Trial Outcomes & Findings for Tapentadol Prolonged Release (PR) Versus Oxycodone/Naloxone Prolonged Release in Severe Chronic Low Back Pain With a Neuropathic Component. (NCT NCT01838616)

NCT ID: NCT01838616

Last Updated: 2016-02-24

Results Overview

For this pain assessment, the participant indicated the level of average pain experienced over the previous 3 days on an 11-point Numeric Rating Scale (NRS-3) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The value reported represents the change from the randomization visit (i.e., the last 3 days in the washout period prior to Investigational Medicinal Product initiation and titration) to the end of the continuation period (i.e., up to 9 weeks on the stable dose). The theoretical values range from -10 to 10. A negative sign indicates a decrease in pain from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (Baseline Visit).

• Recruitment status: COMPLETED
• Study phase: PHASE4
• Target enrollment: 367 participants
• Primary outcome timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)
• Results posted on: 2016-02-24

Participant Flow

The trial started on 22 Mar 2013 with the enrollment of the first participant and was completed on 28 Jan 2014 when the last subject completed the last follow-up examination according to the protocol.

367 participants signed informed consent. 89 participants did not meet the inclusion/exclusion criteria, 16 participants withdrew and 4 participants left the trial for other reasons. Participants randomized to oxycodone/naloxone PR could be switched to tapentadol PR treatment in the pick-up arm of the trial.

Participant milestones

Measure	Tapentadol Prolonged Release All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.	Oxycodone/Naloxone Prolonged Release All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Titration Period STARTED	130	128
Titration Period No Post Baseline Pain Intensity Values	0	2
Titration Period Major Protocol Deviations	13	16
Titration Period Switched to Pick-up Arm	0	43
Titration Period Full Analysis Set	130	128
Titration Period Per Protocol Set	117	112
Titration Period COMPLETED	100	62
Titration Period NOT COMPLETED	30	66
Continuation Period STARTED	100	62
Continuation Period Switched to Pick-up Arm	0	7
Continuation Period COMPLETED	86	48
Continuation Period NOT COMPLETED	14	14
Pick-up Arm STARTED	50	0
Pick-up Arm Full Analysis Set	49	0
Pick-up Arm COMPLETED	35	0
Pick-up Arm NOT COMPLETED	15	0

Reasons for withdrawal

Measure	Tapentadol Prolonged Release All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.	Oxycodone/Naloxone Prolonged Release All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Titration Period Adverse Event	18	48
Titration Period Lack of Efficacy	5	12
Titration Period Withdrawal by Subject	5	5
Titration Period Technical problems	1	0
Titration Period Other	1	0
Titration Period Protocol Violation	0	1
Continuation Period Lack of Efficacy	3	5
Continuation Period Adverse Event	8	4
Continuation Period Protocol Violation	2	0
Continuation Period Lost to Follow-up	1	0
Continuation Period Withdrawal by Subject	0	4
Continuation Period Technical problems	0	1
Pick-up Arm Lack of Efficacy	4	0
Pick-up Arm Adverse Event	9	0
Pick-up Arm Withdrawal by Subject	1	0
Pick-up Arm Technical problems	1	0

Baseline Characteristics

Tapentadol Prolonged Release (PR) Versus Oxycodone/Naloxone Prolonged Release in Severe Chronic Low Back Pain With a Neuropathic Component.

Baseline characteristics by cohort

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.	Oxycodone/Naloxone Prolonged Release n=128 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.	Total n=258 Participants Total of all reporting groups
Age, Continuous	58.1 years STANDARD_DEVIATION 11.48 • n=93 Participants	58.4 years STANDARD_DEVIATION 12.23 • n=4 Participants	58.2 years STANDARD_DEVIATION 11.84 • n=27 Participants
Sex: Female, Male Female	77 Participants n=93 Participants	84 Participants n=4 Participants	161 Participants n=27 Participants
Sex: Female, Male Male	53 Participants n=93 Participants	44 Participants n=4 Participants	97 Participants n=27 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Asian	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Black or African American	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) White	130 Participants n=93 Participants	128 Participants n=4 Participants	258 Participants n=27 Participants
Race (NIH/OMB) More than one race	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=93 Participants	0 Participants n=4 Participants	0 Participants n=27 Participants
Region of Enrollment Spain	20 participants n=93 Participants	19 participants n=4 Participants	39 participants n=27 Participants
Region of Enrollment Austria	8 participants n=93 Participants	9 participants n=4 Participants	17 participants n=27 Participants
Region of Enrollment Germany	102 participants n=93 Participants	100 participants n=4 Participants	202 participants n=27 Participants
Dermatol pain present	121 participants n=93 Participants	111 participants n=4 Participants	232 participants n=27 Participants
Lumbar radiculopathy	76 participants n=93 Participants	75 participants n=4 Participants	151 participants n=27 Participants
Duration of pain [months]	61.5 months n=93 Participants	72 months n=4 Participants	70.5 months n=27 Participants
Height	168.9 centimeters STANDARD_DEVIATION 11.00 • n=93 Participants	167.7 centimeters STANDARD_DEVIATION 9.71 • n=4 Participants	168.3 centimeters STANDARD_DEVIATION 10.38 • n=27 Participants
Weight	85.3 kilogram STANDARD_DEVIATION 18.23 • n=93 Participants	81.6 kilogram STANDARD_DEVIATION 18.43 • n=4 Participants	83.5 kilogram STANDARD_DEVIATION 18.39 • n=27 Participants
painDETECT painDETECT positive	96 participants n=93 Participants	97 participants n=4 Participants	193 participants n=27 Participants
painDETECT painDETECT unclear	33 participants n=93 Participants	27 participants n=4 Participants	60 participants n=27 Participants
painDETECT painDETECT negative	1 participants n=93 Participants	4 participants n=4 Participants	5 participants n=27 Participants

PRIMARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: The primary analysis was performed for the Per Protocol Set (PPS). Last Observation Carried Forward (LOCF).

