Trial Outcomes & Findings for A Study to Evaluate the Efficacy and Safety of CG5503 Prolonged Release (PR) in Subjects With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee (NCT NCT00486811)

Last Updated: 2019-10-18

Results Overview

For this twice daily pain assessment, the participants were required to indicate the level of pain experienced over the previous 12 hours on an 11-point Numeric Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The lower the value the less pain in the treatment group. Negative values indicate a reduction in pain.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

990 participants

Primary outcome timeframe

Change from baseline over the 12 week Maintenance Period

Results posted on

2019-10-18

Participant Flow

First participant was enrolled on 04 June 2007 and the last participant out was on 18 July 2008.

Participant milestones

Participant milestones
Measure	Placebo Matching Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).
Overall Study STARTED	337	320	333
Overall Study COMPLETED	215	179	119
Overall Study NOT COMPLETED	122	141	214

Reasons for withdrawal

Reasons for withdrawal
Measure	Placebo Matching Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).
Overall Study Adverse Event	28	60	135
Overall Study Lack of Efficacy	34	14	7
Overall Study Lost to Follow-up	4	6	4
Overall Study Withdrawal by Subject	33	44	58
Overall Study Study drug non-compliant	5	6	3
Overall Study All other	18	11	7

Baseline Characteristics

A Study to Evaluate the Efficacy and Safety of CG5503 Prolonged Release (PR) in Subjects With Moderate to Severe Chronic Pain Due to Osteoarthritis of the Knee

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo Matching n=337 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=319 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=331 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).	Total n=987 Participants Total of all reporting groups
Region of Enrollment Portugal	8 participants n=5 Participants	4 participants n=7 Participants	3 participants n=5 Participants	15 participants n=4 Participants
Age, Continuous	62.2 years STANDARD_DEVIATION 9.35 • n=5 Participants	62.4 years STANDARD_DEVIATION 9.35 • n=7 Participants	61.8 years STANDARD_DEVIATION 9.09 • n=5 Participants	62.1 years STANDARD_DEVIATION 9.26 • n=4 Participants
Age, Customized Between 18 and 65 years	194 participants n=5 Participants	194 participants n=7 Participants	211 participants n=5 Participants	599 participants n=4 Participants
Age, Customized >=65 years	143 participants n=5 Participants	125 participants n=7 Participants	120 participants n=5 Participants	388 participants n=4 Participants
Sex: Female, Male Female	257 Participants n=5 Participants	231 Participants n=7 Participants	219 Participants n=5 Participants	707 Participants n=4 Participants
Sex: Female, Male Male	80 Participants n=5 Participants	88 Participants n=7 Participants	112 Participants n=5 Participants	280 Participants n=4 Participants
Region of Enrollment Slovakia	7 participants n=5 Participants	8 participants n=7 Participants	9 participants n=5 Participants	24 participants n=4 Participants
Region of Enrollment Spain	29 participants n=5 Participants	23 participants n=7 Participants	25 participants n=5 Participants	77 participants n=4 Participants
Region of Enrollment Austria	14 participants n=5 Participants	12 participants n=7 Participants	15 participants n=5 Participants	41 participants n=4 Participants
Region of Enrollment United Kingdom	23 participants n=5 Participants	24 participants n=7 Participants	28 participants n=5 Participants	75 participants n=4 Participants
Region of Enrollment Hungary	36 participants n=5 Participants	35 participants n=7 Participants	34 participants n=5 Participants	105 participants n=4 Participants
Region of Enrollment Poland	11 participants n=5 Participants	11 participants n=7 Participants	13 participants n=5 Participants	35 participants n=4 Participants
Region of Enrollment Romania	107 participants n=5 Participants	103 participants n=7 Participants	104 participants n=5 Participants	314 participants n=4 Participants
Region of Enrollment Croatia	12 participants n=5 Participants	9 participants n=7 Participants	8 participants n=5 Participants	29 participants n=4 Participants
Region of Enrollment Germany	58 participants n=5 Participants	60 participants n=7 Participants	59 participants n=5 Participants	177 participants n=4 Participants
Region of Enrollment Latvia	24 participants n=5 Participants	21 participants n=7 Participants	24 participants n=5 Participants	69 participants n=4 Participants
Region of Enrollment Netherlands	8 participants n=5 Participants	9 participants n=7 Participants	9 participants n=5 Participants	26 participants n=4 Participants

