Trial Outcomes & Findings for Tapentadol (CG5503) (NCT NCT00421928)

NCT ID: NCT00421928

Last Updated: 2012-04-18

Results Overview

For this twice daily pain assessment, the subjects were to indicate the level of pain experienced over the previous 12 hours on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

1030 participants

Primary outcome timeframe

Baseline and 12 weeks (Primary endpoint is the average pain intensity score during the last week of the maintenance period).

Results posted on

2012-04-18

Participant Flow

The recruitment period for this out-patient, multicenter study occurred between 07 February 2007 and 15 July 08.

The study consisted of a screening period (duration up to 14 days), a washout period (duration 3 to 7 days), a double-blind active treatment period with titration period (duration 3 weeks) and maintenance period (duration 12 weeks)

Participant milestones

Participant milestones
Measure	Tapentadol (CG5503) Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo Matching Placebo twice daily (BID)
Overall Study STARTED	344	342	337
Overall Study COMPLETED	181	118	203
Overall Study NOT COMPLETED	163	224	134

Reasons for withdrawal

Reasons for withdrawal
Measure	Tapentadol (CG5503) Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo Matching Placebo twice daily (BID)
Overall Study Adverse Event	61	140	22
Overall Study Lost to Follow-up	5	0	3
Overall Study Withdrawal by Subject	50	48	43
Overall Study Lack of Efficacy	15	7	35
Overall Study Study drug non-compliant	6	7	4
Overall Study All other	26	21	27
Overall Study Death	0	1	0

Baseline Characteristics

Tapentadol (CG5503)

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Tapentadol (CG5503) n=344 Participants Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone n=342 Participants oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo n=337 Participants Matching Placebo twice daily (BID)	Total n=1023 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants
Age, Categorical Between 18 and 65 years	249 Participants n=5 Participants	249 Participants n=7 Participants	260 Participants n=5 Participants	758 Participants n=4 Participants
Age, Categorical >=65 years	95 Participants n=5 Participants	93 Participants n=7 Participants	77 Participants n=5 Participants	265 Participants n=4 Participants
Age Continuous	58.4 years STANDARD_DEVIATION 10.09 • n=5 Participants	58.2 years STANDARD_DEVIATION 10.29 • n=7 Participants	58.2 years STANDARD_DEVIATION 9.15 • n=5 Participants	58.3 years STANDARD_DEVIATION 9.85 • n=4 Participants
Sex: Female, Male Female	216 Participants n=5 Participants	202 Participants n=7 Participants	200 Participants n=5 Participants	618 Participants n=4 Participants
Sex: Female, Male Male	128 Participants n=5 Participants	140 Participants n=7 Participants	137 Participants n=5 Participants	405 Participants n=4 Participants

PRIMARY outcome

Timeframe: Baseline and 12 weeks (Primary endpoint is the average pain intensity score during the last week of the maintenance period).

Population: Intent-to-treat (ITT) population. Last observation carried forward (LOCF) was used to impute pain score after discontinuation

Outcome measures

Outcome measures
Measure	Tapentadol (CG5503) n=344 Participants Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone n=342 Participants oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo n=337 Participants Matching Placebo twice daily (BID)
Change From Baseline of the Average Pain Intensity Based on an 11-point Numerical Rating Scale(NRS) Over the Last Week of the Maintenance Period at Week 12.	-3.0 Scores on a scale Standard Deviation 2.39	-2.6 Scores on a scale Standard Deviation 2.38	-2.2 Scores on a scale Standard Deviation 2.54

SECONDARY outcome

Timeframe: Baseline and 12 week endpoint

Population: Intent To Treat (ITT), observed cases analysis conducted, no imputation performed.