For this pain assessment, the participant indicated the level of average pain experienced over the previous 3 days on an 11-point Numeric Rating Scale (NRS-3) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine". The value reported represents the change from the randomization visit (i.e., the last 3 days in the washout period prior to Investigational Medicinal Product initiation and titration) to the end of the continuation period (i.e., up to 9 weeks on the stable dose). The theoretical values range from -10 to 10. A negative sign indicates a decrease in pain from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (Baseline Visit).

Outcome measures

Measure	Tapentadol Prolonged Release n=117 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=112 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Change in the Average Pain Intensity Score on an 11-point Numeric Rating Scale (NRS-3)	-3.7 units on a scale Standard Error 0.25	-2.7 units on a scale Standard Error 0.26

PRIMARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: The primary analysis was performed for the Per Protocol Set (PPS).

The Constipation Assessment (PAC-SYM) is a 12-item self-report questionnaire that assessed the severity of symptoms of constipation. Participants were 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 were 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. The change in the assessment of constipation symptoms (PAC-SYM) total score from the Randomization Visit to the Final Evaluation Visit. The PAC-SYM overall score is the sum of scores of all non-missing items divided by the number of non-missing items (if at least 6 items were non-missing).

Outcome measures

Measure	Tapentadol Prolonged Release n=117 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=112 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Change in the Patient Assessment of Constipation Symptoms (PAC-SYM) Total Score	0.07 units on a scale Standard Error 0.060	0.14 units on a scale Standard Error 0.062

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF).

The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS), on this scale 0 indicates no pain and 10 indicates pain as bad as you can imagine. This scale recalls the average pain intensity during the last 3 days. The participant was asked: "Please rate your pain intensity by assessing the one number that best describes your pain on average during the last 3 days (the last 72 hours prior to the visit)".

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=126 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Recalled Average Pain Intensity Baseline	7.7 units on a scale Standard Deviation 1.04	7.6 units on a scale Standard Deviation 0.95
Recalled Average Pain Intensity End of Continuation Period	3.9 units on a scale Standard Deviation 2.68	4.8 units on a scale Standard Deviation 2.43

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF).

The recalled average pain intensity score on the NRS-3 was assessed using an 11-point Numeric Rating Scale (NRS), on this scale 0 indicates no pain and 10 indicates pain as bad as you can imagine. This scale recorded the average pain intensity recalled by the participant during the previous 3 days. The participant was asked: "Please rate your pain intensity by assessing the one number that best describes your pain on average during the last 3 days (the last 72 hours prior to the visit)". A negative sign indicates a decrease in pain from the start of treatment. The higher the absolute values, the greater the change since the start of treatment (baseline visit).

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=126 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Change in Recalled Average Pain Intensity at the End of Treatment	-3.7 units on a scale Standard Error 0.24	-2.8 units on a scale Standard Error 0.24

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

Typical dermatomal pain was defined as being pain that radiates beyond the knee towards the foot (sciatica) or pain evoked by stretching of the sciatic nerve.

The participant was asked to rate their pain intensity over the past 3 days with regards to this particular pain characteristic.

The recalled average pain intensity over the past 3 days for the pain radiating towards or into the leg was assessed by the participant using an 11-point Numeric rating scale, where 0 = no pain and 10 = pain as bad as you can imagine.

Outcome measures

Measure	Tapentadol Prolonged Release n=129 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Average Pain Intensity Over Three Days for Pain Radiating Towards or Into the Leg Baseline	7.5 units on a scale Standard Deviation 1.25	7.6 units on a scale Standard Deviation 1.05
Average Pain Intensity Over Three Days for Pain Radiating Towards or Into the Leg End of Continuation Period	3.7 units on a scale Standard Deviation 2.76	4.7 units on a scale Standard Deviation 2.52

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

Typical dermatomal pain was defined as being pain that radiates beyond the knee towards the foot (sciatica) or pain evoked by stretching of the sciatic nerve.

Therefore, the participant was asked to rate their pain intensity over the past 3 days with regards to this particular pain characteristic.

The recalled average pain intensity during the last 24 hours was assessed using an 11-point Numeric rating scale, where 0 = no pain and 10 = pain as bad as you can imagine.

A negative sign indicates that there was a decrease in the average pain radiating towards or into the leg.

Outcome measures

Measure	Tapentadol Prolonged Release n=129 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Change of Average Pain Intensity Over Three Days for Pain Radiating Towards or Into the Leg at the End of Treatment	-3.9 units on a scale Standard Error 0.25	-2.8 units on a scale Standard Error 0.25

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The recalled worst pain intensity during the last 24 hours was assessed using an 11-point Numeric rating scale, where 0 = no pain and 10 = pain as bad as you can imagine.

The participant was asked: "Please rate your pain intensity by assessing the one number that best describes your worst pain during the last 24 hours prior to the visit"

Outcome measures

Measure	Tapentadol Prolonged Release n=129 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Worst Pain Intensity Over the Past 24 Hours Baseline	8.1 units on a scale Standard Deviation 1.03	8.0 units on a scale Standard Deviation 1.06
Worst Pain Intensity Over the Past 24 Hours End of Continuation Period	4.3 units on a scale Standard Deviation 2.73	5.2 units on a scale Standard Deviation 2.50

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The recalled worst pain intensity during the last 24 hours was assessed using an 11-point Numeric rating scale, where 0 = no pain and 10 = pain as bad as you can imagine.

The participant was asked: "Please rate your pain intensity by assessing the one number that best describes your worst pain during the last 24 hours prior to the visit".

A negative change indicates that the pain intensity decreased from the start of the trial.

