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

• Sponsor: Grünenthal GmbH (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00472303
• Collaborator: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Enrollment: 622
• Locations: 71
• Arms: 3
• Duration (Months): 59
• Patients Per Site: 8.8
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Tumor; Pain	Drug: Tapentadol Extended Release; Drug: Matching Placebo after Tapentadol in the Titration Phase.; Drug: Morphine Sulphate Controlled Release	Phase 3

Detailed Description

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).

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: 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
• Study Start Date: Jul 1, 2007
• Actual Primary Completion Date: Jun 1, 2012
• Actual Study Completion Date: Jun 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Matching Placebo after Tapentadol in Titration Phase 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.	Drug: Tapentadol Extended Release; 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.; Other Names: Palexia Nucynta Yantil ; Drug: Matching Placebo after Tapentadol in the Titration Phase.; 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.
Active Comparator: Morphine Controlled Release 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.	Drug: Morphine Sulphate Controlled Release; 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.; Other Names: MST® CONTINUS®
Experimental: Tapentadol Prolonged Release 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.	Drug: Tapentadol Extended Release; 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.; Other Names: Palexia Nucynta Yantil

Outcome Measures

Primary Outcome Measures

1. Number of Participants Scored as Responder in Maintenance Phase. [Day 18 through Day 43 (End of Maintenance Phase)]

   A "responder" is a participant in the study that: completed 28 days of the maintenance phase 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. 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.

Secondary Outcome Measures

1. Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Tapentadol Treatment Arm. [Day 1 through Day 14 (End of Titration 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".

2. Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Morphine Treatment Arm. [Day 1 through Day 14 (End of Titration 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".

3. Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. [Day 18 through Day 43 (End of 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".

4. Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Tapentadol Arm. [Day 1 through Day 14 (End of Titration 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 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".

5. Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Morphine Arm. [Day 1 through Day 14 (End of Titration 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 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".

6. Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. [Day 15 through Day 43 (End of 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".

7. Use of Rescue Medication in the Titration Phase. [Day 1 through Day 14 (End of 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).

8. Number of Participants Using Immediate Release Morphine Rescue Medication in the Maintenance Phase [Day 15 through Day 43 (End of 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.

9. The Average Mean Total Daily Dose of Rescue Medication. [Day 1 (Start of Titration Phase) through Day 43 (End of Maintenance Phase)]

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

10. Changes in the Short Form 36® Health Survey (SF-36®) During the Titration Phase. [Day 1 (Start of Titration); Day 14 (End of 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.

11. Changes in the Short Form 36® Health Survey (SF-36®) During the Maintenance Phase. [Day 15 (Start of Maintenance); Day 43 (End of 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.

12. Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Change From Start of Titration to Endpoint Titration. [Day 1 (Start of Titration); Day 14 (End of Titration Phase)]

    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).

13. Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Titration Phase. [Day 1 (Start of Titration); Day 14 (End of 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.

14. 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. [Day 15 (Start of Maintenance); Day 43 (End of Maintenance Phase)]

    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).

15. Changes in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Maintenance Phase. [Day 15 (Start of Maintenance); Day 43 (End of 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.

16. Patient Global Impression of Change [Day 43 (End of 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.

17. Quality of Sleep (Sleep Questionnaire) in the Titration Phase. [Day 1 (Start of Titration); Day 14 (end of 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.

18. Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial. [Day 15 (Start of Maintenance); Day 43 (End of Maintenance 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 maintenance to the completion of treatment is reported. The participant could choose one of the following options: Excellent, good, fair and poor.

19. Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase. [Day 14 (End of 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.

20. Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase. [Day 43 (End of 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.

21. Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Titration Phase [Day 1 (Start of Titration); Day 14 (End of 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.

22. Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Maintenance Phase [Day 15 (Start of Maintenance); Day 43 (End of 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.

Eligibility Criteria

Criteria

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

Inclusion Criteria

• Male and non-pregnant, non-lactating female subjects.

• Of at least 18 years of age with chronic malignant tumor-related pain with a mean pain intensity (NRS) of 5 points or higher.

• Subjects who are opioid-naïve or pretreated with an equianalgesic dose range equivalent of up to 160 mg oral morphine per day and are dissatisfied with prior treatment.

• Women must be postmenopausal, surgically sterile, or practicing or agree to practice an effective method of birth control throughout the trial.

• Expected course of the disease and the pain that would permit compliance with the trial protocol over the entire trial period.

