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

• Sponsor: Grünenthal GmbH (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00505414
• Collaborator: Johnson & Johnson Pharmaceutical Research & Development, L.L.C. (Industry)
• Enrollment: 136
• Locations: 37
• Arms: 3
• Duration (Months): 23
• Patients Per Site: 3.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of this study is to determine whether CG5503 (tapentadol) is effective and safe in the treatment of chronic tumor related pain compared to placebo.

Condition or Disease	Intervention/Treatment	Phase
Pain; Neoplasm; Cancer	Drug: Tapentadol in the Titration Phase; Drug: Morphine in the Maintenance Phase; Drug: Matching Placebo in the Maintenance Phase after Tapentadol in the Titration Phase; Drug: Tapentadol in the Maintenance Phase; Drug: Morphine in the Titration Phase	Phase 3

Detailed Description

Normally chronic tumor related pain is controlled when subjects 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, a newly synthesized drug with an Prolonged Release (ER) formulation, also acts as a centrally acting pain reliever but has a dual mode of action.

The aim of this trial is to investigate the effectiveness (level of pain control) and safety (side effects) of Tapentadol Prolonged Release (ER) compared to a tablet with no active ingredient drug (placebo) and a 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, multicenter trial. To maintain the blind all subjects were re-randomized at the start of the maintenance period. To maintain the blind all tapentadol subjects were re-randomized at the start of the maintenance period. Subjects that received morphine in the titration period continued in the maintenance period on morphine.

The trial includes a 2 week titration phase starting with either 45 mg Morphine Sulfate Controlled Release (CR) twice daily or 100 mg tapentadol ER taken twice daily (bid). Based on effectiveness and side effects participants can up-titrate in steps of 50 mg Tapentadol ER or 15 mg Morphine Sulfate CR to a maximal dose of 250 mg Tapentadol ER bid or 90 mg Morphine Sulfate CR twice daily respectively. If subjects meet the stabilization 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.

Assessments of pain relief, defined as a responder include the pain intensity numeric rating scale (NRS). The Patient Global Impression of Change scale (PGIC) will also be used as a secondary efficacy endpoint. Safety evaluations include monitoring of adverse events, physical examinations, and clinical laboratory tests. Venous blood samples will be collected for the determination of serum concentrations of tapentadol.

Study Design

• Study Type: Interventional
• Actual Enrollment: 136 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) Prolonged Release (PR*) in Subjects With Moderate to Severe Chronic Malignant Tumor-related Pain. *Prolonged Release and is the Recommended Nomenclature for Use in the European Union (EU). ER Means Extended Release and is the Recommended Nomenclature for Use in the United States of America (USA). "PR" is Synonymous With "ER" and is Interchangeable.
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Feb 1, 2009
• Actual Study Completion Date: May 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Matching Placebo Oral Tapentadol 100 mg to 250 mg twice daily. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Drug: Matching Placebo in the Maintenance Phase after Tapentadol in the Titration Phase; Participant randomized to placebo in the maintenance phase received 100 mg tapentadol prolonged release twice daily for 3 days to taper them off of the tapentadol dose they had received in the titration period. From the fourth day of the maintenance period onwards they received placebo twice daily.
Active Comparator: Morphine Controlled Release Oral Morphine 45 mg to 90 mg twice daily.	Drug: Morphine in the Maintenance Phase; Participant started the trials with 45 mg morphine controlled release twice daily. Upward titration could then occur at a minimum of 3-day intervals in increments of 15 mg morphine twice daily. The maximum dose of morphine controlled release was 90 mg twice daily. Downward titration (but not below 45 mg twice daily) was permitted. In the maintenance phase participants continued on the dose level established in titration phase. Participants randomized to the morphine arm remained on morphine if they qualified for the maintenance phase of the study. The participants were maintained on the dose established at the end of the titration phase. The adverse events listed were documented in the maintenance phase.; Other Names: MS Contin overencapsulated for blinding ; Drug: Morphine in the Titration Phase; After signing informed consent eligible subjects were randomized to receive morphine controlled release. The oral medication was taken twice daily, morning and evening every 12 hours (with a minimum of 6 hours between doses). Participant started the trials with 45 mg morphine controlled release twice daily. Upward titration could then occur at a minimum of 3-day intervals in increments of 15 mg morphine twice daily. The maximum dose of morphine controlled release was 90 mg twice daily. Downward titration (but not below 45 mg twice daily) was permitted.
Experimental: Tapentadol Extended Release Oral Tapentadol 100 mg to 250 mg twice daily.	Drug: Tapentadol in the Titration Phase; Other Names: Palexia Nucynta ; Drug: Tapentadol in the Maintenance Phase; The participants re-randomized to receive tapentadol prolonged release in the maintenance phase were maintained on the dose established in the titration phase.