Outcome measures

Measure	Tapentadol Prolonged Release n=129 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Change in Worst Pain Intensity Over the Past 24 Hours at the End of Treatment	-3.7 units on a scale Standard Error 0.25	-2.8 units on a scale Standard Error 0.25

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The painDETECT was a participant completed questionnaire. The questionnaire consists of 14 questions in four domains. Based on these questions a final assessment score was calculated. The minimum score ranged from zero to a maximum of 38. Participants with a score between 0 and 12 were scored as being "negative" (had no neuropathic pain component). A value between 19 and 38 was rated as being "positive" (neuropathic component present). Values from 13 to 18 were scored as being "unclear". The theoretical range of change in this trial ranged from -38 to 15. A negative change indicated a decrease in their neuropathic component of pain.

Outcome measures

Measure	Tapentadol Prolonged Release n=124 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=115 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
painDETECT Final Assessment Baseline	22.3 units on a scale Standard Deviation 5.25	22.5 units on a scale Standard Deviation 4.79
painDETECT Final Assessment End of Continuation Period	11.9 units on a scale Standard Deviation 7.76	14.6 units on a scale Standard Deviation 7.37

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The painDETECT was a participant completed questionnaire. The questionnaire consists of 14 questions in four domains. Based on these questions a final assessment score was calculated. The minimum score ranged from zero to a maximum of 38. Participants with a score between 0 and 12 were scored as being "negative" (had no neuropathic pain component). A value between 19 and 38 was rated as being "positive" (neuropathic component present). Values from 13 to 18 were scored as being "unclear". The theoretical range of change in this trial ranged from -38 to 15. A negative change indicated a decrease in their neuropathic component of pain.

Outcome measures

Measure	Tapentadol Prolonged Release n=124 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=115 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Change in painDETECT Final Assessment at the End of Treatment	-10.8 units on a scale Standard Error 0.67	-7.9 units on a scale Standard Error 0.69

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

In the Neuropathic Pain Symptom Inventory (NPSI) the participant rated their symptoms of neuropathic pain. Ten pain questions were answered on an 11-point scale; from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity, e.g. worst burning imaginable). The overall NPSI score was calculated by the summation of all ten responses and ranges between 0 and 1. For pain descriptions burning, pressing, paroxysmal (pain like electric shocks or stabbing), evoked (due to touch) and paresthesia (sensation that is not unpleasant) or dysesthesia (unpleasant) sub-scores are reported. The overall values reported for all participants that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all participants and all participants rated it at its worst possible intensity if a value is 1.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment Baseline Overall Score	0.598 units on a scale Standard Deviation 0.1769	0.612 units on a scale Standard Deviation 0.1445
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment End Continuation Period Overall Score	0.251 units on a scale Standard Deviation 0.2344	0.354 units on a scale Standard Deviation 0.2334
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment Baseline Sub-Score Burning Pain	0.612 units on a scale Standard Deviation 0.2569	0.634 units on a scale Standard Deviation 0.2279
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment End Continuation Period Sub-Score Burning Pain	0.248 units on a scale Standard Deviation 0.2767	0.337 units on a scale Standard Deviation 0.2758
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment Baseline Sub-score pressing pain	0.595 units on a scale Standard Deviation 0.2523	0.608 units on a scale Standard Deviation 0.1848
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment End Continuation Period Sub-Score Pressing Pain	0.276 units on a scale Standard Deviation 0.2650	0.375 units on a scale Standard Deviation 0.2645
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment Baseline Sub-Score Paroxysmal Pain	0.638 units on a scale Standard Deviation 0.2312	0.670 units on a scale Standard Deviation 0.1720
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment End Continuation Period Sub-Score Paroxysmal Pain	0.269 units on a scale Standard Deviation 0.2716	0.375 units on a scale Standard Deviation 0.2673
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment Baseline Sub-Score Evoked Pain	0.555 units on a scale Standard Deviation 0.2536	0.548 units on a scale Standard Deviation 0.2300
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment End Continuation Period Sub-Score Evoked Pain	0.219 units on a scale Standard Deviation 0.2520	0.321 units on a scale Standard Deviation 0.2554
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment Baseline Sub-Score Pare/Dysesthesia	0.621 units on a scale Standard Deviation 0.2292	0.642 units on a scale Standard Deviation 0.1809
Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment End Continuation Period Sub-Score Pare/Dysesthesia	0.260 units on a scale Standard Deviation 0.2656	0.372 units on a scale Standard Deviation 0.2615

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF).

In the Neuropathic Pain Symptom Inventory (NPSI) the participant rated their symptoms of neuropathic pain. Ten pain questions were answered on an 11-point scale, from 0 (symptom not present) to 10 (symptom at its worst imaginable intensity, e.g. worst burning imaginable). The overall NPSI score was calculated by the summation of all ten responses and ranges between 0 and 1. For pain descriptions burning, pressing, paroxysmal (pain like electric shocks or stabbing), evoked (due to touch) and paresthesia (sensation that is not unpleasant) or dysesthesia (unpleasant) sub-scores are reported. The overall values reported for all participants that completed the questionnaire are shown. A symptom was absent if the value is 0, the symptom was present in all participants and all participants rated it at its worst possible intensity if a value is 1. A negative change indicates that the intensity of the symptom has decreased since the start of treatment.