Exclusion Criteria

Key Exclusion Criteria:

• Subjects will be excluded from the study if they have a history of seizure disorder or epilepsy;

• known history and/or presence of cerebral tumor or cerebral metastases.

• history of alcohol or drug abuse;

• uncontrolled hypertension,

• clinical laboratory values reflecting severe renal insufficiency,

• moderate or severe hepatic impairment,

• hepatitis B or C, HIV,

• inadequate bone marrow reserve

• currently treated with radiotherapy,

• pain-inducing chemotherapy,

• anti-parkinsonian drugs, neuroleptics, monoamine oxidase inhibitors, serotonin norepinephrine reuptake inhibitor (SNRI) or any other analgesic therapy than investigational medication or rescue medication during the trial.

• selective serotonin reuptake inhibitor (SSRI) treatments are allowed if taken for at least 30 days before the screening period of the study at an unchanged dose.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Site 043004	Klagenfurt		Austria	9020
2	Site 043002	Vienna		Austria	1020
3	Site 043001	Vienna		Austria	1090
4	Site 043005	Vienna		Austria	1100
5	Site 359013	Gabrovo		Bulgaria	5300
6	Site 359011	Pleven		Bulgaria	5800
7	Site 359014	Plovdiv		Bulgaria	4004
8	Site 359004	Shumen		Bulgaria	9700
9	Site 359008	Sofia		Bulgaria	1784
10	Site 359012	Varna		Bulgaria	9003
11	Site 385007	Osijek		Croatia	31000
12	Site 385001	Slavonski Brod		Croatia	35000
13	Site 385004	Varazdin		Croatia	42000
14	Site 385006	Zabok		Croatia	49210
15	Site 385002	Zagreb		Croatia	10000
16	Site 385003	Zagreb		Croatia	10000
17	Site 420005	Brno		Czechia	62500
18	Site 420002	Ceske Budejovice		Czechia	37087
19	Site 420006	Hradec Kralove		Czechia	50005
20	Site 420007	Liberec		Czechia	46063
21	Site 420008	Olomouc		Czechia	77520
22	Site 420001	Pilsen		Czechia	30460
23	Site 420004	Prague		Czechia	18181
24	Site 033101	Tarbes		France	65000
25	Site 049009	Berlin		Germany	12627
26	Site 049014	Essen		Germany	45122
27	Site 049012	Köln		Germany	50996
28	Site 049007	Löwenstein		Germany	74245
29	Site 049020	Potsdam		Germany	14467
30	Site 049006	Waldkirch		Germany	79183
31	Site 049002	Wiesbaden		Germany	65185
32	Site 036001	Debrecen		Hungary	4043
33	Site 036005	Komárom		Hungary	2900
34	Site 036003	Mátraháza		Hungary	3233
35	Site 036002	Nyiregyhaza		Hungary	4412
36	Site 036010	Szekszard		Hungary	7100
37	Site 036006	Székesfehérvár		Hungary	8000
38	Site 036009	Székesfehérvár		Hungary	8000
39	Site 039001	Napoli		Italy	80131
40	Site 373001	Chisinau		Moldova, Republic of	2025
41	Site 373002	Chisinau		Moldova, Republic of	2025
42	Site 048004	Bydgoszcz		Poland	85796
43	Site 048005	Gdańsk		Poland	80286
44	Site 048007	Poznan		Poland	60355
45	Site 048001	Warszawa		Poland	02781
46	Site 040006	Brasov		Romania	500074
47	Site 040002	Bucharest		Romania	022328
48	Site 040003	Bucharest		Romania	022328
49	Site 040004	Bucharest		Romania	022328
50	Site 040005	Cluj-Napoca		Romania	400015
51	Site 040001	Iasi		Romania	700106
52	Site 040007	Timisoara		Romania	300239
53	Site 007010	Arkhangel'sk		Russian Federation	163045
54	Site 007003	Moscow		Russian Federation	125284
55	Site 007007	Nizhniy Novgorod		Russian Federation	603140
56	Site 007012	Vladikavkaz		Russian Federation	362007
57	Site 007005	Yaroslavl		Russian Federation	150054
58	Site 381003	Belgrade		Serbia	11000
59	Site 381004	Belgrade		Serbia	11000
60	Site 381005	Belgrade		Serbia	11000
61	Site 381002	Nis		Serbia	18000
62	Site 381001	Sremska Kamenica		Serbia	21204
63	Site 421005	Banska Bystrica		Slovakia	97517
64	Site 421001	Kosice		Slovakia	04191
65	Site 034009	Barcelona		Spain	08208
66	Site 034005	Barcelona		Spain	08221
67	Site 034006	Mahón		Spain	07703
68	Site 034012	Pamplona		Spain	31008
69	Site 034004	Sevilla		Spain	1013
70	Site 034002	Valencia		Spain	46014
71	Site 046001	Stockholm		Sweden	17176