PRIMARY outcome

Timeframe: Change from baseline over the 12 week Maintenance Period

Population: Intent-to-treat (ITT), Last Observation Carried Forward (LOCF)

Outcome measures

Outcome measures
Measure	Placebo Matching n=337 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=319 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=331 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Change From Baseline of the Average Pain Intensity Overall in the 12-week Maintenance Period of the Daily Pain Intensity on an 11-point Numeric Rating Scale (NRS).	-2.2 Units on a scale Standard Deviation 2.06	-2.5 Units on a scale Standard Deviation 2.18	-2.1 Units on a scale Standard Deviation 2.17

SECONDARY outcome

Timeframe: Change from Baseline to Week 12 of the Maintenance Period

Population: Intention to treat (ITT). Last Observation Carried Forward (LOCF).

The twice daily pain assessments were averaged. The participants were to indicate their pain on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The lower the value the less pain intensity.

Outcome measures

Outcome measures
Measure	Placebo Matching n=336 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=319 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=331 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Change From Baseline of the Average Pain Intensity Based on an 11-point Numerical Rating Scale (NRS) Over the Last Week of the Maintenance Period at Week 12.	-2.5 Units on a scale Standard Deviation 2.30	-2.7 Units on a scale Standard Deviation 2.4	-2.3 Units on a scale Standard Deviation 2.36

SECONDARY outcome

Timeframe: Baseline; End of 12 week maintenance period

Population: Intention to treat (ITT). Last observation carried forward (LOCF). Assessments obtained more than one day after end of treatment were not included in the analysis.

In the Patient Global Impression of Change (PGIC) the participant indicates the perceived change over the treatment period. The participant is requested to choose one of seven categories. Scores range from very much improved to very much worse.

Outcome measures

Outcome measures
Measure	Placebo Matching n=294 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=248 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=212 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Patient Global Impression of Change Very Much Improved	33 participants	40 participants	25 participants
Patient Global Impression of Change No Change	59 participants	22 participants	30 participants
Patient Global Impression of Change Minimally Worse	15 participants	9 participants	19 participants
Patient Global Impression of Change Much Improved	94 participants	99 participants	65 participants
Patient Global Impression of Change Minimally Improved	76 participants	61 participants	51 participants
Patient Global Impression of Change Much Worse	14 participants	14 participants	19 participants
Patient Global Impression of Change Very Much Worse	3 participants	3 participants	3 participants

SECONDARY outcome

Timeframe: Change from baseline to week 12 of the maintenance period

Population: Intention to treat (ITT). No imputation performed.

Change from baseline to week 12 of Western Ontario McMaster Questionnaire (WOMAC) Global Score: WOMAC is measured with a Likert ordinal scale (the participant gives one of 5 possible answers) from 0 to 4. Higher scores indicate that a symptom is bothersome and physically disabling.

Outcome measures

Outcome measures
Measure	Placebo Matching n=218 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=183 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=114 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Change From Baseline in the Western Ontario McMaster Questionnaire (WOMAC) Global Score Assessing Pain, Disability and Joint Stiffness of the Knee Over the Last Week of the Maintenance Period at Week 12	-1.0 units on a scale Standard Deviation 0.92	-1.0 units on a scale Standard Deviation 0.90	-1.1 units on a scale Standard Deviation 0.83

SECONDARY outcome

Timeframe: Baseline to week 12 of the maintenance period

Population: Intention to treat (ITT) The results for median and interquartile ranges were not estimated as an insufficient number of participants discontinued due to lack of efficacy to estimate values.

The median time to treatment discontinuation due to lack of efficacy from baseline to endpoint.

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Change From Baseline to Week 12 of the Maintenance Period

Population: The number indicate the available responses. For certain categories, e.g. Physical Functioning only 318 participants in the tapentadol treatment were analyzed and in the General Health analysis only 328 oxycodone- and 336 placebo-treated participants were available. Intention to treat (ITT). Last Observation Carried Forward (LOCF).

The Scores Form 36 (SF-36) includes several brief board 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. A higher score indicates an improvement in health. All domains are scored on a scale from 0 (negative health) to 100 (positive health), with 100 representing the best possible health state.