Outcome measures

Measure	Tapentadol Prolonged Release n=129 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment at the End of Treatment Overall Score	-0.353 units on a scale Standard Error 0.0208	-0.248 units on a scale Standard Error 0.0211
Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment at the End of Treatment Sub-Score Burning Pain	-0.375 units on a scale Standard Error 0.0249	-0.278 units on a scale Standard Error 0.0252
Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment at the End of Treatment Sub-Score Pressing Pain	-0.331 units on a scale Standard Error 0.0235	-0.226 units on a scale Standard Error 0.0238
Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment at the End of Treatment Sub-Score Paroxysmal Pain	-0.385 units on a scale Standard Error 0.0246	-0.283 units on a scale Standard Error 0.0250
Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment at the End of Treatment Sub-score Evoked Pain	-0.334 units on a scale Standard Error 0.0222	-0.225 units on a scale Standard Error 0.0225
Change in Neuropathic Pain Symptom Inventory (NPSI) Sub-scores and Overall Score Assessment at the End of Treatment Sub-Score Pare/Dysesthesia	-0.363 units on a scale Standard Error 0.0229	-0.252 units on a scale Standard Error 0.0231

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The Short Form Health Survey (SF-12) has several brief broad questions on 8 aspects of health (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. The physical and mental summary scores were calculated from the individual responses. A higher score indicates a better participant perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Short Form Health Survey (SF-12) Baseline Physical Functioning	33.256 units on a scale Standard Deviation 7.7695	33.813 units on a scale Standard Deviation 6.8734
Short Form Health Survey (SF-12) End Continuation Period Physical functioning	41.701 units on a scale Standard Deviation 10.2556	39.120 units on a scale Standard Deviation 9.4634
Short Form Health Survey (SF-12) Baseline Role-Physical	33.783 units on a scale Standard Deviation 6.5010	33.695 units on a scale Standard Deviation 6.2586
Short Form Health Survey (SF-12) End Continuation Period Role-Physical	41.025 units on a scale Standard Deviation 8.7602	38.757 units on a scale Standard Deviation 7.6342
Short Form Health Survey (SF-12) Baseline Bodily Pain	30.430 units on a scale Standard Deviation 7.9923	31.117 units on a scale Standard Deviation 8.1434
Short Form Health Survey (SF-12) End Continuation Period Bodily Pain	42.003 units on a scale Standard Deviation 10.1964	38.637 units on a scale Standard Deviation 10.3872
Short Form Health Survey (SF-12) Baseline General Health	36.110 units on a scale Standard Deviation 8.3196	34.652 units on a scale Standard Deviation 7.0912
Short Form Health Survey (SF-12) End Continuation Period General Health	44.382 units on a scale Standard Deviation 10.3772	39.941 units on a scale Standard Deviation 10.1717
Short Form Health Survey (SF-12) Baseline Vitality	46.518 units on a scale Standard Deviation 8.5121	45.516 units on a scale Standard Deviation 8.0387
Short Form Health Survey (SF-12) End Continuation Period Vitality	51.202 units on a scale Standard Deviation 9.3262	47.724 units on a scale Standard Deviation 10.0303
Short Form Health Survey (SF-12) Baseline Social Functioning	42.290 units on a scale Standard Deviation 10.5832	41.734 units on a scale Standard Deviation 9.8674
Short Form Health Survey (SF-12) End Continuation Period Social Functioning	47.494 units on a scale Standard Deviation 10.4657	44.475 units on a scale Standard Deviation 10.5281
Short Form Health Survey (SF-12) Baseline Role-Emotional	41.018 units on a scale Standard Deviation 13.0098	37.046 units on a scale Standard Deviation 13.2164
Short Form Health Survey (SF-12) End Continuation Period Role-Emotional	44.727 units on a scale Standard Deviation 12.1390	41.219 units on a scale Standard Deviation 12.7890
Short Form Health Survey (SF-12) Baseline Mental Health	44.967 units on a scale Standard Deviation 9.2036	42.394 units on a scale Standard Deviation 9.1589
Short Form Health Survey (SF-12) End Continuation Period Mental health	49.828 units on a scale Standard Deviation 10.3896	46.451 units on a scale Standard Deviation 10.3372
Short Form Health Survey (SF-12) Baseline Physical Component summary	30.319 units on a scale Standard Deviation 7.2739	31.684 units on a scale Standard Deviation 6.8313
Short Form Health Survey (SF-12) End Continuation Period Physical component summary	40.493 units on a scale Standard Deviation 9.3352	37.765 units on a scale Standard Deviation 8.8375
Short Form Health Survey (SF-12) Baseline Mental Component Summary	48.736 units on a scale Standard Deviation 11.5697	45.216 units on a scale Standard Deviation 11.7462
Short Form Health Survey (SF-12) End Continuation Period Mental Component Summary	51.117 units on a scale Standard Deviation 11.0365	47.595 units on a scale Standard Deviation 11.4544

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS), Last Observation Carried Forward (LOCF). Number of participants with data available.

The Short Form Health Survey (SF-12) has several brief broad questions on 8 aspects of health (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. The physical and mental summary scores were calculated from the individual responses. A higher score indicates a better participant perceived state of health. All domains were scored on a scale from 0 (lowest level of health) to 100 (highest level of health), with 100 representing the best possible health state.

The change in the SF-12 score shows an improvement in health from baseline if the values are positive. The higher the value the greater the improvement since starting the trial.

