Trial Outcomes & Findings for Safety and Efficacy of Buprenorphine Transdermal System (BTDS) in Subjects With Moderate to Severe Osteoarthritis Pain (NCT NCT00312221)

Last Updated: 2012-09-10

Results Overview

The "average pain over the last 24 hours" score was collected using an 11-point numerical scale ranging from 0 to 10, where 0 = no pain and 10 = pain as bad as you can imagine. This variable was obtained at each clinic visit during the double-blind phase of the study (postrandomization weeks 1, 2, 4, 8, and 12).

Recruitment status

TERMINATED

Study phase

PHASE3

Target enrollment

418 participants

Primary outcome timeframe

Weeks 4, 8, and 12 of the double-blind phase

Results posted on

2012-09-10

Participant Flow

Study Dates: 02-Apr-2004 (first subject first visit) to 18 Jul-2005 (last subject last visit); 15-Jun-2005 (first site notified of study termination). The study took place in 82 medical/research sites in the US; 59 sites randomized at least 1 subject.

Men and women aged 40 years or older with OA of the hip, knee, or spine, on 30 to 80 mg/day morphine sulfate (MSO4) or equivalent, with or without nonopioid analgesic medication. (652 subjects entered the run-in period; 418 completed.) Subjects were eligible to enter the double-blind phase if they tolerated BTDS 20 and achieved stable analgesia.

Participant milestones

Participant milestones
Measure	Run-in Period The run-in period was designed to select subjects whose pain was adequately controlled by and who tolerated BTDS 20 treatment. BTDS 10 or 20 was applied for 7-day wear during the 3-week run-in period.	Double-blind BTDS 5 Buprenorphine transdermal patch 5 mcg/h applied for 7-day wear	Double-blind BTDS 20 Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear	Double-blind Oxycodone Immediate-Release Oxycodone immediate-release 40 mg (two 5-mg capsules every 6 hours).
Open-label Run-in Period STARTED	652	0	0	0
Open-label Run-in Period COMPLETED	418	0	0	0
Open-label Run-in Period NOT COMPLETED	234	0	0	0
Double-blind Phase STARTED	0	136	149	133
Double-blind Phase COMPLETED	0	77	77	63
Double-blind Phase NOT COMPLETED	0	59	72	70

Reasons for withdrawal

Reasons for withdrawal
Measure	Run-in Period The run-in period was designed to select subjects whose pain was adequately controlled by and who tolerated BTDS 20 treatment. BTDS 10 or 20 was applied for 7-day wear during the 3-week run-in period.	Double-blind BTDS 5 Buprenorphine transdermal patch 5 mcg/h applied for 7-day wear	Double-blind BTDS 20 Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear	Double-blind Oxycodone Immediate-Release Oxycodone immediate-release 40 mg (two 5-mg capsules every 6 hours).
Open-label Run-in Period Withdrawal by Subject	6	0	0	0
Open-label Run-in Period Adverse Event	74	0	0	0
Open-label Run-in Period Lost to Follow-up	5	0	0	0
Open-label Run-in Period Administrative	42	0	0	0
Open-label Run-in Period Lack of Efficacy	102	0	0	0
Open-label Run-in Period Did not qualify	5	0	0	0
Double-blind Phase Withdrawal by Subject	0	6	8	7
Double-blind Phase Adverse Event	0	10	19	18
Double-blind Phase Lost to Follow-up	0	0	2	2
Double-blind Phase Administrative	0	26	37	33
Double-blind Phase Lack of Efficacy	0	17	6	10

Baseline Characteristics

Safety and Efficacy of Buprenorphine Transdermal System (BTDS) in Subjects With Moderate to Severe Osteoarthritis Pain