Sponsors and Collaborators

• Grünenthal GmbH
• Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Investigators

• Principal Investigator: Hans Georg Kress, Dr., Clinic of Anaesthesiology and Pain Management, AKH Vienna

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Grünenthal GmbH
• ClinicalTrials.gov Identifier: NCT00472303
• Other Study ID Numbers: 761101; 2006-004997-28; KF5503/15
• First Posted: May 11, 2007
• Last Update Posted: Nov 4, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Grünenthal GmbH: Opioid; Central acting analgesic; CG5503 PR; Tumor related pain; Cancer related pain; Morphine; Pain assessment; Placebo
• Additional relevant MeSH terms: Cancer Pain; Morphine; Tapentadol

Study Results

Participant Flow

Recruitment Details	The trial started on 13 Jun 2007 with the enrollment of the first participant and was completed on 04 Jun 2012 with the last follow-up examination. 622 participants signed informed consent. 505 participants were randomized and 504 had at least one dose of trial medication. 496 participants were part of the safety analysis set.
Pre-assignment Detail	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. The participants in the tapentadol titration phase were re-randomized to tapentadol or placebo in the maintenance phase.

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release	Matching Placebo After Tapentadol in Titration Phase
Arm/Group Description	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.	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.	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.
Period Title: Titration Phase
STARTED	338	158	0
COMPLETED	279	129	0
NOT COMPLETED	59	29	0
Period Title: Titration Phase
STARTED	279	129	0
COMPLETED	218	109	0
NOT COMPLETED	61	20	0
Period Title: Titration Phase
STARTED	106	109	112
COMPLETED	89	93	95
NOT COMPLETED	17	16	17

Baseline Characteristics

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release	Total
Arm/Group Description	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.	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.	Total of all reporting groups
Overall Participants	338	158	496
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	224 66.3%	102 64.6%	326 65.7%
>=65 years	114 33.7%	56 35.4%	170 34.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	59.8 (10.39)	61.5 (10.21)	60.4 (10.35)
Sex: Female, Male (Count of Participants)
Female	150 44.4%	75 47.5%	225 45.4%
Male	188 55.6%	83 52.5%	271 54.6%
Region of Enrollment (participants) [Number]
Austria	5 1.5%	3 1.9%	8 1.6%
Bulgaria	21 6.2%	13 8.2%	34 6.9%
Croatia	27 8%	11 7%	38 7.7%
Czech Republic	12 3.6%	3 1.9%	15 3%
France	1 0.3%	0 0%	1 0.2%
Germany	33 9.8%	14 8.9%	47 9.5%
Hungary	40 11.8%	21 13.3%	61 12.3%
Italy	1 0.3%	0 0%	1 0.2%
Moldova, Republic of	14 4.1%	5 3.2%	19 3.8%
Poland	24 7.1%	13 8.2%	37 7.5%
Romania	47 13.9%	21 13.3%	68 13.7%
Russian Federation	51 15.1%	26 16.5%	77 15.5%
Serbia	37 10.9%	19 12%	56 11.3%
Slovakia	4 1.2%	1 0.6%	5 1%
Spain	18 5.3%	6 3.8%	24 4.8%
Sweden	3 0.9%	2 1.3%	5 1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants Scored as Responder in Maintenance Phase.
Description	A "responder" is a participant in the study that: completed 28 days of the maintenance phase 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. 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)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (Maintenance Phase).

Arm/Group Title	Tapentadol Prolonged Release (Maintenance Phase)	Morphine Controlled Release (Maintenance Phase)	Matching Placebo After Tapentadol in Titration Phase
Arm/Group Description	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.	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.
Measure Participants	105	109	111
Number [participants]	65 19.2%	75 47.5%	55 11.1%

2. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (Titration Period), observed.