Outcome measures

Outcome measures
Measure	Placebo Matching n=337 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=319 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=331 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Change in the Health Survey Scores Form (SF-36) Role-Emotional	7.9 units on a scale Standard Deviation 48.63 • Interval 0.0 to 0.0	11.1 units on a scale Standard Deviation 45.74	5.0 units on a scale Standard Deviation 38.95
Change in the Health Survey Scores Form (SF-36) Physical Functioning	11.1 units on a scale Standard Deviation 23.00 • Interval 0.0 to 0.0	11.70 units on a scale Standard Deviation 22.91 • Interval -1.82 to 4.25	9.5 units on a scale Standard Deviation 18.65 • Interval -4.18 to 1.84
Change in the Health Survey Scores Form (SF-36) Role-Physical	18.7 units on a scale Standard Deviation 45.63 • Interval 0.0 to 0.0	20.8 units on a scale Standard Deviation 43.32 • Interval -5.64 to 5.48	13.8 units on a scale Standard Deviation 40.96 • Interval -11.12 to -0.08
Change in the Health Survey Scores Form (SF-36) Bodily Pain	15.4 units on a scale Standard Deviation 22.01 • Interval 0.0 to 0.0	19.1 units on a scale Standard Deviation 20.92 • Interval -0.29 to 5.75	13.9 units on a scale Standard Deviation 20.41 • Interval -5.04 to 0.95
Change in the Health Survey Scores Form (SF-36) General Health	6.8 units on a scale Standard Deviation 17.07 • Interval 0.0 to 0.0	6.8 units on a scale Standard Deviation 17.56	4.8 units on a scale Standard Deviation 15.05
Change in the Health Survey Scores Form (SF-36) Vitality	6.8 units on a scale Standard Deviation 21.37 • Interval 0.0 to 0.0	7.1 units on a scale Standard Deviation 19.40	3.8 units on a scale Standard Deviation 18.40
Change in the Health Survey Scores Form (SF-36) Social Functioning	7.5 units on a scale Standard Deviation 25.76 • Interval 0.0 to 0.0	9.2 units on a scale Standard Deviation 24.30	4.9 units on a scale Standard Deviation 22.91
Change in the Health Survey Scores Form (SF-36) Mental Health	6.3 units on a scale Standard Deviation 19.39 • Interval 0.0 to 0.0	3.7 units on a scale Standard Deviation 18.02	2.7 units on a scale Standard Deviation 16.98

SECONDARY outcome

Timeframe: Comparison of Baseline to Week 12 of the Maintenance Period

Population: Intention to treat (ITT). Last Observation Carried Forward (LOCF).

The participant scored the EuroQol-5. This 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 were 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. The positive values indicate that during the study the health status improved.

Outcome measures

Outcome measures
Measure	Placebo Matching n=337 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=319 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=331 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
EuroQol-5 (EQ-5D) Health Status Index Outcome Over Time	0.2 Index value Standard Error 0.02	0.2 Index value Standard Error 0.02	0.1 Index value Standard Error 0.01

SECONDARY outcome

Timeframe: Week 12 of the maintenance period compared to baseline

Population: Intention to treat (ITT). Last Observation Carried Forward (LOCF).

The Sleep Questionnaire addressed the following question: "How long after bedtime/lights out did you fall asleep last night(hours)?". The mean change from baseline to 12 weeks was studied. Decrease in time, measured in hours, indicates an improvement.

Outcome measures

Outcome measures
Measure	Placebo Matching n=327 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=305 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=314 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Sleep Questionnaire: Change From Baseline in Sleep Latency Time in Hours to the Last Week of the Maintenance Period.	0.4 hours Standard Deviation 3.68	0.2 hours Standard Deviation 2.33	0.2 hours Standard Deviation 2.14

SECONDARY outcome

Timeframe: Baseline to Week 12 of the maintenance period

Population: Intention to treat (ITT). Last Observation Carried Forward (LOCF)

The Sleep Questionnaire addressed the following question: "How long did you sleep last night?". The mean change for the number of hours slept during the night before from baseline to 12 weeks was studied.