Outcome Measures

Primary Outcome Measures

1. Responder Rates in Maintenance Period [End of the 4 week Maintenance Phase (Day 43)]

   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 30 mg of rescue medication per day on average in the 28 day (excluding the first 3 days) 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 fails to meet at least 1 of the 3 criteria is not counted as a responder.

Secondary Outcome Measures

1. Patient Global Impression of Change (PGIC) [Day 15 corresponds with PGIC at end of titration phase; Day 43 corresponds with PGIC at end of maintenance phase]

   The Patient Global Impression of Change (PGIC) is an instrument where the participant indicates their perceived change at the end of a treatment phase. The overall participant status assessed using Patient Global Impression of Change (PGIC) self-assessment questionnaire which was used by participants to report on 7 categories listed as follows; Very Much Improved, Much Improved, Minimally Improved, No Change, Minimally Worse, Much Worse and Very Much Worse in tapentadol and morphine at Day 15 (Start of Maintenance Phase) and repeated in participants completing the Maintenance Phase in the Matching Placebo, Tapentadol and Morphine (Day 43).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• A signed informed consent document.

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

• Female subjects must be post menopausal, surgically sterile, or practicing an effective method of birth control and continue to do so throughout the trial.

• At least 18 years of age.

• Have chronic malignant tumor-related pain

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

• Have a mean pain intensity of at least 5 points on an 11-point Numeric Rating Scale (where 0 indicates no pain and 10 indicates worst possible pain).

• Have an expected course of the disease such that the pain that will permit compliance with the trial protocol over the entire trial period.

Exclusion Criteria:

• Have a life-long history of seizure disorder or epilepsy.

• Have had any of the following within one year: mild/moderate traumatic brain injury, stroke, and transient ischemic attack.

• Have had severe traumatic brain injury within 15 years (consisting of ≥ 1 of the following: brain contusion, intracranial hematoma, and either unconsciousness or post-traumatic amnesia lasting for more than 24 hours) or residual sequelae suggesting transient changes in consciousness.

• Have a known history and/or presence of cerebral metastases.

• Have moderately or severely impaired hepatic function.

• Have laboratory values reflecting inadequate hepatic function.

• Have thrombopenia, leucopenia or hypercalcemia

• Have severely impaired renal function.

• Having uncontrolled hypertension

• Having clinically relevant history of hypersensitivity, allergy or contraindications to morphine or any of the excipients.

• Have chronic hepatitis B or hepatitis C, or Human Immunodeficiency Virus (HIV).

• Subjects currently undergoing the following concomitant therapy: radiotherapy, pain inducing chemotherapy, anti-parkinsonian drugs, neuroleptics, monoamine oxidase inhibitors, serotonin norepinephrine re-uptake inhibitors (SNRI) or any other analgesic therapy than investigational medication or rescue medication during the trial. Selective serotonin re-uptake inhibitor (SSRI) treatments are allowed if taken for at least 30 days before the screening period of the trial at an unchanged dose.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	001013	Saint Petersburg	Florida	United States	80918
2	001002	Elkhart	Indiana	United States	46514
3	001001	Shreveport	Louisiana	United States	71103
4	001010	Cedarhurst	New York	United States	11516
5	001003	Glens Falls	New York	United States	12801
6	001004	Winston-Salem	North Carolina	United States	27103
7	001015	Canton	Ohio	United States	44718
8	054003	La Plata	Buenos Aires	Argentina	B1900BAJ
9	054012	Pergamino	Buenos Aires	Argentina	B2700CPM
10	054022	Quilmes	Buenos Aires	Argentina	B1878AAT
11	054008	Villa Dominico	Buenos Aires	Argentina	B1874ACL
12	054010	Rosario	Santa Fe	Argentina	S2000CVD
13	054013	Rosario	Santa Fe	Argentina	S2000CVD
14	054005	San Miguel de Tucuman	Tucuman	Argentina	T4000IAK
15	54009	Ciudad de Buenos Aires		Argentina	C1185AAT
16	054015	Santa Fe		Argentina	S3000FFU
17	056006	Coquimbo		Chile
18	056011	Santiago		Chile	7510009
19	056008	Santiago		Chile	8380000
20	056005	Santiago		Chile
21	056003	Talcahuano		Chile
22	056004	Temuco		Chile
23	056012	Valparaiso		Chile	236-3058
24	033002	Nice Cedex 1		France	06002
25	033015	Orléans- Cedex		France	45032
26	033001	Villejuif Cedex		France	94805
27	371001	Daugavpils		Latvia	5420
28	371002	Riga		Latvia	1079
29	380015	Cherkasy		Ukraine	18009
30	380011	Donetsk		Ukraine	83092
31	380012	Donetsk		Ukraine	83092
32	380008	Kharkiv		Ukraine	61024
33	380002	Kharkiv		Ukraine	61070
34	380013	Kiev		Ukraine	01601
35	380001	Kiev		Ukraine	61070
36	380009	Lviv		Ukraine	79031
37	380010	Poltava		Ukraine	36011