Outcome measures

Measure	Tapentadol Prolonged Release n=129 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Changes in the Short Form Health Survey (SF-12) at the End of Treatment Physical Functioning	8.358 units on a scale Standard Error 0.8262	5.073 units on a scale Standard Error 0.8361
Changes in the Short Form Health Survey (SF-12) at the End of Treatment Role-Physical	7.260 units on a scale Standard Error 0.7115	4.668 units on a scale Standard Error 0.7224
Changes in the Short Form Health Survey (SF-12) at the End of Treatment Bodily Pain	10.990 units on a scale Standard Error 0.9462	7.458 units on a scale Standard Error 0.9570
Changes in the Short Form Health Survey (SF-12) at the End of Treatment General Health	8.447 units on a scale Standard Error 0.8702	4.309 units on a scale Standard Error 0.8818
Changes in the Short Form Health Survey (SF-12) at the End of Treatment Vitality	4.943 units on a scale Standard Error 0.8062	1.468 units on a scale Standard Error 0.8179
Changes in the Short Form Health Survey (SF-12) at the End of Treatment Social Functioning	5.246 units on a scale Standard Error 0.8870	2.286 units on a scale Standard Error 0.8997
Changes in the Short Form Health Survey (SF-12) at the End of Treatment Role-Emotional	4.764 units on a scale Standard Error 0.9472	2.587 units on a scale Standard Error 0.9807
Changes in the Short Form Health Survey (SF-12) at the End of Treatment Mental Health	5.158 units on a scale Standard Error 0.8386	2.973 units on a scale Standard Error 0.8575
Changes in the Short Form Health Survey (SF-12) at the End of Treatment Physical Component Summary	9.735 units on a scale Standard Error 0.7948	6.202 units on a scale Standard Error 0.8058
Changes in the Short Form Health Survey (SF-12) at the End of Treatment Mental Component Summary	3.077 units on a scale Standard Error 0.8457	1.146 units on a scale Standard Error 0.8679

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The participant scored the EuroQol-5 questionnaire. The EuroQol-5 questionnaire uses a health state classification with 5 dimensions. Each dimension was 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 indicating "full health" and 0 representing "dead"). The higher the values (the closer the value is to 1) the better the health status in a treatment group.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
EuroQol-5 (EQ-5D) Health Status Index Outcome Baseline	0.3186 units on a scale Standard Deviation 0.29464	0.3392 units on a scale Standard Deviation 0.31134
EuroQol-5 (EQ-5D) Health Status Index Outcome End of Continuation Period	0.6686 units on a scale Standard Deviation 0.31683	0.5745 units on a scale Standard Deviation 0.31378

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The participant scored the EuroQol-5 questionnaire. The EuroQol-5 questionnaire uses a health state classification with 5 dimensions. Each dimension was 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 indicating "full health" and 0 representing "dead"). The higher the values (the closer the value is to 1) the better the health status in a treatment group.

Outcome measures

Measure	Tapentadol Prolonged Release n=129 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Change in EuroQol-5 (EQ-5D) Health Status Index Outcome at the End of Treatment	0.3395 units on a scale Standard Error 0.02785	0.2398 units on a scale Standard Error 0.02811

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe anxiety. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate anxiety. A score of 11 or above is considered to be a case of anxiety.

A decrease in values over the trial period indicate that there has been an improvement.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=124 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Hospital Anxiety and Depression Scale: Anxiety Baseline	7.3 units on a scale Standard Deviation 4.06	8.2 units on a scale Standard Deviation 4.28
Hospital Anxiety and Depression Scale: Anxiety End of Continuation Period	5.3 units on a scale Standard Deviation 4.40	6.7 units on a scale Standard Deviation 4.58

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe anxiety. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate anxiety. A score of 11 or above is considered to be a case of anxiety.

A negative sign indicates that there has been a decrease in anxiety since the start of treatment.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=124 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Change in Hospital Anxiety and Depression Scale at the End of Treatment: Anxiety	-2.1 units on a scale Standard Error 0.34	-1.1 units on a scale Standard Error 0.35

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last observation carried forward (LOCF). Number of participants with data available.

The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe depression. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate depression. A score of 11 or above is considered to be a case of depression. A decrease in values over time indicates that there has been an improvement.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Hospital Anxiety and Depression Scale: Depression Baseline	7.4 units on a scale Standard Deviation 4.08	8.0 units on a scale Standard Deviation 4.08
Hospital Anxiety and Depression Scale: Depression End of Continuation Period	5.1 units on a scale Standard Deviation 4.17	6.5 units on a scale Standard Deviation 4.86

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last observation carried forward (LOCF). Number of participants with data available.

The Hospital Anxiety and Depression Scale (HADS) is a self-assessment scale for the symptom severity of anxiety disorders and depression. It comprises 14 items. Seven statements describe depression. Each answer is scored on a four-point scale (0-3). All seven answers are summed to a total score with a maximum score of 21 points. A score below 7 is not considered to indicate depression. A score of 11 or above is considered to be a case of depression. A decrease in values over time indicates that there has been an improvement. A negative change value indicates a decrease in the depression score since the start of treatment.

Outcome measures

Measure	Tapentadol Prolonged Release n=124 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=114 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Change in Hospital Anxiety and Depression Scale at the End of Treatment: Depression	-2.4 units on a scale Standard Error 0.34	-1.1 units on a scale Standard Error 0.36

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

In the Patient Global Impression of Change (PGIC) the participant indicated the perceived change over the treatment period. PGIC is a 7 point scale depicting a patient's rating of overall improvement. Patients rate their change as "very much improved," "much improved," "minimally improved," "no change," "minimally worse," "much worse," or "very much worse."

Outcome measures

Measure	Tapentadol Prolonged Release n=129 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Patient Global Impression of Change at the End of Treatment Very Much Improved	27 participants	18 participants
Patient Global Impression of Change at the End of Treatment Much Improved	43 participants	19 participants
Patient Global Impression of Change at the End of Treatment Minimally Improved	32 participants	46 participants
Patient Global Impression of Change at the End of Treatment No Change	21 participants	29 participants
Patient Global Impression of Change at the End of Treatment Minimally Worse	3 participants	6 participants
Patient Global Impression of Change at the End of Treatment Much Worse	2 participants	4 participants
Patient Global Impression of Change at the End of Treatment Very Much Worse	1 participants	3 participants

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF).

In the Clinician Global Impression of Change (CGIC) the clinician indicated the perceived change over the treatment period. The clinician was requested to choose one of seven categories for each participant. The Clinician rated the participants change as "very much improved," "much improved," "minimally improved," "no change," "minimally worse," "much worse," or "very much worse."

