Trial Outcomes & Findings for A Study to Evaluate Tapentadol (CG5503) in the Treatment of Chronic Tumor-Related Pain Compared With Placebo and Morphine (NCT NCT00472303)

NCT ID: NCT00472303

Last Updated: 2019-11-04

Results Overview

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

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 622 participants
• Primary outcome timeframe: Day 18 through Day 43 (End of Maintenance Phase)
• Results posted on: 2019-11-04

Participant Flow

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.

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.

Participant milestones

Measure	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.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily. Participants randomized to placebo received 100 mg tapentadol prolonged release (PR) twice daily for 3 days to taper them off the tapentadol dose they had received in the Titration Phase. From the 4th day (Day 18) all participants received matching placebo in the maintenance (i.e. randomized withdrawal) phase.
Titration Phase STARTED	338	158	0
Titration Phase COMPLETED	279	129	0
Titration Phase NOT COMPLETED	59	29	0
Discontinuations After Titration Phase STARTED	279	129	0
Discontinuations After Titration Phase COMPLETED	218	109	0
Discontinuations After Titration Phase NOT COMPLETED	61	20	0
Maintenance Phase STARTED	106	109	112
Maintenance Phase COMPLETED	89	93	95
Maintenance Phase NOT COMPLETED	17	16	17

Reasons for withdrawal

Measure	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.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily. Participants randomized to placebo received 100 mg tapentadol prolonged release (PR) twice daily for 3 days to taper them off the tapentadol dose they had received in the Titration Phase. From the 4th day (Day 18) all participants received matching placebo in the maintenance (i.e. randomized withdrawal) phase.
Titration Phase Adverse Event	22	12	0
Titration Phase Death	4	2	0
Titration Phase Lack of Efficacy	10	0	0
Titration Phase Withdrawal by Subject	16	13	0
Titration Phase Trial Medication non-compliant	4	1	0
Titration Phase Other	3	1	0
Discontinuations After Titration Phase Adverse Event	6	0	0
Discontinuations After Titration Phase Lack of Efficacy	48	17	0
Discontinuations After Titration Phase Withdrawal by Subject	2	2	0
Discontinuations After Titration Phase Trial Medication non-compliant	0	1	0
Discontinuations After Titration Phase Other	5	0	0
Maintenance Phase Adverse Event	5	6	6
Maintenance Phase Death	3	0	2
Maintenance Phase Lack of Efficacy	2	2	4
Maintenance Phase Withdrawal by Subject	6	7	3
Maintenance Phase Trial medication non-compliant	0	0	1
Maintenance Phase Resolution of pain	0	0	1
Maintenance Phase Other	1	1	0

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Tapentadol Prolonged Release n=338 Participants 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.	Morphine Controlled Release n=158 Participants 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 n=496 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Age, Categorical Between 18 and 65 years	224 Participants n=93 Participants	102 Participants n=4 Participants	326 Participants n=27 Participants
Age, Categorical >=65 years	114 Participants n=93 Participants	56 Participants n=4 Participants	170 Participants n=27 Participants
Age, Continuous	59.8 years STANDARD_DEVIATION 10.39 • n=93 Participants	61.5 years STANDARD_DEVIATION 10.21 • n=4 Participants	60.4 years STANDARD_DEVIATION 10.35 • n=27 Participants
Sex: Female, Male Female	150 Participants n=93 Participants	75 Participants n=4 Participants	225 Participants n=27 Participants
Sex: Female, Male Male	188 Participants n=93 Participants	83 Participants n=4 Participants	271 Participants n=27 Participants
Region of Enrollment Austria	5 participants n=93 Participants	3 participants n=4 Participants	8 participants n=27 Participants
Region of Enrollment Bulgaria	21 participants n=93 Participants	13 participants n=4 Participants	34 participants n=27 Participants
Region of Enrollment Croatia	27 participants n=93 Participants	11 participants n=4 Participants	38 participants n=27 Participants
Region of Enrollment Czech Republic	12 participants n=93 Participants	3 participants n=4 Participants	15 participants n=27 Participants
Region of Enrollment France	1 participants n=93 Participants	0 participants n=4 Participants	1 participants n=27 Participants
Region of Enrollment Germany	33 participants n=93 Participants	14 participants n=4 Participants	47 participants n=27 Participants
Region of Enrollment Hungary	40 participants n=93 Participants	21 participants n=4 Participants	61 participants n=27 Participants
Region of Enrollment Italy	1 participants n=93 Participants	0 participants n=4 Participants	1 participants n=27 Participants
Region of Enrollment Moldova, Republic of	14 participants n=93 Participants	5 participants n=4 Participants	19 participants n=27 Participants
Region of Enrollment Poland	24 participants n=93 Participants	13 participants n=4 Participants	37 participants n=27 Participants
Region of Enrollment Romania	47 participants n=93 Participants	21 participants n=4 Participants	68 participants n=27 Participants
Region of Enrollment Russian Federation	51 participants n=93 Participants	26 participants n=4 Participants	77 participants n=27 Participants
Region of Enrollment Serbia	37 participants n=93 Participants	19 participants n=4 Participants	56 participants n=27 Participants
Region of Enrollment Slovakia	4 participants n=93 Participants	1 participants n=4 Participants	5 participants n=27 Participants
Region of Enrollment Spain	18 participants n=93 Participants	6 participants n=4 Participants	24 participants n=27 Participants
Region of Enrollment Sweden	3 participants n=93 Participants	2 participants n=4 Participants	5 participants n=27 Participants