Arm/Group Title	Tapentadol Prolonged Release
Arm/Group Description	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.
Measure Participants	329
Prior to start of the Titration Phase	6.315 (1.4435)
End of Week 1 of the Titration Phase	5.324 (1.7476)
End of Week 2 of the Titration Phase	4.021 (1.6872)

3. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (Titration Period), observed.

Arm/Group Title	Morphine Controlled Release
Arm/Group Description	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.
Measure Participants	156
Prior to start of the Titration Phase	6.162 (1.5693)
End of Week 1 of the Titration Phase	4.906 (1.9039)
End of Week 2 of the Titration Phase	3.669 (1.7851)

4. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Tapentadol Prolonged Release (Maintenance Phase)	Matching Placebo After Tapentadol in the Titration Phase	Morphine Controlled Release
Arm/Group Description	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 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. The participant continued at the dose that was effective at the end of the Titration Phase.
Measure Participants	105	111	109
Prior to start of Maintenance Phase	3.198 (1.2043)	2.928 (1.2353)	2.928 (1.4106)
End of Week 1 of the Maintenance Phase	3.220 (1.2385)	3.115 (1.3799)	2.903 (1.4645)
End of Week 2 of the Maintenance Phase	3.248 (1.3724)	3.005 (1.5723)	2.858 (1.4783)
End of Week 3 of the Maintenance Phase	3.129 (1.3267)	3.055 (1.6702)	2.775 (1.4312)
End of Week 4 of the Maintenance Phase	3.121 (1.3768)	3.095 (1.7349)	2.768 (1.5065)

5. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (Titration Phase), observed.

Arm/Group Title	Tapentadol Prolonged Release (Titration Phase)
Arm/Group Description	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.
Measure Participants	331
Start of Titration	6.344 (1.4568)
End of Week 1	5.326 (1.7650)
End of Week 2	4.049 (1.8015)

6. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Morphine Controlled Release (Titration Phase)
Arm/Group Description	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.
Measure Participants	157
Start of Titration	6.258 (1.5609)
End of Week 1	4.937 (1.9080)
End of Week 2	3.690 (1.8365)

7. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Tapentadol Prolonged Release (Maintenance Phase)	Matching Placebo After Tapentadol in the Titration Phase	Morphine Controlled Release
Arm/Group Description	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 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. The participant continued at the dose that was effective at the end of the Titration Phase.
Measure Participants	105	111	109
Prior to start of maintenance phase	3.1444 (1.16485)	2.8686 (1.19387)	2.832 (1.3895)
End of Week 1	3.0869 (1.22550)	3.0073 (1.32110)	2.780 (1.3706)
End of Week 2	3.1148 (1.27905)	2.8683 (1.47838)	2.790 (1.4170)
End of Week 3	3.0137 (1.26515)	2.9122 (1.60299)	2.733 (1.4512)
End of Week 4	3.0002 (1.37551)	2.9220 (1.68601)	2.728 (1.4481)

8. Secondary Outcome

Title	Use of Rescue Medication in the Titration Phase.
Description	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)

Outcome Measure Data

Analysis Population Description

Full Analysis Set (Titration phase), observed.

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release
Arm/Group Description	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.	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.
Measure Participants	335	157
Number [participants]	241 71.3%	91 57.6%

9. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full Analysis Set (Maintenance phase), observed.

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release	Matching Placebo After Tapentadol in Titration Phase
Arm/Group Description	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.	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.
Measure Participants	105	109	111
Number [participants]	75 22.2%	67 42.4%	80 16.1%

10. Secondary Outcome

Title	The Average Mean Total Daily Dose of Rescue Medication.
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Tapentadol Prolonged Release (Titration Phase)	Morphine Controlled Release Titration Phase	Tapentadol Prolonged Release (Maintenance Phase)	Matching Placebo After Tapentadol in Titration Phase	Morphine Controlled Release Maintenance Phase
Arm/Group Description	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.	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	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 Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by 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. The participant continued at the dose that was effective at the end of the Titration Phase.
Measure Participants	335	157	105	111	109
Mean (Standard Deviation) [milligrams per day of morphine rescue]	13.31 (17.41)	8.87 (12.50)	11.2 (12.739)	13.65 (13.666)	8.91 (14.951)

11. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release
Arm/Group Description	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.	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.
Measure Participants	285	131
Mental Component Summary	1.3 (10.63)	1.1 (11.78)
Physical Component Summary	2.0 (5.99)	3.1 (6.48)

12. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Tapentadol Extended Release	Morphine Controlled Release	Matching Placebo After Tapentadol in Titration Phase
Arm/Group Description	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.	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.
Measure Participants	95	97	103
Mental Component Summary	-0.4 (10.81)	-2.164 (9.42)	-1.5 (9.99)
Physical Component Summary	-1.1 (6.26)	-0.671 (7.21)	-0.9 (6.29)

13. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full analysis set (Titration Phase), observed.