Outcome measures

Measure	Tapentadol Prolonged Release n=128 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=123 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Clinician Global Impression of Change at the End of Treatment Minimally Worse	6 participants	7 participants
Clinician Global Impression of Change at the End of Treatment Much Worse	3 participants	9 participants
Clinician Global Impression of Change at the End of Treatment Very Much Worse	0 participants	1 participants
Clinician Global Impression of Change at the End of Treatment Very Much Improved	32 participants	18 participants
Clinician Global Impression of Change at the End of Treatment Much Improved	44 participants	25 participants
Clinician Global Impression of Change at the End of Treatment Minimally Improved	22 participants	37 participants
Clinician Global Impression of Change at the End of Treatment No Change	21 participants	26 participants

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF).

The sleep evaluation questionnaire was completed by the participant. The questionnaire measures 4 main concepts: 1 of the 4 main concepts being the overall quality of sleep.

The participant rated this categorically as being one of the following: excellent, good, fair or poor.

The improvement, no change or worsening is reported based on the replies scored by the participants given at their End of Continuation Visit.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=126 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Sleep Evaluation at the End of Treatment: Change in the Overall Quality of Sleep Improvement	62 participants	43 participants
Sleep Evaluation at the End of Treatment: Change in the Overall Quality of Sleep No Change	46 participants	56 participants
Sleep Evaluation at the End of Treatment: Change in the Overall Quality of Sleep Worsening	16 participants	15 participants
Sleep Evaluation at the End of Treatment: Change in the Overall Quality of Sleep Missing	6 participants	12 participants

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The participants were requested to answer the following question:

How many times did you wake up during the night? The values were calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline) and for the night prior to the End of the Continuation Visit (12 weeks after randomization).

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Sleep Evaluation: Number of Awakenings Baseline	3.0 number of awakenings Standard Deviation 2.80	2.6 number of awakenings Standard Deviation 1.67
Sleep Evaluation: Number of Awakenings End of Continuation Period	2.0 number of awakenings Standard Deviation 1.66	2.2 number of awakenings Standard Deviation 1.65

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF). Number of participants with data available.

The participants were requested to answer the question: How many times did you wake up during the night? The values were calculated from the data that participants self-reported. The change from baseline in the number of times of waking up during the night in a treatment group is reported. A negative symbol indicates that there was a reduction in the number of awakenings.

Outcome measures

Measure	Tapentadol Prolonged Release n=124 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=114 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Sleep Evaluation at the End of Treatment: Change in the Number of Awakenings	-0.8 number of awakenings Standard Error 0.15	-0.5 number of awakenings Standard Error 0.16

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF).

The participants were requested to answer the following question:

How long did you sleep last night [hours]? The values were calculated from the data that participants self-reported for the night prior to their Randomization Visit (Baseline) and for the night prior to the End of the Continuation Visit (12 weeks after randomization).

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=125 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Sleep Evaluation: Number of Hours Slept Baseline	5.781 hours Standard Deviation 1.5908	5.675 hours Standard Deviation 1.7118
Sleep Evaluation: Number of Hours Slept End of Continuation Period	6.207 hours Standard Deviation 1.8007	6.218 hours Standard Deviation 1.8426

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS). Last Observation Carried Forward (LOCF).

The sleep evaluation questionnaire was completed by the participant. The answer was in response to the question: Sleep evaluation: How long did you sleep last night [hours]? The value reported is the change in the number of hours of sleep from baseline. The positive value indicates that there was an increase in the number of hours of sleep in a treatment group.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=126 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Sleep Evaluation at the End of Treatment: Change in the Number of Hours Slept	0.460 hours Standard Error 0.1714	0.412 hours Standard Error 0.1763

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Period (Week 12)

Population: Full Analysis Set (FAS).

The sleep evaluation questionnaire was completed by the participant. The participant was asked: How long after bedtime/lights out did you fall asleep last night [hours]? The values are for the night prior to the Randomization Visit (Baseline) and for the night prior to the Final Evaluation Visit (12 weeks after randomization). The higher the value the longer it took to fall asleep.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=126 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Sleep Evaluation: Latency (Time Taken to Fall Asleep) Baseline	1.047 hours Standard Deviation 1.1746	1.203 hours Standard Deviation 1.3029
Sleep Evaluation: Latency (Time Taken to Fall Asleep) End of Continuation Period	0.803 hours Standard Deviation 1.1154	0.865 hours Standard Deviation 1.0301

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Continuation Visit (Week 12)

Population: Full Analysis Set (FAS). Last Observation carried Forward (LOCF). Number of participants taken into account for the analyses.

The sleep evaluation questionnaire was completed by the participant. The participant was asked: How long after bedtime/lights out did you fall asleep last night [hours]? The values are for the night prior to the visits. The negative change from baseline indicates that the time to falling asleep decreased from baseline in a treatment group.

Outcome measures

Measure	Tapentadol Prolonged Release n=124 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=114 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Sleep Evaluation at the End of Treatment: Change in Latency (Change in the Time Taken to Fall Asleep)	-0.300 hours Standard Error 0.1000	-0.177 hours Standard Error 0.1025

SECONDARY outcome

Timeframe: Baseline (Randomization Visit) to End of Titration Period (End of Week 3)

Population: Safety Set (SAF).

In this outcome measure the number of participants affected by early gastrointestinal-related treatment emergent adverse events (TEAEs). As the trial population was opioid-naïve this was considered of interest.