Change from baseline to Week 12 of WOMAC Global Score: WOMAC is measure with a Likert ordinal scale from 0-4 with lower scores indicating lower levels of symptoms or physical disability

Outcome measures

Outcome measures
Measure	Tapentadol (CG5503) n=149 Participants Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone n=92 Participants oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo n=158 Participants Matching Placebo twice daily (BID)
Change From Baseline in Western Ontario McMaster Questionnaire (WOMAC) Assessing Pain, Disability and Joint Stiffness of the Knee Over the Last Week of the Maintenance Period at Week 12	-1.2 Scores on a scale Standard Deviation 0.82	-1.1 Scores on a scale Standard Deviation 0.87	-0.9 Scores on a scale Standard Deviation 0.84

SECONDARY outcome

Timeframe: Baseline and 12 week endpoint

Population: ITT

A Sleep Questionniare addressed the following question: "How long after bedtime/lights out did you fall asleep last night (hours)?" 12 week endpoint-mean changes from baseline at endpoint for sleep latency. Decrease in time(hours) indicates improvement.

Outcome measures

Outcome measures
Measure	Tapentadol (CG5503) n=339 Participants Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone n=337 Participants oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo n=331 Participants Matching Placebo twice daily (BID)
Change From Baseline in Sleep Latency Time in Hours Over the Last Week of the Maintenance Period at Week 12.	0.2 Hours Standard Deviation 2.8	0.1 Hours Standard Deviation 1.81	0.3 Hours Standard Deviation 2.72

SECONDARY outcome

Timeframe: Baseline and 12 week endpoint

Population: ITT

Ordinal measure indicating change from start of treatment (on a scale of 7 = Very much worse to 1 = Very much improved)

Outcome measures

Outcome measures
Measure	Tapentadol (CG5503) n=317 Participants Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone n=308 Participants oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo n=309 Participants Matching Placebo twice daily (BID)
Percentage of Patients Who Reported Very Much Improved or Much Improved From Baseline in Patient Global Impression of Change Over the Last Week of the Maintenance Period at Week 12	51.1 percentage of participants	37.7 percentage of participants	32.4 percentage of participants

SECONDARY outcome

Timeframe: Baseline to 12 weeks

Population: ITT: The results for median and interquartile ranges were not estimable because insufficient number of subjects discontinued due to lack of efficacy to estimate the values.

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

Outcome measures

Outcome data not reported

SECONDARY outcome

Timeframe: Baseline and 12 week endpoint

Population: ITT

Change from baseline to end point in EuroQol-5 (EQ-5D) Dimension Questionnaire. A higher score indicates an improvement in health in the Health Status Index. The EQ-5D is a five dimensional health state classification. Each dimension is assessed on a 3-point ordinal scale (1=no problems, 2=some problems, 3=extreme problems). The responses to the five EQ-5D dimensions were scored using a utility-weighted algorithm to derive an EQ-5D health status index score between 0 to 1, with 1.00 indicating "full health" and 0 representing dead

Outcome measures

Outcome measures
Measure	Tapentadol (CG5503) n=344 Participants Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone n=342 Participants oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo n=337 Participants Matching Placebo twice daily (BID)
Change From Baseline in EuroQol-5 (EQ-5D) Health Status Index to Week 12	0.6 scores on a scale Standard Deviation 0.26	0.5 scores on a scale Standard Deviation 0.28	0.5 scores on a scale Standard Deviation 0.29

SECONDARY outcome

Timeframe: Baseline and Week 12

Population: ITT. Subjects who discontinued from the study were considered non-responders.

Defined by the percentage of subjects achieving at least 50% improvement from baseline in the primary endpoint based on the 11-point NRS at week 12. For this twice daily pain assessment, the subjects were to indicate the level of pain experienced over the previous 12 hours on an 11-point Numerical Rating Scale (NRS) where a score of 0 indicated "no pain" and a score of 10 indicated "pain as bad as you can imagine".