PRIMARY outcome

Timeframe: Day 18 through Day 43 (End of Maintenance Phase)

Population: Full Analysis Set (Maintenance Phase).

A "responder" is a participant in the study that:

1. completed 28 days of the maintenance phase

2. had a numeric rating scale score below 5 on the 11 point scale (where 0 indicates no pain and 10 indicates worst possible pain. This twice daily current pain score was averaged over Day 18 to Day 43.

3. did not use more than 20 mg of rescue medication per day on average in the 28 day maintenance period (from Day 18 to Day 43).

A participant that met all 3 of the above-mentioned criteria is counted as a responder, in other words the participant benefited from the assigned drug treatment. A participant that failed to meet only 1 of the 3 criteria is not counted as a responder.

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=105 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=109 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=111 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. The participant continued at the dose that was effective at the end of the Titration Phase.
Number of Participants Scored as Responder in Maintenance Phase.	65 participants	75 participants	55 participants	—	—

SECONDARY outcome

Timeframe: Day 1 through Day 14 (End of Titration Phase)

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

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

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=329 Participants 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.	Morphine Controlled Release (Maintenance Phase) Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. The participant continued at the dose that was effective at the end of the Titration Phase.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Tapentadol Treatment Arm. Prior to start of the Titration Phase	6.315 units on a scale Standard Deviation 1.4435	—	—	—	—
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Tapentadol Treatment Arm. End of Week 1 of the Titration Phase	5.324 units on a scale Standard Deviation 1.7476	—	—	—	—
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Tapentadol Treatment Arm. End of Week 2 of the Titration Phase	4.021 units on a scale Standard Deviation 1.6872	—	—	—	—

SECONDARY outcome

Timeframe: Day 1 through Day 14 (End of Titration Phase)

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

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

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=156 Participants 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.	Morphine Controlled Release (Maintenance Phase) Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. The participant continued at the dose that was effective at the end of the Titration Phase.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Morphine Treatment Arm. Prior to start of the Titration Phase	6.162 units on a scale Standard Deviation 1.5693	—	—	—	—
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Morphine Treatment Arm. End of Week 1 of the Titration Phase	4.906 units on a scale Standard Deviation 1.9039	—	—	—	—
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Titration Phase in the Morphine Treatment Arm. End of Week 2 of the Titration Phase	3.669 units on a scale Standard Deviation 1.7851	—	—	—	—

SECONDARY outcome

Timeframe: Day 18 through Day 43 (End of Maintenance Phase)