The composition score from participant who reported:

Mild, moderate to severe nausea and/or Mild, moderate to severe vomiting and/or Mild, moderate to severe constipation was evaluated.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=128 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Comparison of the Number of Participants Affected by Gastrointestinal Treatment Emergent Adverse Events (TEAEs) Typical for Opioids	42 participants	59 participants

SECONDARY outcome

Timeframe: Baseline (Randomization Visit); End of Week 3 (End of Titration Period)

Population: Safety Set (SAF).

In this outcome measure the early gastrointestinal-related treatment emergent events (TEAEs) were evaluated. As the trial population was opioid-naïve this was considered of interest.

The composition score of reported events of Mild, moderate to severe nausea and/or Mild, moderate to severe vomiting and/or Mild, moderate to severe constipation was evaluated.

Outcome measures

Measure	Tapentadol Prolonged Release n=130 Participants All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks	Oxycodone/Naloxone Prolonged Release n=128 Participants All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.
Composite Event Based Comparison of Gastrointestinal Treatment Emergent Adverse Events (TEAEs) Typical for Opioids	56 number of events	81 number of events

Adverse Events

Tapentadol Prolonged Release (PR)

Serious events: 3 serious events

Other events: 97 other events

Deaths: 0 deaths

Oxycodone/Naloxone Prolonged Release (PR)

Serious events: 2 serious events

Other events: 105 other events

Deaths: 0 deaths

Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment

Serious events: 0 serious events

Other events: 29 other events

Deaths: 0 deaths

Serious adverse events

Measure	Tapentadol Prolonged Release (PR) n=130 participants at risk All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.	Oxycodone/Naloxone Prolonged Release (PR) n=128 participants at risk All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.	Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment n=50 participants at risk Participants in the oxycodone/naloxone PR treatment arm that did not reach the minimum target of titration or experiencing intolerable side effects at the end of the Titration Period could be switched to the Pick-up Arm. They could also enter the Pick-up Arm at any time during the Titration Period or Continuation Period, via an unscheduled visit, due to lack of tolerability or lack of efficacy under treatment with oxycodone/naloxone PR. Participants were directly switched from oxycodone/naloxone PR to tapentadol PR using an equianalgesic ratio of 1:5 (oxycodone : tapentadol), together with a down-titration step under tapentadol PR (except for participants on oxycodone/naloxone PR 10 mg/5 mg twice daily).
Eye disorders Retinal detachment	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Hepatobiliary disorders Bile duct stone	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Hepatobiliary disorders Cholelithiasis	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Tracheobronchitis	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.