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release
Arm/Group Description	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.	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.
Measure Participants	286	132
Mean (Standard Deviation) [units on a scale]	0.093 (0.3294)	0.131 (0.3162)

14. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

Full analysis set (Titration Phase), observed.

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release
Arm/Group Description	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.	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.
Measure Participants	286	131
Mean (Standard Deviation) [units on a scale]	3.8 (22.63)	5.6 (20.42)

15. Secondary Outcome

Title	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.
Description	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)

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Tapentadol Prolonged Release	Matching Placebo After Tapentadol in Titration Phase
Arm/Group Description	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 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.
Measure Participants	95	103
Mean (Standard Deviation) [units on a scale]	-0.0626 (0.3130)	-0.058 (0.2909)

16. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release	Matching Placebo After Tapentadol in the Titration Phase
Arm/Group Description	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.	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.
Measure Participants	95	97	103
Mean (Standard Deviation) [units on a scale]	-2.1 (19.80)	-0.6 (16.94)	-1.5 (18.55)

17. Secondary Outcome

Title	Patient Global Impression of Change
Description	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)

Outcome Measure Data

Analysis Population Description

Full Analysis Set, observed.

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release	Matching Placebo After Tapentadol in Titration Phase
Arm/Group Description	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.	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.
Measure Participants	94	97	103
Very Much Improved	4 1.2%	6 3.8%	6 1.2%
Much Improved	29 8.6%	23 14.6%	31 6.3%
Minimally Improved	33 9.8%	38 24.1%	38 7.7%
No Change	10 3%	12 7.6%	11 2.2%
Minimally Worse	10 3%	6 3.8%	9 1.8%
Much Worse	7 2.1%	12 7.6%	7 1.4%
Very Much Worse	1 0.3%	0 0%	1 0.2%

18. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release
Arm/Group Description	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.	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.
Measure Participants	338	158
Excellent at the start of the titration phase	9 2.7%	4 2.5%
Excellent at the end of the titration phase	12 3.6%	3 1.9%
Good at the start of the titration phase	77 22.8%	47 29.7%
Good at the end of the titration phase	139 41.1%	64 40.5%
Fair at the start of the titration phase	142 42%	51 32.3%
Fair at the end of the titration phase	121 35.8%	61 38.6%
Poor at the start of the titration phase	74 21.9%	41 25.9%
Poor at the end of the titration phase	37 10.9%	14 8.9%
Not completed at the start of titration	36 10.7%	15 9.5%
Not completed at the end of the titration	29 8.6%	16 10.1%

19. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release	Matching Placebo After Tapentadol in Titration Phase
Arm/Group Description	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	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.
Measure Participants	105	108	110
Excellent at start of maintenance phase	8 2.4%	2 1.3%	4 0.8%
Excellent at the end of maintenance phase	8 2.4%	9 5.7%	8 1.6%
Good at start of maintenance phase	55 16.3%	51 32.3%	60 12.1%
Good at the end of maintenance phase	43 12.7%	40 25.3%	49 9.9%
Fair at start of maintenance phase	35 10.4%	50 31.6%	42 8.5%
Fair at the end of maintenance phase	38 11.2%	53 33.5%	37 7.5%
Poor at start of maintenance phase	7 2.1%	5 3.2%	4 0.8%
Poor at the end of maintenance phase	14 4.1%	5 3.2%	13 2.6%

20. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release	Matching Placebo After Tapentadol in Titration Phase
Arm/Group Description	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.	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.	Oral Tapentadol 100 mg to 250 mg twice daily. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).
Measure Participants	7	6	9
None	7 2.1%	5 3.2%	8 1.6%
Mild	0 0%	1 0.6%	1 0.2%
Moderate	0 0%	0 0%	0 0%
Moderately Severe	0 0%	0 0%	0 0%
Severe	0 0%	0 0%	0 0%

21. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release	Matching Placebo After Tapentadol in Titration Phase
Arm/Group Description	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.	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.
Measure Participants	26	29	29
None	19 5.6%	23 14.6%	21 4.2%
Mild	7 2.1%	6 3.8%	8 1.6%
Moderate	0 0%	0 0%	0 0%
Moderately Severe	0 0%	0 0%	0 0%
Severe	0 0%	0 0%	0 0%

22. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release
Arm/Group Description	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.	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.
Measure Participants	216	93
Overall abdominal subscale	-0.062 (0.6507)	-0.076 (0.7242)
Overall rectal subscale	0.059 (0.6442)	-0.006 (0.6736)
Overall stool subscale	0.02 (0.812)	0.13 (0.870)
Overall PAC-SYM score	0.003 (0.5782)	0.027 (0.6154)

23. Secondary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Tapentadol Prolonged Release	Morphine Controlled Release	Matching Placebo After Tapentadol in Titration Phase
Arm/Group Description	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.	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.
Measure Participants	95	96	103
Overall abdominal subscale	-0.105 (0.6280)	0.026 (0.5966)	-0.075 (0.5330)
Overall rectal subscale	0.017 (0.5086)	0.014 (0.5090)	-0.033 (0.5822)
Overall stool subscale	-0.07 (0.743)	0.03 (0.724)	-0.03 (0.667)
Overall PAC-SYM score	-0.059 (0.4992)	0.024 (0.4584)	-0.048 (0.4771)

