Trial Outcomes & Findings for Efficacy Study to Evaluate Buprenorphine HCl Buccal Film in Opioid-Naive Subjects (NCT NCT01633944)

Last Updated: 2017-02-27

Results Overview

Change in pain intensity = average of daily pain scores from the last 7 days prior to Week 12 visit - average of daily pain scores for the last 7 days prior to randomization. Average pain intensity over the last 24 hours was rated on an 11-point numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable).

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

752 participants

Primary outcome timeframe

Baseline, Week 12

Results posted on

2017-02-27

Participant Flow

Of 1633 subjects screened, a total of 752 subjects were enrolled into the open-label (OL) titration phase. Subjects who completed the OL titration phase (462) were eligible for randomization in the double-blind (DB) treatment phase.

Participant milestones

Participant milestones
Measure	OL Buprenorphine HCl Buccal Film Buprenorphine hydrochloride (HCl) buccal film, 75, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for up to 8 weeks in the open-label titration phase	DB Buprenorphine HCl Buccal Film Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Open-label Titration Phase STARTED	752	0	0
Open-label Titration Phase COMPLETED	462	0	0
Open-label Titration Phase NOT COMPLETED	290	0	0
Double-blind Treatment Phase STARTED	0	230	232
Double-blind Treatment Phase COMPLETED	0	176	174
Double-blind Treatment Phase NOT COMPLETED	0	54	58

Reasons for withdrawal

Reasons for withdrawal
Measure	OL Buprenorphine HCl Buccal Film Buprenorphine hydrochloride (HCl) buccal film, 75, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for up to 8 weeks in the open-label titration phase	DB Buprenorphine HCl Buccal Film Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Open-label Titration Phase Adverse Event	109	0	0
Open-label Titration Phase Lack of Efficacy	33	0	0
Open-label Titration Phase Withdrawal by Subject	34	0	0
Open-label Titration Phase Protocol Violation	24	0	0
Open-label Titration Phase Lost to Follow-up	22	0	0
Open-label Titration Phase Other	68	0	0
Double-blind Treatment Phase Adverse Event	0	13	7
Double-blind Treatment Phase Lack of Efficacy	0	8	23
Double-blind Treatment Phase Withdrawal by Subject	0	11	8
Double-blind Treatment Phase Protocol Violation	0	7	10
Double-blind Treatment Phase Lost to Follow-up	0	4	9
Double-blind Treatment Phase Withdrawal due to opioid withdrawal	0	3	1
Double-blind Treatment Phase Not exposed to DB study medication	0	1	0
Double-blind Treatment Phase Other	0	7	0

Baseline Characteristics

Efficacy Study to Evaluate Buprenorphine HCl Buccal Film in Opioid-Naive Subjects

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	DB Buprenorphine HCl Buccal Film n=209 Participants Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film n=211 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	Total n=420 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
Age, Categorical Between 18 and 65 years	180 Participants n=5 Participants	186 Participants n=7 Participants	366 Participants n=5 Participants
Age, Categorical >=65 years	29 Participants n=5 Participants	25 Participants n=7 Participants	54 Participants n=5 Participants
Age, Continuous	52.0 years n=5 Participants	49.0 years n=7 Participants	51.0 years n=5 Participants
Gender Female	107 Participants n=5 Participants	124 Participants n=7 Participants	231 Participants n=5 Participants
Gender Male	102 Participants n=5 Participants	87 Participants n=7 Participants	189 Participants n=5 Participants
Region of Enrollment United States	209 participants n=5 Participants	211 participants n=7 Participants	420 participants n=5 Participants

PRIMARY outcome

Timeframe: Baseline, Week 12

Population: Analysis based on ITT population; all randomized subjects who received at least 1 dose of double-blind study medication. One (1) subject did not receive double-blind study medication and an additional 41 subjects from 1 site were excluded from the population.

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=209 Participants Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film n=211 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Change From Baseline to Week 12 in Average Daily Pain Intensity Scores	0.94 units on a scale Standard Deviation 1.846	1.59 units on a scale Standard Deviation 2.040

SECONDARY outcome

Timeframe: Prior to open-label titration to Week 12 in double-blind treatment

Responders are subjects who achieve a relative reduction in pain intensity from the start of open-label titration to Week 12 in double-blind treatment. Average pain intensity over the last 24 hours was rated on an 11-point NRS ranging from 0 (no pain) to 10 (worst pain imaginable).