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Double-blind BTDS 5 n=136 Participants Buprenorphine transdermal patch 5 mcg/h applied for 7-day wear	Double-blind BTDS 20 n=149 Participants Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear	Double-blind Oxycodone Immediate-Release n=133 Participants Oxycodone immediate-release 40 mg (two 5-mg capsules every 6 hours).	Total n=418 Participants Total of all reporting groups
Age Continuous	58.7 years STANDARD_DEVIATION 10.71 • n=93 Participants	57.9 years STANDARD_DEVIATION 9.45 • n=4 Participants	58.1 years STANDARD_DEVIATION 10.36 • n=27 Participants	58.3 years STANDARD_DEVIATION 10.15 • n=483 Participants
Sex: Female, Male Female	101 Participants n=93 Participants	116 Participants n=4 Participants	94 Participants n=27 Participants	311 Participants n=483 Participants
Sex: Female, Male Male	35 Participants n=93 Participants	33 Participants n=4 Participants	39 Participants n=27 Participants	107 Participants n=483 Participants

PRIMARY outcome

Timeframe: Weeks 4, 8, and 12 of the double-blind phase

Population: Full Analysis Population (N = 418) consisted of subjects who were randomized and received at least 1 dose of double-blind study drug.

Outcome measures

Outcome measures
Measure	Double-blind BTDS 5 n=136 Participants Buprenorphine transdermal patch 5 mcg/h applied for 7-day wear	Double-blind BTDS 20 n=149 Participants Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear	Double-blind Oxycodone Immediate-Release n=133 Participants Oxycodone immediate-release 40 mg (two 5-mg capsules every 6 hours).
"Average Pain Over the Last 24 Hours" Scores at Weeks 4, 8, and 12 of the Double-blind Phase. Screening	6.60 Units on a scale Standard Error 0.116	6.58 Units on a scale Standard Error 0.103	6.44 Units on a scale Standard Error 0.117
"Average Pain Over the Last 24 Hours" Scores at Weeks 4, 8, and 12 of the Double-blind Phase. Prerandomization	3.25 Units on a scale Standard Error 0.114	3.02 Units on a scale Standard Error 0.093	3.03 Units on a scale Standard Error 0.099
"Average Pain Over the Last 24 Hours" Scores at Weeks 4, 8, and 12 of the Double-blind Phase. Week 4	4.21 Units on a scale Standard Error 0.219	3.57 Units on a scale Standard Error 0.195	3.45 Units on a scale Standard Error 0.209
"Average Pain Over the Last 24 Hours" Scores at Weeks 4, 8, and 12 of the Double-blind Phase. Week 8	3.78 Units on a scale Standard Error 0.239	3.37 Units on a scale Standard Error 0.190	3.59 Units on a scale Standard Error 0.217
"Average Pain Over the Last 24 Hours" Scores at Weeks 4, 8, and 12 of the Double-blind Phase. Week 12	3.67 Units on a scale Standard Error 0.246	3.56 Units on a scale Standard Error 0.230	3.37 Units on a scale Standard Error 0.232

SECONDARY outcome

Timeframe: Double-blind phase (84 days)

Population: Full Analysis Population (N = 418) consisted of subjects who were randomized and received at least 1 dose of double-blind study drug.

The mean daily number of supplemental analgesic medication tablets included sponsor-supplied ibuprofen, acetaminophen, or OxyIR®.

Outcome measures

Outcome measures
Measure	Double-blind BTDS 5 n=136 Participants Buprenorphine transdermal patch 5 mcg/h applied for 7-day wear	Double-blind BTDS 20 n=149 Participants Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear	Double-blind Oxycodone Immediate-Release n=133 Participants Oxycodone immediate-release 40 mg (two 5-mg capsules every 6 hours).
The Mean Daily Number of Supplemental Analgesic Medication Tablets Prerandomization	2.0 Tablets Standard Error 0.19	1.7 Tablets Standard Error 0.13	1.6 Tablets Standard Error 0.13
The Mean Daily Number of Supplemental Analgesic Medication Tablets Double-blind	3.3 Tablets Standard Error 0.26	2.3 Tablets Standard Error 0.19	2.3 Tablets Standard Error 0.22

SECONDARY outcome

Timeframe: Weeks 4, 8 and 12 of the double-blind phase

Population: Full Analysis Population (N = 418) consisted of subjects who were randomized and received at least 1 dose of double-blind study drug.