Sponsors and Collaborators

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

Investigators

• Principal Investigator: P. Poulain, Dr., Gustave Roussy, Cancer Campus, Grand Paris

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Grünenthal GmbH
• ClinicalTrials.gov Identifier: NCT00505414
• Other Study ID Numbers: 672519; 2007-001985-34; KF5503/16
• First Posted: Jul 23, 2007
• Last Update Posted: Nov 1, 2019
• Last Verified: Oct 1, 2019

• Keywords provided by Grünenthal GmbH: Chronic Tumor Related Pain; Analgesic; Tapentadol Extended Release; Morphine Sulfate Controlled Release; Pain assessment; Placebo
• Additional relevant MeSH terms: Cancer Pain; Morphine; Tapentadol

Study Results

Participant Flow

Recruitment Details	First participant in was enrolled on 29 June 2007 and the Last participant out was on the 02 February 2009. In general this was an out-patient study subject to country specific regulations.
Pre-assignment Detail	Eligible participants were required to stop their previous analgesic [pain treatment] therapy at randomization. 136 participants consented. 43 participants were not eligible for randomization to tapentadol extended release or morphine controlled release at baseline. 93 participants started the titration period.

Arm/Group Title	Morphine (Maintenance Phase)	Tapentadol (Maintenance Phase)	Matching Placebo (Maintenance Phase)	Tapentadol (Titration Phase)	Morphine (Titration Phase)
Arm/Group Description	Participants in the maintenance phase continued on the dose level established in titration phase, i.e. 45 mg to 90 mg twice daily.	Participants re-randomized to tapentadol prolonged release in the maintenance phase continued on the dose level established at the end of the titration phase. Oral tapentadol 100 mg to 250 mg twice daily.	Participants were re-randomized to placebo after being on tapentadol in the titration phase. At the start of this phase participants received 100 mg tapentadol prolonged release twice daily for 3 days to taper them off of the tapentadol dose they had received in the titration period. From the fourth day of the maintenance period onwards they received placebo twice daily.	After signing informed consent eligible participants were randomized to receive tapentadol extended release. Oral tapentadol 100 mg up to 250 mg twice daily. The oral medication was taken twice daily, morning and evening every 12 hours (with a minimum of 6 hours between doses).	After signing informed consent eligible participants were randomized to receive morphine controlled release. The oral medication was taken twice daily starting at 45 mg up to 90 mg twice daily, morning and evening every 12 hours (with a minimum of 6 hours between doses).
Period Title: Titration Phase
STARTED	0	0	0	62	31
COMPLETED	0	0	0	32	19
NOT COMPLETED	0	0	0	30	12
Period Title: Titration Phase
STARTED	18	15	14	0	0
Did Not Qualify for Maintenance Phase	0	0	0	3	1
COMPLETED	12	10	6	0	0
NOT COMPLETED	6	5	8	0	0