Outcome measures

Outcome measures
Measure	Placebo Matching n=327 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=305 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=314 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Sleep Questionnaire: Amount of Time Slept in Hours	0.2 hours Standard Deviation 2.10	0.2 hours Standard Deviation 2.29	0.3 hours Standard Deviation 2.01

SECONDARY outcome

Timeframe: Week 12 of the maintenance period compared with baseline

Population: Intention to treat (ITT). Last Observation Carried Forward (LOCF). The number reflects the number of participants that had the specified awakenings.

The Sleep Questionnaire addressed the following question: "How many times did you wake up during the night?". Sleep was assessed by the subject once a week during the entire double-blind treatment period. Reported are the baseline and end of maintenance period. Generally the less the number of awakenings the better the sleep.

Outcome measures

Outcome measures
Measure	Placebo Matching n=337 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=319 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=328 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Sleep Questionnaire: Number of Awakenings During Sleep No awakening during night baseline	32 participants	33 participants	29 participants
Sleep Questionnaire: Number of Awakenings During Sleep No awakening during night end point	55 participants	44 participants	46 participants
Sleep Questionnaire: Number of Awakenings During Sleep 1 awakening per night baseline	56 participants	53 participants	57 participants
Sleep Questionnaire: Number of Awakenings During Sleep 1 awakening per night end point	89 participants	92 participants	67 participants
Sleep Questionnaire: Number of Awakenings During Sleep 2 awakening per night baseline	102 participants	88 participants	85 participants
Sleep Questionnaire: Number of Awakenings During Sleep 2 awakening per night end point	84 participants	94 participants	89 participants
Sleep Questionnaire: Number of Awakenings During Sleep 3 awakening per night baseline	82 participants	66 participants	77 participants
Sleep Questionnaire: Number of Awakenings During Sleep 3 awakening per night end point	66 participants	46 participants	61 participants
Sleep Questionnaire: Number of Awakenings During Sleep 4 awakening per night baseline	33 participants	39 participants	38 participants
Sleep Questionnaire: Number of Awakenings During Sleep 4 awakening per night end point	21 participants	22 participants	42 participants
Sleep Questionnaire: Number of Awakenings During Sleep 5 or more awakenings per night baseline	22 participants	26 participants	28 participants
Sleep Questionnaire: Number of Awakenings During Sleep 5 or more awakenings per night end point	22 participants	21 participants	23 participants

SECONDARY outcome

Timeframe: Week 12 of the maintenance period compared to baseline

Population: Intention to treat (ITT). Last Observation Carried Forward (LOCF). The number of participants reporting the appropriate sleep quality category are shown.

The Sleep Questionnaire addressed the following question: "Please rate the overall quality of your sleep last night?" The quality of sleep at baseline and prior to completion of treatment are reported. The participant can choose one of the following options: Excellent, good, fair and poor.

Outcome measures

Outcome measures
Measure	Placebo Matching n=337 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=319 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=328 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Number of Participants Reporting a Category From the Quality of Sleep (Sleep Questionnaire) Fair at end point	124 participants	107 participants	125 participants
Number of Participants Reporting a Category From the Quality of Sleep (Sleep Questionnaire) Poor at end point	29 participants	20 participants	26 participants
Number of Participants Reporting a Category From the Quality of Sleep (Sleep Questionnaire) Excellent at baseline	11 participants	8 participants	5 participants
Number of Participants Reporting a Category From the Quality of Sleep (Sleep Questionnaire) Excellent at end point	10 participants	15 participants	19 participants
Number of Participants Reporting a Category From the Quality of Sleep (Sleep Questionnaire) Good at baseline	134 participants	122 participants	118 participants
Number of Participants Reporting a Category From the Quality of Sleep (Sleep Questionnaire) Good at end point	174 participants	177 participants	158 participants
Number of Participants Reporting a Category From the Quality of Sleep (Sleep Questionnaire) Fair at baseline	146 participants	138 participants	151 participants
Number of Participants Reporting a Category From the Quality of Sleep (Sleep Questionnaire) Poor at baseline	36 participants	37 participants	40 participants

SECONDARY outcome

Timeframe: Change from Baseline to Week 12 of the Maintenance Period

Population: Safety Set

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 on rectal symptoms and 5 on stool symptoms. Responses are rated on a 5-point Likert scale ranging from 0 (absence of symptom) to 4 (very severe symptoms). If the changes in the overall or subscale scores are positive then there is a worsening in symptoms associated with constipation.