The WOMAC (Version LK 3.1) measures symptoms and physical functioning of patients with OA of the hip and knee. It contains 24 items (5 pain, 2 stiffness, 17 physical function) and takes less than 5 minutes to complete. The WOMAC physical function subscale has 17 items coded as 0 to 4 (best to worst), which are summed, giving a range of 0 to 68 (best to worst).

Outcome measures

Outcome measures
Measure	Double-blind BTDS 5 n=136 Participants Buprenorphine transdermal patch 5 mcg/h applied for 7-day wear	Double-blind BTDS 20 n=149 Participants Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear	Double-blind Oxycodone Immediate-Release n=133 Participants Oxycodone immediate-release 40 mg (two 5-mg capsules every 6 hours).
The Physical Function Subscale of The Western Ontario and McMaster's Universities Osteoarthritis (WOMAC OA) Index at Weeks 4, 8, and 12 of the Double Blind Phase Screening	36.88 Units on a scale Standard Error 1.093	37.69 Units on a scale Standard Error 0.930	36.81 Units on a scale Standard Error 1.043
The Physical Function Subscale of The Western Ontario and McMaster's Universities Osteoarthritis (WOMAC OA) Index at Weeks 4, 8, and 12 of the Double Blind Phase Prerandomization	25.96 Units on a scale Standard Error 0.993	24.19 Units on a scale Standard Error 0.947	24.42 Units on a scale Standard Error 0.930
The Physical Function Subscale of The Western Ontario and McMaster's Universities Osteoarthritis (WOMAC OA) Index at Weeks 4, 8, and 12 of the Double Blind Phase Week 4	30.60 Units on a scale Standard Error 1.187	28.34 Units on a scale Standard Error 1.025	26.65 Units on a scale Standard Error 1.253
The Physical Function Subscale of The Western Ontario and McMaster's Universities Osteoarthritis (WOMAC OA) Index at Weeks 4, 8, and 12 of the Double Blind Phase Week 8	28.70 Units on a scale Standard Error 1.364	28.34 Units on a scale Standard Error 1.199	26.59 Units on a scale Standard Error 1.405
The Physical Function Subscale of The Western Ontario and McMaster's Universities Osteoarthritis (WOMAC OA) Index at Weeks 4, 8, and 12 of the Double Blind Phase Week 12	29.68 Units on a scale Standard Error 1.500	29.35 Units on a scale Standard Error 1.253	27.25 Units on a scale Standard Error 1.651

SECONDARY outcome

Timeframe: Weeks 4, 8, and 12 of the Double-blind Phase

Population: Full Analysis Population (N = 418) consisted of subjects who were randomized and received at least 1 dose of double-blind study drug.

The MOS-Sleep Scale consists of 12 individual items: (4 sleep disturbance, 2 sleep adequacy, 1 quantity of optimal sleep, 3 somnolence, 1 snoring, and 1 shortness of breath) and takes 5 to 10 minutes to complete. Question 1 is scored on a scale of 1 to 5 and Questions 2 to 12 are scored on a scale of 1 to 6. The Sleep Disturbance Subscale score is derived from the scores to Questions 1, 3, 7 and 8, and ranges from 0 to 100, where higher scores indicate greater sleep disturbance.