Baseline Characteristics

Arm/Group Title	Tapentadol (Titration Phase)	Morphine (Titration Phase)	Total
Arm/Group Description	After signing informed consent eligible participants were randomized to receive tapentadol extended release. Oral tapentadol 100 mg to 250 mg twice daily. The oral medication was taken twice daily, morning and evening every 12 hours (with a minimum of 6 hours between doses).	After signing informed consent eligible subjects were randomized to receive morphine controlled release. The oral medication was taken twice daily starting at 45 mg up to 90 mg twice daily, morning and evening every 12 hours (with a minimum of 6 hours between doses).	Total of all reporting groups
Overall Participants	62	31	93
Age (years) [Mean (Standard Deviation) ]
Titration Phase	62.4 (12.51)	60.6 (11.77)	61.8 (12.23)
Tapentadol Maintenance	63.5 (9.34)	63.5 (9.34)
Placebo Maintenance	61.0 (12.93)	61.0 (12.93)
Morphine Maintenance	58.4 (12.65)	58.4 (12.65)
Sex/Gender, Customized (participants) [Number]
Female (Titration)	35 56.5%	12 38.7%	47 50.5%
Male (Titration)	27 43.5%	19 61.3%	46 49.5%
Female (Morphine (Maintenance)	0 0%	8 25.8%	8 8.6%
Male (Morphine Maintenance)	0 0%	10 32.3%	10 10.8%
Female (Tapentadol Maintenance)	9 14.5%	0 0%	9 9.7%
Male (Tapentadol Maintenance)	6 9.7%	0 0%	6 6.5%
Female (Placebo Maintenance)	8 12.9%	0 0%	8 8.6%
Male (Placebo Maintenance)	6 9.7%	0 0%	6 6.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	0 0%	1 3.2%	1 1.1%
White	41 66.1%	19 61.3%	60 64.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	21 33.9%	11 35.5%	32 34.4%
Region of Enrollment (participants) [Number]
France	5 8.1%	0 0%	5 5.4%
United States	3 4.8%	4 12.9%	7 7.5%
Argentina	14 22.6%	7 22.6%	21 22.6%
Ukraine	16 25.8%	5 16.1%	21 22.6%
Chile	18 29%	9 29%	27 29%
Latvia	6 9.7%	6 19.4%	12 12.9%

Outcome Measures

1. Primary Outcome

Title	Responder Rates in Maintenance Period
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 30 mg of rescue medication per day on average in the 28 day (excluding the first 3 days) 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 fails to meet at least 1 of the 3 criteria is not counted as a responder.
Time Frame	End of the 4 week Maintenance Phase (Day 43)

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Number of participants with data available.

Arm/Group Title	Morphine (Maintenance Phase)	Tapentadol (Maintenance Phase)	Matching Placebo (Maintenance Phase)
Arm/Group Description	Participants in the maintenance phase continued on the dose level established in titration phase, i.e. 45 mg to 90 mg twice daily.	Participants re-randomized to tapentadol prolonged release in the maintenance phase continued on the dose level established at the end of the titration phase. Oral tapentadol 100 mg to 250 mg twice daily.	Participants were re-randomized to placebo after being on tapentadol in the titration phase. At the start of this phase participants received 100 mg tapentadol prolonged release twice daily for 3 days to taper them off of the tapentadol dose they had received in the titration period. From the fourth day of the maintenance period onwards they received placebo twice daily.
Measure Participants	18	15	14
Number [participants]	6 9.7%	8 25.8%	3 3.2%

2. Secondary Outcome

Title	Patient Global Impression of Change (PGIC)
Description	The Patient Global Impression of Change (PGIC) is an instrument where the participant indicates their perceived change at the end of a treatment phase. The overall participant status assessed using Patient Global Impression of Change (PGIC) self-assessment questionnaire which was used by participants to report on 7 categories listed as follows; Very Much Improved, Much Improved, Minimally Improved, No Change, Minimally Worse, Much Worse and Very Much Worse in tapentadol and morphine at Day 15 (Start of Maintenance Phase) and repeated in participants completing the Maintenance Phase in the Matching Placebo, Tapentadol and Morphine (Day 43).
Time Frame	Day 15 corresponds with PGIC at end of titration phase; Day 43 corresponds with PGIC at end of maintenance phase

Outcome Measure Data

Analysis Population Description

Full Analysis Set. Number of participants with data available.