Outcome measures

Outcome measures
Measure	Placebo Matching n=285 Participants Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=235 Participants Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=197 Participants Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Patient Assessment of Constipation Symptoms (PAC-SYM) Over Time Overall abdominal subscale change	-0.1 Units on a scale Standard Deviation 0.69	0.1 Units on a scale Standard Deviation 0.78	0.3 Units on a scale Standard Deviation 0.85
Patient Assessment of Constipation Symptoms (PAC-SYM) Over Time Overall rectal subscale change	0.0 Units on a scale Standard Deviation 0.52	0.1 Units on a scale Standard Deviation 0.65	0.4 Units on a scale Standard Deviation 0.81
Patient Assessment of Constipation Symptoms (PAC-SYM) Over Time Overall stool subscale change	0.0 Units on a scale Standard Deviation 0.74	0.2 Units on a scale Standard Deviation 0.83	0.6 Units on a scale Standard Deviation 0.97
Patient Assessment of Constipation Symptoms (PAC-SYM) Over Time Overall PAC-SYM score change	0.0 Units on a scale Standard Deviation 0.56	0.1 Units on a scale Standard Deviation 0.64	0.4 Units on a scale Standard Deviation 0.72

Adverse Events

Placebo Matching

Serious events: 4 serious events

Other events: 187 other events

Deaths: 0 deaths

Tapentadol ER

Serious events: 2 serious events

Other events: 214 other events

Deaths: 0 deaths

Oxycodone CR

Serious events: 13 serious events

Other events: 281 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Placebo Matching n=337 participants at risk Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=319 participants at risk Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=331 participants at risk Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Gastrointestinal disorders Nausea	6.2% 21/337 • Baseline to week 12 of the maintenance period	20.4% 65/319 • Baseline to week 12 of the maintenance period	37.2% 123/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Constipation	9.2% 31/337 • Baseline to week 12 of the maintenance period	17.6% 56/319 • Baseline to week 12 of the maintenance period	34.4% 114/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Vomiting	3.9% 13/337 • Baseline to week 12 of the maintenance period	10.0% 32/319 • Baseline to week 12 of the maintenance period	26.0% 86/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Dry Mouth	2.1% 7/337 • Baseline to week 12 of the maintenance period	6.0% 19/319 • Baseline to week 12 of the maintenance period	3.9% 13/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Diarrhoea	4.5% 15/337 • Baseline to week 12 of the maintenance period	4.4% 14/319 • Baseline to week 12 of the maintenance period	7.9% 26/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Abdominal Pain Upper	5.9% 20/337 • Baseline to week 12 of the maintenance period	3.4% 11/319 • Baseline to week 12 of the maintenance period	4.5% 15/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Addominal Pain	2.1% 7/337 • Baseline to week 12 of the maintenance period	1.3% 4/319 • Baseline to week 12 of the maintenance period	5.4% 18/331 • Baseline to week 12 of the maintenance period
Nervous system disorders Dizziness	8.6% 29/337 • Baseline to week 12 of the maintenance period	21.9% 70/319 • Baseline to week 12 of the maintenance period	26.6% 88/331 • Baseline to week 12 of the maintenance period
Nervous system disorders Somnolence	3.9% 13/337 • Baseline to week 12 of the maintenance period	10.7% 34/319 • Baseline to week 12 of the maintenance period	14.5% 48/331 • Baseline to week 12 of the maintenance period
Nervous system disorders Headache	9.2% 31/337 • Baseline to week 12 of the maintenance period	10.3% 33/319 • Baseline to week 12 of the maintenance period	8.2% 27/331 • Baseline to week 12 of the maintenance period
General disorders Fatigue	3.3% 11/337 • Baseline to week 12 of the maintenance period	7.8% 25/319 • Baseline to week 12 of the maintenance period	10.0% 33/331 • Baseline to week 12 of the maintenance period
Skin and subcutaneous tissue disorders Hyperhidrosis	2.4% 8/337 • Baseline to week 12 of the maintenance period	9.1% 29/319 • Baseline to week 12 of the maintenance period	8.2% 27/331 • Baseline to week 12 of the maintenance period
Skin and subcutaneous tissue disorders Pruritus	1.8% 6/337 • Baseline to week 12 of the maintenance period	1.3% 4/319 • Baseline to week 12 of the maintenance period	10.9% 36/331 • Baseline to week 12 of the maintenance period
Ear and labyrinth disorders Vertigo	2.1% 7/337 • Baseline to week 12 of the maintenance period	6.0% 19/319 • Baseline to week 12 of the maintenance period	6.0% 20/331 • Baseline to week 12 of the maintenance period