Outcome measures

Outcome measures
Measure	Double-blind BTDS 5 n=136 Participants Buprenorphine transdermal patch 5 mcg/h applied for 7-day wear	Double-blind BTDS 20 n=149 Participants Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear	Double-blind Oxycodone Immediate-Release n=133 Participants Oxycodone immediate-release 40 mg (two 5-mg capsules every 6 hours).
The Sleep Disturbance Subscale in The Medical Outcomes (MOS)-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase Screening	51.91 Units on a scale Standard Error 2.139	55.28 Units on a scale Standard Error 2.035	55.74 Units on a scale Standard Error 2.197
The Sleep Disturbance Subscale in The Medical Outcomes (MOS)-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase Prerandomization	34.64 Units on a scale Standard Error 1.950	28.65 Units on a scale Standard Error 1.782	33.03 Units on a scale Standard Error 1.926
The Sleep Disturbance Subscale in The Medical Outcomes (MOS)-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase Week 4	39.23 Units on a scale Standard Error 2.144	32.40 Units on a scale Standard Error 1.941	35.72 Units on a scale Standard Error 2.298
The Sleep Disturbance Subscale in The Medical Outcomes (MOS)-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase Week 8	35.95 Units on a scale Standard Error 2.791	31.71 Units on a scale Standard Error 2.473	34.13 Units on a scale Standard Error 2.746
The Sleep Disturbance Subscale in The Medical Outcomes (MOS)-Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase Week 12	39.13 Units on a scale Standard Error 3.089	32.95 Units on a scale Standard Error 2.819	36.32 Units on a scale Standard Error 3.290

Adverse Events

Double-blind BTDS 5

Serious events: 3 serious events

Other events: 30 other events

Deaths: 0 deaths

Double-blind BTDS 20

Serious events: 7 serious events

Other events: 70 other events

Deaths: 0 deaths

Double-blind Oxycodone Immediate-Release

Serious events: 7 serious events

Other events: 56 other events

Deaths: 0 deaths

Run-in, Open-label BTDS 10 and 20

Serious events: 8 serious events

Other events: 187 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Clinical Leader, Medical Director

Purdue Pharma L.P.

Phone: 800-733-1333

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60

Serious adverse events
Measure	Double-blind BTDS 5 n=136 participants at risk Buprenorphine transdermal patch 5 mcg/h applied for 7-day wear during the 12-week double-blind phase	Double-blind BTDS 20 n=149 participants at risk Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear during the 12-week double-blind phase	Double-blind Oxycodone Immediate-Release n=133 participants at risk Oxycodone immediate-release 40 mg (two 5-mg capsules every 6 hours) during the 12-week double-blind phase.	Run-in, Open-label BTDS 10 and 20 n=652 participants at risk The run-in period was designed to select subjects whose pain was adequately controlled by and who tolerated BTDS 20 treatment. BTDS 10 or 20 was applied for 7-day wear during the 3-week run-in period.
Cardiac disorders Paroxysmal supraventricular tachycardia	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Gastrointestinal disorders Acute abdomen	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Cardiac disorders Acute coronary syndrome	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Renal and urinary disorders Acute renal failure	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Hepatobiliary disorders Acute cholecystitis	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Cardiac disorders Bradycardia	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Respiratory, thoracic and mediastinal disorders Bronchospasm	0.74% 1/136 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
General disorders Chest pain	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Cardiac disorders Chest pain with ischemic episode	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Hepatobiliary disorders Cholelithiasis	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Vascular disorders Deep vein thrombosis	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Metabolism and nutrition disorders Dehydration	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Congenital, familial and genetic disorders Dermoid ovarian cyst	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Gastrointestinal disorders Diarrhea	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Reproductive system and breast disorders Enlarged uterus	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Gastrointestinal disorders Exacerbation of Crohn's disease	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Nervous system disorders Exacerbation of lumbar spinal stenosis	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
General disorders Fall	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
General disorders Fell	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Injury, poisoning and procedural complications Fractured left hip	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Gastrointestinal disorders GI bleeding	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Liver cancer	0.74% 1/136 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Musculoskeletal and connective tissue disorders Muscle spasms right knee	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Reproductive system and breast disorders Metrorrhagia	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Gastrointestinal disorders Nausea	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Social circumstances OxyIR abuse	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Cardiac disorders Palpitations	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Injury, poisoning and procedural complications Postsurgical hip joint dislocation, left hip	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Possible bone cancer	0.74% 1/136 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostatic adenocarcinoma	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Musculoskeletal and connective tissue disorders Recurrent L4-L5 disc herniation	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Nervous system disorders Recurrent L5-S1 disc herniation with impingement of the S1 nerve root	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Renal and urinary disorders Renal calculi	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Nervous system disorders Transischemic attack	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.75% 1/133 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Respiratory, thoracic and mediastinal disorders Worsening asthma	0.74% 1/136 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Gastrointestinal disorders Vomiting	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Gastrointestinal disorders Acid reflux	0.74% 1/136 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Musculoskeletal and connective tissue disorders End stage OA of the right knee	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Number of events 1 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.