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=209 Participants Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film n=211 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Number of Participants With Response to Treatment (Responder) Using NRS Scale Responders with ≥30% pain reduction	131 participants	99 participants
Number of Participants With Response to Treatment (Responder) Using NRS Scale Responders with ≥50% pain reduction	86 participants	69 participants

SECONDARY outcome

Timeframe: Week 1 to Week 12 in double-blind treatment

Use of analgesic rescue medication recorded in subject diary.

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=209 Participants Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film n=211 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Number of Subjects With Rescue Medication Use Week 1	123 participants	140 participants
Number of Subjects With Rescue Medication Use Week 3	85 participants	107 participants
Number of Subjects With Rescue Medication Use Week 4	81 participants	98 participants
Number of Subjects With Rescue Medication Use Week 5	76 participants	92 participants
Number of Subjects With Rescue Medication Use Week 11	62 participants	72 participants
Number of Subjects With Rescue Medication Use Week 12	56 participants	72 participants
Number of Subjects With Rescue Medication Use Week 2	112 participants	132 participants
Number of Subjects With Rescue Medication Use Week 6	74 participants	94 participants
Number of Subjects With Rescue Medication Use Week 7	73 participants	85 participants
Number of Subjects With Rescue Medication Use Week 8	64 participants	85 participants
Number of Subjects With Rescue Medication Use Week 9	67 participants	82 participants
Number of Subjects With Rescue Medication Use Week 10	60 participants	81 participants

SECONDARY outcome

Timeframe: Up to 8 weeks in open-label titration

Population: Analysis based on randomized subjects in the Safety population; all subjects who received at least 1 dose of study medication and were randomized into double-blind treatment.

Overall time to reach the "optimal" dose of study medication required to progress to double-blind treatment.

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=462 Participants Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Time to Optimal Dose of Open-label Study Medication	17.1 days Standard Deviation 7.77	—

SECONDARY outcome

Timeframe: Baseline to treatment failure or end of double-blind treatment phase (up to 12 weeks)

Treatment failure is defined as study discontinuation due to lack of efficacy or discontinuation due to adverse events in the double-blind treatment phase.

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=209 Participants Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film n=211 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks)	9.6 percentage of participants	14.2 percentage of participants

SECONDARY outcome

Timeframe: Week 12

Population: Analysis based on Patient-Reported Outcomes (PRO) population; randomized subjects who received at least 1 dose of double-blind medication and had at least 1 post-dose assessment on PRO measures. Subjects from 1 site excluded from population (41). Includes only participants with PGIC assessment at week 12 (n=198 buprenorphine and n=194 placebo).

Subjects assessed their change in activity limitations as they relate to their painful condition since beginning treatment using the Patient Global Impression of Change (PGIC) questionnaire, a 7-point scale ranging from 1 (no change \[or condition has got worse\]) to 7 (a great deal better, and a considerable improvement that made all the difference)

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=198 Participants Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film n=194 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Patient Global Impression of Change	4.5 units on a scale Standard Deviation 1.75	3.9 units on a scale Standard Deviation 1.99

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: Analysis based on PRO population; randomized subjects who received at least 1 dose of double-blind study medication and had at least 1 post-dose assessment on PRO measures. Subjects from 1 site are excluded from the population (41). Includes only participants with RMDQ assessment at week 12 (n=193 buprenorphine and n=189 placebo).

Subjects assess disability due to back pain using the Roland Morris Disability Questionnaire (RMDQ) consisting of 24 statements of disability. The score of the RMDQ is the total number of items checked, ranging from 0 to 24 with higher scores indicating greater disability.

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=193 Participants Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film n=189 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Change From Baseline to Week 12 in Roland Morris Disability Questionnaire	0.6 units on a scale Standard Deviation 5.37	1.2 units on a scale Standard Deviation 5.75

SECONDARY outcome

Timeframe: Baseline, Week 12

Population: Analysis based on PRO population; randomized subjects who received at least 1 dose of double-blind study medication and had at least 1 post-dose assessment on PRO measures. Subjects from 1 site are excluded from the population (41). Includes only participants with MOS assessment at week 12 (n=199 buprenorphine and n=194 placebo).

Medical Outcomes Score (MOS) Sleep Scale uses 12 items to measure 6 dimensions of sleep (sleep disturbance, somnolence, sleep adequacy, snoring, awaken short of breath or headache, and quantity of sleep/optimal sleep) and an overall sleep problems index score. The scores of the dimensions (except quantity of sleep/optimal sleep) and of the sleep problem index range on a 0 to 100 scale, with higher scores reflecting more of the attribute implied by the name (eg, greater sleep disturbance, greater adequacy of sleep).