Arm/Group Title	Morphine (Maintenance Phase)	Tapentadol (Maintenance Phase)	Matching Placebo (Maintenance Phase)	Tapentadol (Titration Phase)	Morphine (Titration Phase)
Arm/Group Description	Participants in the maintenance phase continued on the dose level established in titration phase, i.e. 45 mg to 90 mg twice daily.	Participants re-randomized to tapentadol prolonged release in the maintenance phase continued on the dose level established at the end of the titration phase. Oral tapentadol 100 mg to 250 mg twice daily.	Participants were re-randomized to placebo after being on tapentadol in the titration phase. At the start of this phase participants received 100 mg tapentadol prolonged release twice daily for 3 days to taper them off of the tapentadol dose they had received in the titration period. From the fourth day of the maintenance period onwards they received placebo twice daily.	After signing informed consent eligible participants were randomized to receive tapentadol extended release. Oral tapentadol 100 mg to 250 mg twice daily. The oral medication was taken twice daily, morning and evening every 12 hours (with a minimum of 6 hours between doses).	After signing informed consent eligible subjects were randomized to receive morphine controlled release. The oral medication was taken twice daily starting at 45 mg up to 90 mg twice daily, morning and evening every 12 hours (with a minimum of 6 hours between doses).
Measure Participants	18	15	14	62	31
Very Much Improved	1 1.6%	0 0%	0 0%	0 NaN	0 NaN
Much Improved	3 4.8%	8 25.8%	2 2.2%	5 NaN	1 NaN
Minimally Improved	4 6.5%	4 12.9%	4 4.3%	8 NaN	4 NaN
No Change	4 6.5%	1 3.2%	1 1.1%	3 NaN	2 NaN
Minimally Worse	0 0%	1 3.2%	0 0%	4 NaN	0 NaN
Much Worse	1 1.6%	1 3.2%	2 2.2%	2 NaN	0 NaN
Very Much Worse	0 0%	0 0%	0 0%	0 NaN	0 NaN
Missing	5 8.1%	0 0%	5 5.4%	40 NaN	24 NaN