Other adverse events

Measure	Tapentadol Prolonged Release (PR) n=130 participants at risk All participants started with 50 mg tapentadol prolonged release (twice daily). The dose of tapentadol prolonged release was adjusted in increments of 50 mg to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 250 mg twice a day (500 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.	Oxycodone/Naloxone Prolonged Release (PR) n=128 participants at risk All participants started with 10 mg/5 mg oxycodone/naloxone prolonged release (twice daily). The dose of oxycodone/naloxone prolonged release could be adjusted in increments of 10 mg/5 mg oxycodone/naloxone to a level that provided adequate analgesia. The next titration step was after a minimum of 3 days on a dose. Participants were permitted a maximum dose of 50 mg/20 mg oxycodone/naloxone twice daily a day (100 mg/40 mg total daily dose). After titration participants remained on the stable dose for 9 weeks.	Tapentadol (PR) After Oxycodone/Naloxone (PR) Treatment n=50 participants at risk Participants in the oxycodone/naloxone PR treatment arm that did not reach the minimum target of titration or experiencing intolerable side effects at the end of the Titration Period could be switched to the Pick-up Arm. They could also enter the Pick-up Arm at any time during the Titration Period or Continuation Period, via an unscheduled visit, due to lack of tolerability or lack of efficacy under treatment with oxycodone/naloxone PR. Participants were directly switched from oxycodone/naloxone PR to tapentadol PR using an equianalgesic ratio of 1:5 (oxycodone : tapentadol), together with a down-titration step under tapentadol PR (except for participants on oxycodone/naloxone PR 10 mg/5 mg twice daily).
Vascular disorders Hot flush	5.4% 7/130 • Number of events 7 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	3.1% 4/128 • Number of events 4 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Vascular disorders Hypertension	2.3% 3/130 • Number of events 3 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	4.0% 2/50 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Vascular disorders Hypertensive crisis	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Vascular disorders Hypotension	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Cardiac disorders Palpitations	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Cardiac disorders Tachycardia	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	1.6% 2/128 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Cardiac disorders Tachycardia paroxysmal	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Ear and labyrinth disorders Tinnitus	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Ear and labyrinth disorders Vertigo	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	1.6% 2/128 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Eye disorders Ocular hyperaemia	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Eye disorders Vision blurred	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Eye disorders Visual impairment	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	1.6% 2/128 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Abdominal distension	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Abdominal pain	1.5% 2/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Abdominal pain lower	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Abdominal pain upper	3.8% 5/130 • Number of events 5 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	3.9% 5/128 • Number of events 6 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Bowel movement irregularity	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Colitis	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Constipation	15.4% 20/130 • Number of events 20 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	25.8% 33/128 • Number of events 34 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Diarrhoea	4.6% 6/130 • Number of events 6 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	6.0% 3/50 • Number of events 3 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Dry mouth	6.9% 9/130 • Number of events 9 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	5.5% 7/128 • Number of events 8 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Dyspepsia	1.5% 2/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Eructation	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Flatulence	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.3% 3/128 • Number of events 3 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Gastritis	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Gastrooesophageal reflux disease	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Nausea	22.3% 29/130 • Number of events 31 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	18.0% 23/128 • Number of events 23 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	10.0% 5/50 • Number of events 7 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Paraesthesia oral	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Saliva altered	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Gastrointestinal disorders Vomiting	7.7% 10/130 • Number of events 11 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	16.4% 21/128 • Number of events 24 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	8.0% 4/50 • Number of events 4 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Chills	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Drug withdrawal syndrome	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Fatigue	30.0% 39/130 • Number of events 42 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	24.2% 31/128 • Number of events 32 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	4.0% 2/50 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Influenza like illness	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Irritability	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Local swelling	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	1.6% 2/128 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Malaise	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Oedema peripheral	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Pain	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Pyrexia	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
General disorders Thirst	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Hepatobiliary disorders Biliary colic	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Bronchitis	0.77% 1/130 • Number of events 3 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Cystitis	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Furuncle	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Gastroenteritis	2.3% 3/130 • Number of events 3 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.3% 3/128 • Number of events 3 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Gastrointestinal infection	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Influenza	0.77% 1/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Nasopharyngitis	6.2% 8/130 • Number of events 8 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	3.9% 5/128 • Number of events 5 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	4.0% 2/50 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Oral herpes	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Otitis media	1.5% 2/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Pulpitis dental	1.5% 2/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Respiratory tract infection	0.77% 1/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Tooth abscess	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Urinary tract Infection	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Infections and infestations Viral upper respiratory tract infection	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Injury, poisoning and procedural complications Contusion	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Injury, poisoning and procedural complications Fall	0.77% 1/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Injury, poisoning and procedural complications Injury	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Injury, poisoning and procedural complications Ligament sprain	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	1.6% 2/128 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Injury, poisoning and procedural complications Thermal burn	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Injury, poisoning and procedural complications Traumatic haematoma	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Investigations Biopsy chest wall	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Investigations Blood phosphorus decreased	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Investigations Blood testosterone decreased	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Investigations Creatinine renal clearance decreased	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Investigations Hepatic enzyme increased	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Investigations Weight decreased	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Metabolism and nutrition disorders Decreased appetite	3.1% 4/130 • Number of events 5 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	3.9% 5/128 • Number of events 5 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Metabolism and nutrition disorders Fluid retention	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Metabolism and nutrition disorders Neck pain	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Musculoskeletal and connective tissue disorders Exostosis	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Musculoskeletal and connective tissue disorders Flank pain	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Musculoskeletal and connective tissue disorders Muscle spasms	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Musculoskeletal and connective tissue disorders Myosclerosis	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Musculoskeletal and connective tissue disorders Osteoporosis	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Musculoskeletal and connective tissue disorders Pain in extremity	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	1.6% 2/128 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Musculoskeletal and connective tissue disorders Plantar fasciitis	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Musculoskeletal and connective tissue disorders Spinal pain	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Musculoskeletal and connective tissue disorders Tendon pain	1.5% 2/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Melanocytic naevus	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Balance disorder	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Carpal tunnel syndrome	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Cervicobrachial syndrome	1.5% 2/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Dizziness	18.5% 24/130 • Number of events 26 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	17.2% 22/128 • Number of events 22 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	12.0% 6/50 • Number of events 6 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Headache	7.7% 10/130 • Number of events 10 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	3.9% 5/128 • Number of events 5 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Hypoaesthesia	2.3% 3/130 • Number of events 3 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	3.9% 5/128 • Number of events 6 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Neuromuscular blockade	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Orthostatic intolerance	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Paraesthesia	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Sciatica	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Somnolence	2.3% 3/130 • Number of events 4 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.3% 3/128 • Number of events 3 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Speech disorder	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Syncope	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Tremor	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	1.6% 2/128 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Nervous system disorders Vertigo cns origin	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Psychiatric disorders Apathy	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Psychiatric disorders Claustrophobia	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Psychiatric disorders Drug dependence	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Psychiatric disorders Euphoric mood	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Psychiatric disorders Insomnia	3.1% 4/130 • Number of events 4 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	1.6% 2/128 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Psychiatric disorders Nervousness	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Psychiatric disorders Restlessness	1.5% 2/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	1.6% 2/128 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Psychiatric disorders Sleep disorder	0.77% 1/130 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	1.6% 2/128 • Number of events 2 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Psychiatric disorders Tic	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Psychiatric disorders Withdrawal syndrome	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Renal and urinary disorders Renal impairment	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Renal and urinary disorders Renal pain	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Renal and urinary disorders Urinary retention	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Respiratory, thoracic and mediastinal disorders Dry throat	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Respiratory, thoracic and mediastinal disorders Dyspnoea	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	2.0% 1/50 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Respiratory, thoracic and mediastinal disorders Epistaxis	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Respiratory, thoracic and mediastinal disorders Respiratory distress	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Skin and subcutaneous tissue disorders Cold sweat	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Skin and subcutaneous tissue disorders Eczema	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Skin and subcutaneous tissue disorders Erythema	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Skin and subcutaneous tissue disorders Haematidrosis	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/128 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Skin and subcutaneous tissue disorders Hyperhidrosis	6.2% 8/130 • Number of events 8 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	10.2% 13/128 • Number of events 13 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	8.0% 4/50 • Number of events 4 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Skin and subcutaneous tissue disorders Pruritus	6.2% 8/130 • Number of events 9 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	8.6% 11/128 • Number of events 12 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Skin and subcutaneous tissue disorders Rash	0.77% 1/130 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Skin and subcutaneous tissue disorders Rash pruritic	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Skin and subcutaneous tissue disorders Skin irritation	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Skin and subcutaneous tissue disorders Urticaria	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.
Surgical and medical procedures Vocal cord polypectomy	0.00% 0/130 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.78% 1/128 • Number of events 1 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.	0.00% 0/50 • Adverse events occurring after first administration of study drug were listed (Treatment emergent adverse events - TEAEs) and within 3 days after the last intake were considered as TEAEs. Pre-treatment adverse events that worsened were considered TEAEs.

Additional Information

Study Director

Grünenthal GmbH

Phone: +49 241 569

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 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