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

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

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=105 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=111 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=109 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. Prior to start of Maintenance Phase	3.198 units on a scale Standard Deviation 1.2043	2.928 units on a scale Standard Deviation 1.2353	2.928 units on a scale Standard Deviation 1.4106	—	—
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. End of Week 1 of the Maintenance Phase	3.220 units on a scale Standard Deviation 1.2385	3.115 units on a scale Standard Deviation 1.3799	2.903 units on a scale Standard Deviation 1.4645	—	—
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. End of Week 2 of the Maintenance Phase	3.248 units on a scale Standard Deviation 1.3724	3.005 units on a scale Standard Deviation 1.5723	2.858 units on a scale Standard Deviation 1.4783	—	—
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. End of Week 3 of the Maintenance Phase	3.129 units on a scale Standard Deviation 1.3267	3.055 units on a scale Standard Deviation 1.6702	2.775 units on a scale Standard Deviation 1.4312	—	—
Average Daily Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. End of Week 4 of the Maintenance Phase	3.121 units on a scale Standard Deviation 1.3768	3.095 units on a scale Standard Deviation 1.7349	2.768 units on a scale Standard Deviation 1.5065	—	—

SECONDARY outcome

Timeframe: Day 1 through Day 14 (End of Titration Phase)

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

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".

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=331 Participants 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.	Morphine Controlled Release (Maintenance Phase) Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. The participant continued at the dose that was effective at the end of the Titration Phase.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Tapentadol Arm. Start of Titration	6.344 units on a scale Standard Deviation 1.4568	—	—	—	—
Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Tapentadol Arm. End of Week 1	5.326 units on a scale Standard Deviation 1.7650	—	—	—	—
Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Tapentadol Arm. End of Week 2	4.049 units on a scale Standard Deviation 1.8015	—	—	—	—

SECONDARY outcome

Timeframe: Day 1 through Day 14 (End of Titration Phase)

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

Participants were asked to record their current pain intensity in the morning and evening. Average pain scores are the averages of all scores recorded during 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".

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=157 Participants 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.	Morphine Controlled Release (Maintenance Phase) Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. The participant continued at the dose that was effective at the end of the Titration Phase.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Morphine Arm. End of Week 1	4.937 units on a scale Standard Deviation 1.9080	—	—	—	—
Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Morphine Arm. Start of Titration	6.258 units on a scale Standard Deviation 1.5609	—	—	—	—
Current Pain Intensity Scores, Averaged Per Week, During the Titration Phase in the Morphine Arm. End of Week 2	3.690 units on a scale Standard Deviation 1.8365	—	—	—	—

SECONDARY outcome

Timeframe: Day 15 through Day 43 (End of Maintenance Phase)

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

Participants were asked to record their current pain intensity in the morning and evening. Average pain scores are the averages of all scores recorded during the 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".

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=105 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=111 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=109 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. Prior to start of maintenance phase	3.1444 units on a scale Standard Deviation 1.16485	2.8686 units on a scale Standard Deviation 1.19387	2.832 units on a scale Standard Deviation 1.3895	—	—
Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. End of Week 3	3.0137 units on a scale Standard Deviation 1.26515	2.9122 units on a scale Standard Deviation 1.60299	2.733 units on a scale Standard Deviation 1.4512	—	—
Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. End of Week 4	3.0002 units on a scale Standard Deviation 1.37551	2.9220 units on a scale Standard Deviation 1.68601	2.728 units on a scale Standard Deviation 1.4481	—	—
Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. End of Week 1	3.0869 units on a scale Standard Deviation 1.22550	3.0073 units on a scale Standard Deviation 1.32110	2.780 units on a scale Standard Deviation 1.3706	—	—
Current Pain Intensity Scores, Averaged Per Week by Treatment, During the Maintenance Phase. End of Week 2	3.1148 units on a scale Standard Deviation 1.27905	2.8683 units on a scale Standard Deviation 1.47838	2.790 units on a scale Standard Deviation 1.4170	—	—

SECONDARY outcome

Timeframe: Day 1 through Day 14 (End of Titration Phase)

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

The number of participants using rescue medication morphine sulfate immediate release 10 mg tablets in the titration phase were counted. This data was captured in an electronic diary.

During the trial, morphine immediate release 10 mg was allowed as required without a maximum dose defined. However, participants were only re-randomized if their mean consumption of rescue medication was less or equal to 2 doses (20 mg) per day during the last 3 days of the titration phase).