Adverse Events

Time Frame	Participants were to be treated for up to 42 days: Titration (14 days) and Maintenance Phase (up to 28 days).
Adverse Event Reporting Description	More than one event might have occured in the same participant.
Arm/Group Title	Morphine (Maintenance Phase)		Tapentadol (Maintenance Phase)		Matching Placebo (Maintenance Phase)		Tapentadol (Titration Phase)		Morphine (Titration Phase)
Arm/Group Description	Participants in the maintenance phase continued on the dose level established in titration phase, i.e. 45 mg to 90 mg twice daily.		Participants re-randomized to tapentadol prolonged release in the maintenance phase continued on the dose level established at the end of the titration phase. Oral tapentadol 100 mg to 250 mg twice daily.		Participants were re-randomized to placebo after being on tapentadol in the titration phase. At the start of this phase participants received 100 mg tapentadol prolonged release twice daily for 3 days to taper them off of the tapentadol dose they had received in the titration period. From the fourth day of the maintenance period onwards they received placebo twice daily.		After signing informed consent eligible participants were randomized to receive tapentadol extended release. Oral tapentadol 100 mg to 250 mg twice daily. The oral medication was taken twice daily, morning and evening every 12 hours (with a minimum of 6 hours between doses).		After signing informed consent eligible subjects were randomized to receive morphine controlled release. The oral medication was taken twice daily starting at 45 mg up to 90 mg twice daily, morning and evening every 12 hours (with a minimum of 6 hours between doses).
All Cause Mortality
	Morphine (Maintenance Phase)		Tapentadol (Maintenance Phase)		Matching Placebo (Maintenance Phase)		Tapentadol (Titration Phase)		Morphine (Titration 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
	Morphine (Maintenance Phase)		Tapentadol (Maintenance Phase)		Matching Placebo (Maintenance Phase)		Tapentadol (Titration Phase)		Morphine (Titration Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/18 (22.2%)		2/15 (13.3%)		4/14 (28.6%)		11/62 (17.7%)		4/31 (12.9%)
Blood and lymphatic system disorders
Anemia	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		1/62 (1.6%)		0/31 (0%)
Gastrointestinal disorders
Abdominal Pain	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Diarrhoea	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Dysphagia	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		0/62 (0%)		0/31 (0%)
Intestinal Obstruction	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Nausea	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Vomiting	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
General disorders
Asthenia	0/18 (0%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		1/31 (3.2%)
Chest Pain	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Death	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Infections and infestations
Pneumonia	0/18 (0%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		2/31 (6.5%)
Pyelonephritis	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Injury, poisoning and procedural complications
Hip Fracture	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Metabolism and nutrition disorders
Diabetes Mellitus Inadequate Control	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Musculoskeletal and connective tissue disorders
Back Pain	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant Neoplasm Progression	1/18 (5.6%)		2/15 (13.3%)		2/14 (14.3%)		3/62 (4.8%)		1/31 (3.2%)
Psychiatric disorders
Disorientation	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Mental Status Change	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Respiratory, thoracic and mediastinal disorders
Respiratory Failure	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Vascular disorders
Deep Vein Thrombosis	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Other (Not Including Serious) Adverse Events
	Morphine (Maintenance Phase)		Tapentadol (Maintenance Phase)		Matching Placebo (Maintenance Phase)		Tapentadol (Titration Phase)		Morphine (Titration Phase)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	12/18 (66.7%)		9/15 (60%)		7/14 (50%)		28/62 (45.2%)		17/31 (54.8%)
Cardiac disorders
Tachycardia	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		0/62 (0%)		0/31 (0%)
Ear and labyrinth disorders
Vertigo	1/18 (5.6%)		0/15 (0%)		1/14 (7.1%)		4/62 (6.5%)		0/31 (0%)
Gastrointestinal disorders
Abdominal Pain	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Abdominal Pain Upper	0/18 (0%)		1/15 (6.7%)		1/14 (7.1%)		2/62 (3.2%)		0/31 (0%)
Constipation	2/18 (11.1%)		1/15 (6.7%)		0/14 (0%)		6/62 (9.7%)		3/31 (9.7%)
Diarrhoea	3/18 (16.7%)		1/15 (6.7%)		0/14 (0%)		2/62 (3.2%)		0/31 (0%)
Dry Mouth	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		2/62 (3.2%)		1/31 (3.2%)
Flatulence	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		2/62 (3.2%)		0/31 (0%)
Lip Oedema	0/18 (0%)		1/15 (6.7%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Nausea	2/18 (11.1%)		1/15 (6.7%)		2/14 (14.3%)		7/62 (11.3%)		4/31 (12.9%)
Vomiting	2/18 (11.1%)		2/15 (13.3%)		1/14 (7.1%)		9/62 (14.5%)		2/31 (6.5%)
General disorders
Asthenia	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		2/62 (3.2%)		2/31 (6.5%)
Chills	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		1/31 (3.2%)
Oedema	0/18 (0%)		1/15 (6.7%)		0/14 (0%)		0/62 (0%)		1/31 (3.2%)
Pyrexia	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		3/62 (4.8%)		1/31 (3.2%)
Thirst	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		1/31 (3.2%)
Infections and infestations
Bronchitis	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		2/62 (3.2%)		0/31 (0%)
Pneumonia	0/18 (0%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		2/31 (6.5%)
Rhinitis	0/18 (0%)		1/15 (6.7%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Urinary Tract Infection	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		2/62 (3.2%)		0/31 (0%)
Investigations
Blood Lactate Dehydrogenase Increased	0/18 (0%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		2/31 (6.5%)
Metabolism and nutrition disorders
Anorexia	2/18 (11.1%)		0/15 (0%)		1/14 (7.1%)		2/62 (3.2%)		1/31 (3.2%)
Hypokalaemia	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		0/62 (0%)		0/31 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		1/31 (3.2%)
Back Pain	1/18 (5.6%)		1/15 (6.7%)		0/14 (0%)		1/62 (1.6%)		0/31 (0%)
Torticollis	0/18 (0%)		1/15 (6.7%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Malignant Neoplasm Progression	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		1/31 (3.2%)
Nervous system disorders
Dizziness	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		4/62 (6.5%)		1/31 (3.2%)
Hemiparesis	0/18 (0%)		1/15 (6.7%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Somnolence	0/18 (0%)		0/15 (0%)		0/14 (0%)		2/62 (3.2%)		2/31 (6.5%)
Tremor	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		2/62 (3.2%)		0/31 (0%)
Psychiatric disorders
Depression	0/18 (0%)		1/15 (6.7%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Insomnia	0/18 (0%)		0/15 (0%)		2/14 (14.3%)		5/62 (8.1%)		0/31 (0%)
Nervousness	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		0/62 (0%)		1/31 (3.2%)
Renal and urinary disorders
Choluria	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/18 (0%)		1/15 (6.7%)		0/14 (0%)		2/62 (3.2%)		1/31 (3.2%)
Haemoptysis	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Rhinorrhoea	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Skin and subcutaneous tissue disorders
Pruritus	0/18 (0%)		0/15 (0%)		0/14 (0%)		1/62 (1.6%)		3/31 (9.7%)
Skin Lesion	1/18 (5.6%)		0/15 (0%)		0/14 (0%)		0/62 (0%)		0/31 (0%)
Vascular disorders
Hypotension	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		0/62 (0%)		0/31 (0%)
Orthostatic Hypotension	0/18 (0%)		0/15 (0%)		1/14 (7.1%)		3/62 (4.8%)		0/31 (0%)

Limitations/Caveats

Early termination, due to a recall of the morphine rescue medication and issues regarding supply of an alternative, lead to only 93 participants out of the 573 planned (16%) being available for analysis. The data should be interpreted with caution.

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Certain Agreements

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

The Sponsor and the Sponsor's designee 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.