Outcome measures

Outcome measures
Measure	Tapentadol (CG5503) n=344 Participants Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone n=342 Participants oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo n=337 Participants Matching Placebo twice daily (BID)
Change From Baseline in Responder Analysis 50% Improvement to Week 12	32.0 Percentage of participants	17.3 Percentage of participants	24.3 Percentage of participants

Adverse Events

Tapentadol (CG5503)

Serious events: 4 serious events

Other events: 200 other events

Deaths: 0 deaths

Oxycodone

Serious events: 10 serious events

Other events: 269 other events

Deaths: 0 deaths

Placebo

Serious events: 6 serious events

Other events: 134 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Other adverse events
Measure	Tapentadol (CG5503) n=344 participants at risk Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone n=342 participants at risk oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo n=337 participants at risk Matching Placebo twice daily (BID)
Gastrointestinal disorders Nausea	21.5% 74/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	36.5% 125/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	6.8% 23/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Gastrointestinal disorders Constipation	18.9% 65/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	36.8% 126/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	6.5% 22/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Gastrointestinal disorders Dry Mouth	6.4% 22/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	4.4% 15/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	2.4% 8/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Gastrointestinal disorders Vomiting	5.2% 18/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	17.8% 61/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	3.3% 11/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Gastrointestinal disorders Diarrhoea	4.7% 16/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	5.0% 17/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	5.9% 20/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Nervous system disorders Dizziness	17.7% 61/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	19.0% 65/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	4.7% 16/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Nervous system disorders Headache	14.8% 51/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	14.6% 50/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	16.6% 56/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Nervous system disorders Somnolence	10.8% 37/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	19.6% 67/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	4.2% 14/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
General disorders Fatigue	10.8% 37/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	10.2% 35/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	4.5% 15/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Skin and subcutaneous tissue disorders Pruritus	7.0% 24/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	12.6% 43/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	1.2% 4/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Musculoskeletal and connective tissue disorders Arthralgia	2.9% 10/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	1.8% 6/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	5.0% 17/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Musculoskeletal and connective tissue disorders Back Pain	2.0% 7/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	1.5% 5/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	6.5% 22/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.

Additional Information

Senior Director, Clinical Leader

Johnson & Johnson Pharmaceutical Research & Development, L.L.C.

Phone: 609-730-4537

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: LTE60

Measure	Tapentadol (CG5503) n=344 participants at risk Tapentadol(CG5503) extended release (ER) 100-250mg twice daily (BID)	Oxycodone n=342 participants at risk oxycodone controlled release (CR)20-50mg twice daily (BID)	Placebo n=337 participants at risk Matching Placebo twice daily (BID)
Cardiac disorders Myocardial Infarction	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.30% 1/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Cardiac disorders Cardiac Failure Congestive	0.29% 1/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Cardiac disorders Angina Pectoris	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Cardiac disorders Atrial Flutter	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Ear and labyrinth disorders Meniere's Disease	0.29% 1/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Infections and infestations Pneumonia	0.29% 1/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Infections and infestations Influenza	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Infections and infestations Pyelonephritis Acute	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.30% 1/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.29% 1/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Musculoskeletal and connective tissue disorders Pain in Extremity	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.30% 1/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Blood and lymphatic system disorders Anaemia	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Gastrointestinal disorders Abdominal Pain	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.30% 1/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Gastrointestinal disorders Intestinal Mass	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
General disorders Drug Withdrawal Syndrome	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung Cancer Metastatic	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Nervous system disorders Embolic Stroke	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.30% 1/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Psychiatric disorders Confusional State	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Psychiatric disorders Suicidal Ideation	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Renal and urinary disorders Renal Failure Acute	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.58% 2/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Respiratory, thoracic and mediastinal disorders Asthma	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.30% 1/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.
Surgical and medical procedures Spinal Fusion Surgery	0.00% 0/344 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.29% 1/342 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.	0.00% 0/337 • All adverse events were reported from the time a signed and dated informed consent was obtained throughout the follow-up phase of the study. Serious adverse events were collected for 30 days after the last dose of study drug.