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=335 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=157 Participants 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.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Use of Rescue Medication in the Titration Phase.	241 participants	91 participants	—	—	—

SECONDARY outcome

Timeframe: Day 15 through Day 43 (End of Maintenance Phase)

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

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

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=105 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=109 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=111 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase Oral Morphine 40 mg to 100 mg twice daily. Capsule taken orally, twice daily, morning \& evening with preferably 12 hours (not less than 6 hours) between doses. The participant continued at the dose that was effective at the end of the Titration Phase.
Number of Participants Using Immediate Release Morphine Rescue Medication in the Maintenance Phase	75 participants	67 participants	80 participants	—	—

SECONDARY outcome

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

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

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

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=335 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=157 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=105 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=111 Participants Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase n=109 Participants 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.
The Average Mean Total Daily Dose of Rescue Medication.	13.31 milligrams per day of morphine rescue Standard Deviation 17.41	8.87 milligrams per day of morphine rescue Standard Deviation 12.50	11.2 milligrams per day of morphine rescue Standard Deviation 12.739	13.65 milligrams per day of morphine rescue Standard Deviation 13.666	8.91 milligrams per day of morphine rescue Standard Deviation 14.951

SECONDARY outcome

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

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

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.

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=285 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=131 Participants 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.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Changes in the Short Form 36® Health Survey (SF-36®) During the Titration Phase. Mental Component Summary	1.3 units on a scale Standard Deviation 10.63	1.1 units on a scale Standard Deviation 11.78	—	—	—
Changes in the Short Form 36® Health Survey (SF-36®) During the Titration Phase. Physical Component Summary	2.0 units on a scale Standard Deviation 5.99	3.1 units on a scale Standard Deviation 6.48	—	—	—

SECONDARY outcome

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

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

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

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=95 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=97 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=103 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Changes in the Short Form 36® Health Survey (SF-36®) During the Maintenance Phase. Mental Component Summary	-0.4 units on a scale Standard Deviation 10.81	-2.164 units on a scale Standard Deviation 9.42	-1.5 units on a scale Standard Deviation 9.99	—	—
Changes in the Short Form 36® Health Survey (SF-36®) During the Maintenance Phase. Physical Component Summary	-1.1 units on a scale Standard Deviation 6.26	-0.671 units on a scale Standard Deviation 7.21	-0.9 units on a scale Standard Deviation 6.29	—	—

SECONDARY outcome

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

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

The participant scores the EuroQol-5D. The EuroQoL-5D is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1 = no problems, 2 = some problems, 3 = extreme problems).

The responses to the five EQ-5D dimensions are scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead. A 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).

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=286 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=132 Participants 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.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Change in the EuroQoL (EQ-5D) Health Status Index (United Kingdom Time Trade-off Value Set) Change From Start of Titration to Endpoint Titration.	0.093 units on a scale Standard Deviation 0.3294	0.131 units on a scale Standard Deviation 0.3162	—	—	—

SECONDARY outcome

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

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

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

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=286 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=131 Participants 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.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Titration Phase.	3.8 units on a scale Standard Deviation 22.63	5.6 units on a scale Standard Deviation 20.42	—	—	—

SECONDARY outcome

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

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

The 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).

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=95 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=103 Participants 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.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
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.	-0.0626 units on a scale Standard Deviation 0.3130	-0.058 units on a scale Standard Deviation 0.2909	—	—	—

SECONDARY outcome

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

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

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.

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=95 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=97 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=103 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Changes in Health Related Quality of Life: EuroQol-5D Health State Visual Analog Scale (VAS) Maintenance Phase.	-2.1 units on a scale Standard Deviation 19.80	-0.6 units on a scale Standard Deviation 16.94	-1.5 units on a scale Standard Deviation 18.55	—	—

SECONDARY outcome

Timeframe: Day 43 (End of Maintenance Phase)

Population: Full Analysis Set, observed.

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

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=94 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=97 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=103 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Patient Global Impression of Change Much Improved	29 participants	23 participants	31 participants	—	—
Patient Global Impression of Change Minimally Improved	33 participants	38 participants	38 participants	—	—
Patient Global Impression of Change No Change	10 participants	12 participants	11 participants	—	—
Patient Global Impression of Change Minimally Worse	10 participants	6 participants	9 participants	—	—
Patient Global Impression of Change Much Worse	7 participants	12 participants	7 participants	—	—
Patient Global Impression of Change Very Much Worse	1 participants	0 participants	1 participants	—	—
Patient Global Impression of Change Very Much Improved	4 participants	6 participants	6 participants	—	—

SECONDARY outcome

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

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

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.