Outcome measures

Outcome measures
Measure	DB Buprenorphine HCl Buccal Film n=199 Participants Buprenorphine HCl buccal film, 150, 300, or 450 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film n=194 Participants Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale Somnolence	0.90 units on a scale Standard Deviation 15.823	0.14 units on a scale Standard Deviation 17.381
Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale Sleep adequacy	1.71 units on a scale Standard Deviation 19.204	6.19 units on a scale Standard Deviation 19.285
Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale Sleep problems index	-0.23 units on a scale Standard Deviation 8.274	0.10 units on a scale Standard Deviation 8.480
Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale Sleep disturbance	-1.43 units on a scale Standard Deviation 12.405	-1.68 units on a scale Standard Deviation 12.515

Adverse Events

OL Buprenorphine HCl Buccal Film

Serious events: 4 serious events

Other events: 443 other events

Deaths: 0 deaths

DB Buprenorphine HCl Buccal Film

Serious events: 3 serious events

Other events: 43 other events

Deaths: 0 deaths

DB Placebo Film

Serious events: 1 serious events

Other events: 31 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	OL Buprenorphine HCl Buccal Film n=749 participants at risk Buprenorphine HCl buccal film, 75, 150, 300, or 450 μg, applied to the buccal mucosa every 12 hours for up to 8 weeks in the open-label titration treatment phase	DB Buprenorphine HCl Buccal Film n=229 participants at risk Buprenorphine HCl buccal film, 150, 300, or 450 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film n=232 participants at risk Placebo buccal film, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Cardiac disorders Atrial fibrillation	0.00% 0/749 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.44% 1/229 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/232 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Gastrointestinal disorders Ileus	0.00% 0/749 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/229 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.43% 1/232 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Gastrointestinal disorders Small intestinal obstruction	0.00% 0/749 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.44% 1/229 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/232 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Infections and infestations Osteomyelitis	0.13% 1/749 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/229 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/232 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Infections and infestations Pneumonia	0.13% 1/749 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/229 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/232 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/749 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.44% 1/229 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/232 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung cancer metastatic	0.13% 1/749 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/229 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/232 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Nervous system disorders Cerebrovascular accident	0.13% 1/749 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/229 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/232 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Skin and subcutaneous tissue disorders Dry gangrene	0.13% 1/749 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/229 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.00% 0/232 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)

Other adverse events

Other adverse events
Measure	OL Buprenorphine HCl Buccal Film n=749 participants at risk Buprenorphine HCl buccal film, 75, 150, 300, or 450 μg, applied to the buccal mucosa every 12 hours for up to 8 weeks in the open-label titration treatment phase	DB Buprenorphine HCl Buccal Film n=229 participants at risk Buprenorphine HCl buccal film, 150, 300, or 450 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	DB Placebo Film n=232 participants at risk Placebo buccal film, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Gastrointestinal disorders Nausea	49.8% 373/749 • Number of events 669 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	10.0% 23/229 • Number of events 32 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	7.3% 17/232 • Number of events 23 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Gastrointestinal disorders Constipation	13.0% 97/749 • Number of events 105 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	3.9% 9/229 • Number of events 9 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	2.6% 6/232 • Number of events 6 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Gastrointestinal disorders Vomiting	7.7% 58/749 • Number of events 62 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	3.9% 9/229 • Number of events 10 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.43% 1/232 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Nervous system disorders Dizziness	6.4% 48/749 • Number of events 52 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	1.7% 4/229 • Number of events 4 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.43% 1/232 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Nervous system disorders Headache	8.0% 60/749 • Number of events 62 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	2.2% 5/229 • Number of events 5 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	3.4% 8/232 • Number of events 9 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)
Nervous system disorders Somnolence	6.9% 52/749 • Number of events 56 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.87% 2/229 • Number of events 2 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)	0.43% 1/232 • Number of events 1 • From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks) Analysis based on Safety population; all enrolled subjects who received at least 1 dose of study drug in the respective period (open-label titration and double-blind treatment)

Additional Information

Clinical Trial Coordinator

Endo Pharmaceuticals Inc.

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee PI and Institution reserve the right to publish and present the results of the work performed provided that Institution and/or PI submits a copy of any proposed publication to Sponsor's agent for review and comment at least 90 days in advance of its presentation or submission for publication. In addition, if Sponsor's agent requests, Institution and/or PI will withhold publication or presentation for an additional 60 days to allow for establishing and preserving its proprietary rights.
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