Adverse Events

Time Frame	Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Arm/Group Title	Tapentadol Prolonged Release (Titration Phase)		Morphine Controlled Release (Titration Phase)		Tapentadol Prolonged Release (Maintenance Phase)		Matching Placebo After Tapentadol in Titration Phase		Morphine Controlled Release (Maintenance Phase)
Arm/Group Description	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.		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.		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.		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. The dose that was effective at the end of the Titration Phase.
All Cause Mortality
	Tapentadol Prolonged Release (Titration Phase)		Morphine Controlled Release (Titration Phase)		Tapentadol Prolonged Release (Maintenance Phase)		Matching Placebo After Tapentadol in Titration Phase		Morphine Controlled Release (Maintenance Phase)
	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
	Tapentadol Prolonged Release (Titration Phase)		Morphine Controlled Release (Titration Phase)		Tapentadol Prolonged Release (Maintenance Phase)		Matching Placebo After Tapentadol in Titration Phase		Morphine Controlled Release (Maintenance Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	25/338 (7.4%)		6/158 (3.8%)		12/106 (11.3%)		10/112 (8.9%)		6/109 (5.5%)
Blood and lymphatic system disorders
Anaemia	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		1/109 (0.9%)
Anaemia	0/338 (0%)		0/158 (0%)		0/106 (0%)		1/112 (0.9%)		1/109 (0.9%)
Febrile neutropenia	0/338 (0%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		1/109 (0.9%)
Thrombocytopenia	0/338 (0%)		0/158 (0%)		0/106 (0%)		1/112 (0.9%)		0/109 (0%)
Cardiac disorders
Cardio-respiratory arrest	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Cor pulmonale acute	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Cardiovascular insufficiency	0/338 (0%)		0/158 (0%)		2/106 (1.9%)		0/112 (0%)		0/109 (0%)
Coronary artery disease	0/338 (0%)		0/158 (0%)		0/106 (0%)		1/112 (0.9%)		0/109 (0%)
Endocrine disorders
Adrenocortical insufficiency acute	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Gastrointestinal disorders
Diarrhoea	2/338 (0.6%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Ascites	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		2/112 (1.8%)		0/109 (0%)
Haematemesis	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Melaena	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Vomiting	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Intestinal perforation	0/338 (0%)		0/158 (0%)		1/106 (0.9%)		0/112 (0%)		0/109 (0%)
General disorders
Asthenia	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Hospitalization due to travel problems	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Pyrexia	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Death	0/338 (0%)		0/158 (0%)		2/106 (1.9%)		0/112 (0%)		0/109 (0%)
General physical health deterioration	0/338 (0%)		0/158 (0%)		1/106 (0.9%)		0/112 (0%)		0/109 (0%)
Hepatobiliary disorders
Hepatic failure	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Infections and infestations
Lobar pneumonia	0/338 (0%)		0/158 (0%)		0/106 (0%)		1/112 (0.9%)		0/109 (0%)
Peritonitis	0/338 (0%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		1/109 (0.9%)
Pneumonia	0/338 (0%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		1/109 (0.9%)
Injury, poisoning and procedural complications
Femur fracture	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Spinal compression fracture	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Lower limb fracture	0/338 (0%)		0/158 (0%)		0/106 (0%)		1/112 (0.9%)		0/109 (0%)
Investigations
Blood urea increased	0/338 (0%)		0/158 (0%)		1/106 (0.9%)		0/112 (0%)		0/109 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Muscular weakness	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Osteonecrosis	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Trismus	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm malignant	5/338 (1.5%)		1/158 (0.6%)		4/106 (3.8%)		2/112 (1.8%)		1/109 (0.9%)
Metastases to central nervous system	1/338 (0.3%)		1/158 (0.6%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Tumour pain	1/338 (0.3%)		0/158 (0%)		1/106 (0.9%)		0/112 (0%)		0/109 (0%)
Psychiatric disorders
Confusional state	0/338 (0%)		1/158 (0.6%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Withdrawal syndrome	0/338 (0%)		0/158 (0%)		0/106 (0%)		1/112 (0.9%)		0/109 (0%)
Renal and urinary disorders
Renal failure acute	0/338 (0%)		0/158 (0%)		1/106 (0.9%)		0/112 (0%)		0/109 (0%)
Reproductive system and breast disorders
Female genital tract fistula	0/338 (0%)		1/158 (0.6%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Respiratory, thoracic and mediastinal disorders
Acute respiratory failure	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Dyspnoea	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		1/109 (0.9%)
Pulmonary embolism	1/338 (0.3%)		1/158 (0.6%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Pulmonary haemorrhage	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Pulmonary oedema	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Respiratory failure	0/338 (0%)		0/158 (0%)		1/106 (0.9%)		0/112 (0%)		0/109 (0%)
Chronic obstructive pulmonary disease	0/338 (0%)		0/158 (0%)		0/106 (0%)		1/112 (0.9%)		0/109 (0%)
Vascular disorders
Deep vein thrombosis	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Superior vena cava syndrome	1/338 (0.3%)		0/158 (0%)		0/106 (0%)		0/112 (0%)		0/109 (0%)
Thrombosis	0/338 (0%)		1/158 (0.6%)		0/106 (0%)		0/112 (0%)		1/109 (0.9%)
Other (Not Including Serious) Adverse Events
	Tapentadol Prolonged Release (Titration Phase)		Morphine Controlled Release (Titration Phase)		Tapentadol Prolonged Release (Maintenance Phase)		Matching Placebo After Tapentadol in Titration Phase		Morphine Controlled Release (Maintenance Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	112/338 (33.1%)		80/158 (50.6%)		41/106 (38.7%)		34/112 (30.4%)		37/109 (33.9%)
Gastrointestinal disorders
Nausea	42/338 (12.4%)		38/158 (24.1%)		16/106 (15.1%)		17/112 (15.2%)		11/109 (10.1%)
Constipation	48/338 (14.2%)		28/158 (17.7%)		12/106 (11.3%)		13/112 (11.6%)		12/109 (11%)
Vomiting	17/338 (5%)		25/158 (15.8%)		8/106 (7.5%)		3/112 (2.7%)		6/109 (5.5%)
Dry Mouth	4/338 (1.2%)		10/158 (6.3%)		3/106 (2.8%)		2/112 (1.8%)		1/109 (0.9%)
General disorders
Fatigue	10/338 (3%)		8/158 (5.1%)		4/106 (3.8%)		6/112 (5.4%)		6/109 (5.5%)
Metabolism and nutrition disorders
Decreased Appetite	9/338 (2.7%)		6/158 (3.8%)		8/106 (7.5%)		6/112 (5.4%)		6/109 (5.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm Malignant	3/338 (0.9%)		0/158 (0%)		6/106 (5.7%)		2/112 (1.8%)		3/109 (2.8%)
Nervous system disorders
Dizziness	17/338 (5%)		10/158 (6.3%)		5/106 (4.7%)		4/112 (3.6%)		0/109 (0%)
Somnolence	14/338 (4.1%)		10/158 (6.3%)		3/106 (2.8%)		2/112 (1.8%)		6/109 (5.5%)
Skin and subcutaneous tissue disorders
Hyperhidrosis	9/338 (2.7%)		7/158 (4.4%)		4/106 (3.8%)		1/112 (0.9%)		7/109 (6.4%)

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 at least 30 days before it is submitted for publication. Neither party has the right to prohibit publication unless publication can be shown to affect possible patent rights.