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=338 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=158 Participants 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.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Quality of Sleep (Sleep Questionnaire) in the Titration Phase. Poor at the end of the titration phase	37 participants	14 participants	—	—	—
Quality of Sleep (Sleep Questionnaire) in the Titration Phase. Not completed at the start of titration	36 participants	15 participants	—	—	—
Quality of Sleep (Sleep Questionnaire) in the Titration Phase. Not completed at the end of the titration	29 participants	16 participants	—	—	—
Quality of Sleep (Sleep Questionnaire) in the Titration Phase. Poor at the start of the titration phase	74 participants	41 participants	—	—	—
Quality of Sleep (Sleep Questionnaire) in the Titration Phase. Excellent at the start of the titration phase	9 participants	4 participants	—	—	—
Quality of Sleep (Sleep Questionnaire) in the Titration Phase. Excellent at the end of the titration phase	12 participants	3 participants	—	—	—
Quality of Sleep (Sleep Questionnaire) in the Titration Phase. Good at the start of the titration phase	77 participants	47 participants	—	—	—
Quality of Sleep (Sleep Questionnaire) in the Titration Phase. Good at the end of the titration phase	139 participants	64 participants	—	—	—
Quality of Sleep (Sleep Questionnaire) in the Titration Phase. Fair at the start of the titration phase	142 participants	51 participants	—	—	—
Quality of Sleep (Sleep Questionnaire) in the Titration Phase. Fair at the end of the titration phase	121 participants	61 participants	—	—	—

SECONDARY outcome

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

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

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

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=105 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=108 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=110 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial. Excellent at start of maintenance phase	8 participants	2 participants	4 participants	—	—
Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial. Excellent at the end of maintenance phase	8 participants	9 participants	8 participants	—	—
Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial. Good at start of maintenance phase	55 participants	51 participants	60 participants	—	—
Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial. Good at the end of maintenance phase	43 participants	40 participants	49 participants	—	—
Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial. Fair at start of maintenance phase	35 participants	50 participants	42 participants	—	—
Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial. Fair at the end of maintenance phase	38 participants	53 participants	37 participants	—	—
Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial. Poor at start of maintenance phase	7 participants	5 participants	4 participants	—	—
Quality of Sleep (Sleep Questionnaire) During the Maintenance Phase of the Trial. Poor at the end of maintenance phase	14 participants	5 participants	13 participants	—	—

SECONDARY outcome

Timeframe: Day 14 (End of Titration Phase)

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

This instrument was developed by the National Institute on Drug Abuse. The physical components of withdrawal are primarily evaluated and based on questions and clinical observations. The possible opioid withdrawal effects are assessed using the Clinical Opioid Withdrawal Score (COWS). The COWS is a clinician rated 11-item scale that primarily evaluates the physical components of opioid withdrawal and is based on questions and clinical observations. Responses are rated on a Likert-type scale ranging from 0 to 4 or 5 depending on the item. The total COWS score is the sum of all individual items.

The following withdrawal categories are based on the total COWS score:

• None: total score below 5;
• Mild: total score from 5 to 12;
• Moderate: total score 13 to 24;
• Moderately Severe: total score 25 to 36;
• Severe: total score above 36. The investigator completes the COWS after participants discontinued trial medication 2 to less than 5 days after last intake of trial medication.

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=7 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=6 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=9 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase. None	7 participants	5 participants	8 participants	—	—
Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase. Mild	0 participants	1 participants	1 participants	—	—
Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase. Moderate	0 participants	0 participants	0 participants	—	—
Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase. Moderately Severe	0 participants	0 participants	0 participants	—	—
Clinical Opioid Withdrawal Scale (COWS) at the End of the Titration Phase. Severe	0 participants	0 participants	0 participants	—	—

SECONDARY outcome

Timeframe: Day 43 (End of Maintenance Phase)

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

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.

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=26 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=29 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=29 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase. None	19 participants	23 participants	21 participants	—	—
Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase. Mild	7 participants	6 participants	8 participants	—	—
Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase. Moderate	0 participants	0 participants	0 participants	—	—
Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase. Moderately Severe	0 participants	0 participants	0 participants	—	—
Clinical Opioid Withdrawal Score (COWS) at the End of the Maintenance Phase. Severe	0 participants	0 participants	0 participants	—	—

SECONDARY outcome

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

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

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.