Additional Information

Claudia Leinweber

Grünenthal GmbH

Phone: +49 241 569 2509

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee The Sponsor and the Sponsor's designee reserves the right to review any publication pertaining to the trial at least 30 days before it is submitted for publication. Neither party has the right to prohibit publication unless publication can be shown to affect possible patent rights.
Publication restrictions are in place

Restriction type: OTHER

Measure	Placebo Matching n=337 participants at risk Drug: Matching Placebo (twice daily) The starting dose of placebo was matched with the active treatment arms taken twice daily for the first 3 days. The dose was then increased to match the active treatments for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days as in the active treatment arms. Dose decreases were allowed without time restrictions.	Tapentadol ER n=319 participants at risk Tapentadol ER (100 to 250 mg twice daily) The starting dose was tapentadol ER 50 mg twice daily for 3 days. The dose was then increased to 100 mg tapentadol ER twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Tapentadol ER 50, 100, 150, 200 or 250 mg twice a day (BID) during 15 weeks were dosed by participants (3 weeks titration and 12 weeks maintenance).	Oxycodone CR n=331 participants at risk Oxycodone CR (20 to 50 mg twice daily). The starting dose was oxycodone CR 10 mg twice daily for 3 days. The dose was then increased to 20 mg oxycodone CR twice daily for at least 4 days. Thereafter, during the titration and maintenance phase participants were allowed to increase the dose every 3 days. Dose decreases were allowed without time restrictions. Oxycodone doses were thus 10, 20, 30, 40 or 50 mg twice a day (BID) were dosed by participants during 15 weeks (3 weeks titration and 12 weeks maintenance).
Gastrointestinal disorders Abdominal Pain Upper	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.31% 1/319 • Baseline to week 12 of the maintenance period	0.00% 0/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Constipation	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.31% 1/319 • Baseline to week 12 of the maintenance period	0.60% 2/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Diarrhoea	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.31% 1/319 • Baseline to week 12 of the maintenance period	0.00% 0/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Vomiting	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.31% 1/319 • Baseline to week 12 of the maintenance period	0.00% 0/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Colonic Polyp	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Gastrointestinal disorders Nausea	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Nervous system disorders Syncope	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.31% 1/319 • Baseline to week 12 of the maintenance period	0.00% 0/331 • Baseline to week 12 of the maintenance period
Nervous system disorders Dizziness	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Cardiac disorders Atrial Fibrillation	0.30% 1/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.91% 3/331 • Baseline to week 12 of the maintenance period
Cardiac disorders Myocardial Infarction	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.00% 0/331 • Baseline to week 12 of the maintenance period
Cardiac disorders Tachycardia Paroxysmal	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Cardiac disorders Ventricular Arrhythmia	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Ear and labyrinth disorders Vertigo	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Endocrine disorders Inappropriate Antidiuretic Hormone Secretion	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Infections and infestations Lower Respiratory Tract Infection Viral	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Injury, poisoning and procedural complications Foot Fracture	0.30% 1/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.00% 0/331 • Baseline to week 12 of the maintenance period
Injury, poisoning and procedural complications Neck injury	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Rectal Cancer	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumour Haemorrhage	0.30% 1/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.00% 0/331 • Baseline to week 12 of the maintenance period
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine Leimyoma	0.30% 1/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.00% 0/331 • Baseline to week 12 of the maintenance period
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period
Respiratory, thoracic and mediastinal disorders Interstitial Lung Disease	0.00% 0/337 • Baseline to week 12 of the maintenance period	0.00% 0/319 • Baseline to week 12 of the maintenance period	0.30% 1/331 • Baseline to week 12 of the maintenance period