis Set (N = 325)

Note:

One site was excluded from all analysis sets (efficacy and safety) due to GCP non-compliance. Thus 8 participants who were randomized and treated are not reported in the tables below.

Director of Clinical Trials

Oral Tapentadol 100 mg to 250 mg twice daily. Tablet taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. The participant continued at the dose that was effective at the end of the Titration Phase.

Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. The participant continued at the dose that was effective at the end of the Titration Phase.

Number of Participants Scored as Responder in Maintenance Phase.

Prior to start of the Titration Phase

End of Week 1 of the Titration Phase

End of Week 2 of the Titration Phase

Full Analysis Set (Titration Period), observed.

Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Tapentadol Treatment Arm.

Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Morphine Treatment Arm.

Prior to start of Maintenance Phase

End of Week 1 of the Maintenance Phase

End of Week 2 of the Maintenance Phase

End of Week 3 of the Maintenance Phase

End of Week 4 of the Maintenance Phase

Matching Placebo After Tapentadol in the Titration Phase

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

Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase.

Start of Titration

End of Week 1

End of Week 2

Full Analysis Set (Titration Phase), observed.

Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Tapentadol Arm.

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

Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Morphine Arm.

Prior to start of maintenance phase

End of Week 3

End of Week 4

Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase.

Full Analysis Set (Titration phase), observed.

Use of Rescue Medication in the Titration Phase.

Full Analysis Set (Maintenance phase), observed.

Number of Participants Using Immediate Release Morphine Rescue Medication in the Maintenance Phase

Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses

Morphine Controlled Release Titration Phase

Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).

Morphine Controlled Release Maintenance Phase

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

The Average Mean Total Daily Dose of Rescue Medication.

Mental Component Summary

Physical Component Summary

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

Changes in the Short Form 36® Health Survey (SF-36®) During the Titration Phase.

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

Changes in the Short Form 36® Health Survey (SF-36®) During the Maintenance Phase.

Full analysis set (Titration Phase), observed.

Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Change From Start of Titration to Endpoint Titration.

Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Titration Phase.

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

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.

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

Changes in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Maintenance Phase.

Very Much Improved

Much Improved

Minimally Improved

No Change

Minimally Worse

Much Worse

Very Much Worse

Patient Global Impression of Change

Excellent at the start of the titration phase

Excellent at the end of the titration phase

Good at the start of the titration phase

Good at the end of the titration phase

Fair at the start of the titration phase

Fair at the end of the titration phase

Poor at the start of the titration phase

Poor at the end of the titration phase

Not completed at the start of titration

Not completed at the end of the titration

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.

Quality of Sleep (Sleep Questionnaire) in the Titration Phase.

Excellent at start of maintenance phase

Excellent at the end of maintenance phase

Good at start of maintenance phase

Good at the end of maintenance phase

Fair at start of maintenance phase

Fair at the end of maintenance phase

Poor at start of maintenance phase

Poor at the end of maintenance phase

Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. The participant continued at the dose that was effective at the end of the Titration Phase

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.

Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial.

None

Mild

Moderate

Moderately Severe

Severe

Oral Tapentadol 100 mg to 250 mg twice daily. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).

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.

Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase.

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.

Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase.

Overall abdominal subscale

Overall rectal subscale

Overall stool subscale

Overall PAC-SYM score

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

Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Titration Phase

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

Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Maintenance Phase

Oral Tapentadol 100 mg to 250 mg twice daily. Participants randomized to placebo received 100 mg tapentadol prolonged release (PR) twice daily for 3 days to taper them off the tapentadol dose they had received in the Titration Phase. From the 4th day (Day 18) all participants received matching placebo in the maintenance (i.e. randomized withdrawal) phase.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Study to Evaluate Tapentadol (CG5503) in the Treatment of Chronic Tumor-Related Pain Compared With Placebo and Morphine	NCT00472303	Tumor Pain	Tapentadol Exte... Matching Placeb... Morphine Sulpha...	18 Years -	Grünenthal GmbH
A Study to Evaluate Tapentadol (CG5503) in the Treatment of Chronic Tumor-Related Pain Compared With Placebo and Morphine	NCT00472303	Tumor Pain	Tapentadol Exte... Matching Placeb... Morphine Sulpha...	18 Years -	Grünenthal GmbH

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