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=216 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=93 Participants 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.	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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Titration Phase Overall stool subscale	0.02 units on a scale Standard Deviation 0.812	0.13 units on a scale Standard Deviation 0.870	—	—	—
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Titration Phase Overall abdominal subscale	-0.062 units on a scale Standard Deviation 0.6507	-0.076 units on a scale Standard Deviation 0.7242	—	—	—
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Titration Phase Overall rectal subscale	0.059 units on a scale Standard Deviation 0.6442	-0.006 units on a scale Standard Deviation 0.6736	—	—	—
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Titration Phase Overall PAC-SYM score	0.003 units on a scale Standard Deviation 0.5782	0.027 units on a scale Standard Deviation 0.6154	—	—	—

SECONDARY outcome

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

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

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

Outcome measures

Measure	Tapentadol Prolonged Release (Maintenance Phase) n=95 Participants 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.	Morphine Controlled Release (Maintenance Phase) n=96 Participants 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.	Matching Placebo After Tapentadol in Titration Phase n=103 Participants 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.	Matching Placebo After Tapentadol in Titration Phase Oral Tapentadol 100 mg to 250 mg twice daily in the titration phase. Followed by matching placebo in the maintenance (i.e. randomized withdrawal phase).	Morphine Controlled Release Maintenance Phase 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.
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Maintenance Phase Overall stool subscale	-0.07 units on a scale Standard Deviation 0.743	0.03 units on a scale Standard Deviation 0.724	-0.03 units on a scale Standard Deviation 0.667	—	—
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Maintenance Phase Overall PAC-SYM score	-0.059 units on a scale Standard Deviation 0.4992	0.024 units on a scale Standard Deviation 0.4584	-0.048 units on a scale Standard Deviation 0.4771	—	—
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Maintenance Phase Overall abdominal subscale	-0.105 units on a scale Standard Deviation 0.6280	0.026 units on a scale Standard Deviation 0.5966	-0.075 units on a scale Standard Deviation 0.5330	—	—
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) During the Maintenance Phase Overall rectal subscale	0.017 units on a scale Standard Deviation 0.5086	0.014 units on a scale Standard Deviation 0.5090	-0.033 units on a scale Standard Deviation 0.5822	—	—

Adverse Events

Tapentadol Prolonged Release (Titration Phase)

Serious events: 25 serious events

Other events: 112 other events

Deaths: 0 deaths

Morphine Controlled Release (Titration Phase)

Serious events: 6 serious events

Other events: 80 other events

Deaths: 0 deaths

Tapentadol Prolonged Release (Maintenance Phase)

Serious events: 12 serious events

Other events: 41 other events

Deaths: 0 deaths

Matching Placebo After Tapentadol in Titration Phase

Serious events: 10 serious events

Other events: 34 other events

Deaths: 0 deaths

Morphine Controlled Release (Maintenance Phase)