Other adverse events
Measure	Double-blind BTDS 5 n=136 participants at risk Buprenorphine transdermal patch 5 mcg/h applied for 7-day wear during the 12-week double-blind phase	Double-blind BTDS 20 n=149 participants at risk Buprenorphine transdermal patch 20 mcg/h applied for 7-day wear during the 12-week double-blind phase	Double-blind Oxycodone Immediate-Release n=133 participants at risk Oxycodone immediate-release 40 mg (two 5-mg capsules every 6 hours) during the 12-week double-blind phase.	Run-in, Open-label BTDS 10 and 20 n=652 participants at risk The run-in period was designed to select subjects whose pain was adequately controlled by and who tolerated BTDS 20 treatment. BTDS 10 or 20 was applied for 7-day wear during the 3-week run-in period.
Gastrointestinal disorders Nausea	2.9% 4/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	10.7% 16/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	12.8% 17/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	14.4% 94/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Gastrointestinal disorders Constipation	2.2% 3/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	5.4% 8/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	6.8% 9/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	3.4% 22/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Gastrointestinal disorders Vomiting NOS	0.00% 0/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	5.4% 8/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	4.5% 6/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	4.9% 32/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Gastrointestinal disorders Abdominal pain upper	0.74% 1/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.00% 0/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	4.5% 6/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.15% 1/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
General disorders Application site pruritus	9.6% 13/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	14.8% 22/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	9.0% 12/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	7.2% 47/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
General disorders Application site rash	3.7% 5/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	6.0% 9/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	6.0% 8/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	1.4% 9/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
General disorders Application site erythema	6.6% 9/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	9.4% 14/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	3.8% 5/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	1.4% 9/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
General disorders Pain NOS	3.7% 5/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.67% 1/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	5.3% 7/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	1.7% 11/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Infections and infestations Upper respiratory tract infection NOS	4.4% 6/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	4.0% 6/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	6.0% 8/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	0.77% 5/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Infections and infestations Urinary tract infection NOS	3.7% 5/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	5.4% 8/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	3.8% 5/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	1.4% 9/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Musculoskeletal and connective tissue disorders Arthralgia	3.7% 5/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	6.0% 9/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	3.0% 4/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	1.8% 12/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Musculoskeletal and connective tissue disorders Pain in limb	5.1% 7/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	1.3% 2/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	2.3% 3/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	2.1% 14/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Nervous system disorders Headache	7.4% 10/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	14.8% 22/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	12.0% 16/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	10.7% 70/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Nervous system disorders Dizziness	2.9% 4/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	6.7% 10/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	5.3% 7/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	6.6% 43/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.
Nervous system disorders Somnolence	1.5% 2/136 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	1.3% 2/149 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	7.5% 10/133 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.	4.4% 29/652 • Adverse Events (AEs) occurring after the signing of informed consent up to study completion or discontinuation; during 7 days after last visit; serious AEs up to 30 days following the last study visit were followed until the event resolved. AEs were obtained through spontaneous reports and subject interview.