Serious events: 6 serious events

Other events: 37 other events

Deaths: 0 deaths

Serious adverse events

Measure	Tapentadol Prolonged Release (Titration Phase) n=338 participants at risk 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.	Morphine Controlled Release (Titration Phase) n=158 participants at risk 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.	Tapentadol Prolonged Release (Maintenance Phase) n=106 participants at risk 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.	Matching Placebo After Tapentadol in Titration Phase n=112 participants at risk 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.	Morphine Controlled Release (Maintenance Phase) n=109 participants at risk Oral Morphine 40 mg to 100 mg twice daily. The dose that was effective at the end of the Titration Phase.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm malignant	1.5% 5/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.63% 1/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	3.8% 4/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	1.8% 2/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.92% 1/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Metastases to central nervous system	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.63% 1/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour pain	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.94% 1/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Gastrointestinal disorders Diarrhoea	0.59% 2/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Gastrointestinal disorders Ascites	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	1.8% 2/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Gastrointestinal disorders Haematemesis	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Gastrointestinal disorders Melaena	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Gastrointestinal disorders Vomiting	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.92% 1/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.63% 1/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary haemorrhage	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Respiratory, thoracic and mediastinal disorders Pulmonary oedema	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Musculoskeletal and connective tissue disorders Arthralgia	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Musculoskeletal and connective tissue disorders Muscular weakness	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Musculoskeletal and connective tissue disorders Osteonecrosis	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Musculoskeletal and connective tissue disorders Trismus	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
General disorders Asthenia	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
General disorders Hospitalization due to travel problems	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
General disorders Pyrexia	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Cardiac disorders Cardio-respiratory arrest	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Cardiac disorders Cor pulmonale acute	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Injury, poisoning and procedural complications Femur fracture	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Injury, poisoning and procedural complications Spinal compression fracture	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Vascular disorders Deep vein thrombosis	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Vascular disorders Superior vena cava syndrome	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Vascular disorders Thrombosis	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.63% 1/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.92% 1/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Blood and lymphatic system disorders Anaemia	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.89% 1/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.92% 1/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Endocrine disorders Adrenocortical insufficiency acute	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Hepatobiliary disorders Hepatic failure	0.30% 1/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Psychiatric disorders Confusional state	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.63% 1/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Reproductive system and breast disorders Female genital tract fistula	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.63% 1/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
General disorders Death	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	1.9% 2/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
General disorders General physical health deterioration	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.94% 1/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Cardiac disorders Cardiovascular insufficiency	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	1.9% 2/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Cardiac disorders Coronary artery disease	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.89% 1/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Gastrointestinal disorders Intestinal perforation	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.94% 1/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Investigations Blood urea increased	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.94% 1/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Renal and urinary disorders Renal failure acute	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.94% 1/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.94% 1/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.89% 1/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Blood and lymphatic system disorders Febrile neutropenia	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.92% 1/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Blood and lymphatic system disorders Thrombocytopenia	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.89% 1/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Infections and infestations Lobar pneumonia	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.89% 1/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Infections and infestations Peritonitis	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.92% 1/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Infections and infestations Pneumonia	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.92% 1/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Injury, poisoning and procedural complications Lower limb fracture	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.89% 1/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Psychiatric disorders Withdrawal syndrome	0.00% 0/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.89% 1/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.

Other adverse events

Measure	Tapentadol Prolonged Release (Titration Phase) n=338 participants at risk 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.	Morphine Controlled Release (Titration Phase) n=158 participants at risk 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.	Tapentadol Prolonged Release (Maintenance Phase) n=106 participants at risk 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.	Matching Placebo After Tapentadol in Titration Phase n=112 participants at risk 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.	Morphine Controlled Release (Maintenance Phase) n=109 participants at risk Oral Morphine 40 mg to 100 mg twice daily. The dose that was effective at the end of the Titration Phase.
Gastrointestinal disorders Nausea	12.4% 42/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	24.1% 38/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	15.1% 16/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	15.2% 17/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	10.1% 11/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Gastrointestinal disorders Constipation	14.2% 48/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	17.7% 28/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	11.3% 12/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	11.6% 13/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	11.0% 12/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Gastrointestinal disorders Vomiting	5.0% 17/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	15.8% 25/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	7.5% 8/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	2.7% 3/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	5.5% 6/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Gastrointestinal disorders Dry Mouth	1.2% 4/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	6.3% 10/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	2.8% 3/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	1.8% 2/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.92% 1/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Nervous system disorders Dizziness	5.0% 17/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	6.3% 10/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	4.7% 5/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	3.6% 4/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Nervous system disorders Somnolence	4.1% 14/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	6.3% 10/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	2.8% 3/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	1.8% 2/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	5.5% 6/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
General disorders Fatigue	3.0% 10/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	5.1% 8/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	3.8% 4/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	5.4% 6/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	5.5% 6/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Metabolism and nutrition disorders Decreased Appetite	2.7% 9/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	3.8% 6/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	7.5% 8/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	5.4% 6/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	5.5% 6/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Neoplasm Malignant	0.89% 3/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.00% 0/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	5.7% 6/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	1.8% 2/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	2.8% 3/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.
Skin and subcutaneous tissue disorders Hyperhidrosis	2.7% 9/338 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	4.4% 7/158 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	3.8% 4/106 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	0.89% 1/112 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.	6.4% 7/109 • Serious adverse events reported any time after treatment is taken, to within 30 days after end of treatment.

Additional Information

Director of Clinical Trials

Grünenthal GmbH

Phone: +49 241 569 3223

Email: Clinical-Trials@grunenthal.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER