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

• Sponsor: BioDelivery Sciences International (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01633944
• Collaborator: (none)
• Enrollment: 752
• Locations: 60
• Arms: 2
• Duration (Months): 16
• Patients Per Site: 12.5
• Patients Per Site Per Month: 0.8

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if buprenorphine hydrochloride (HCl) buccal film is effective in treating opioid-naive subjects, with moderate to severe chronic low back pain (CLBP), who require continuous around-the-clock (ATC) pain relief for an extended period of time.

Condition or Disease	Intervention/Treatment	Phase
Low Back Pain	Drug: Buprenorphine; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 752 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Phase 3, Double-Blind, Placebo-Controlled, Study to Evaluate the Analgesic Efficacy, Safety, and Tolerability of Buprenorphine HCl Buccal Film in Opioid-Naive Subjects With Chronic Lower Back Pain Requiring Opioid Analgesia
• Study Start Date: Aug 1, 2012
• Actual Primary Completion Date: Dec 1, 2013
• Actual Study Completion Date: Dec 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Twice Daily Dosing	Drug: Placebo; Matching Placebo Buccal Film twice daily; Other Names: Placebo Buccal Film BEMA Placebo
Experimental: Buprenorphine HCl Buccal Film Twice Daily Dosing	Drug: Buprenorphine; Buprenorphine HCl Buccal Film at doses ranging from 75-600 mcg twice daily; Other Names: BELBUCA Buprenorphine HCl Buccal Film BEMA Buprenorphine EN3409

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Week 12 in Average Daily Pain Intensity Scores [Baseline, Week 12]

   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).

Secondary Outcome Measures

1. Number of Participants With Response to Treatment (Responder) Using NRS Scale [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).

2. Number of Subjects With Rescue Medication Use [Week 1 to Week 12 in double-blind treatment]

   Use of analgesic rescue medication recorded in subject diary.

3. Time to Optimal Dose of Open-label Study Medication [Up to 8 weeks in open-label titration]

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

4. Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks) [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.

5. Patient Global Impression of Change [Week 12]

   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)

6. Change From Baseline to Week 12 in Roland Morris Disability Questionnaire [Baseline, Week 12]

   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.

7. Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale [Baseline, Week 12]

   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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of moderate to severe low back pain for ≥6 months

• Treating CLBP with a stable daily maintenance dose of non-opioid analgesic medication up to 10 mg morphine sulfate equivalents (MSE) per day for ≥4 weeks. (Additional as needed [PRN] non-opioid analgesic medications permitted on top of the stable daily maintenance dose of non-opioid analgesic)

• Stable health, as determined by Principal Investigator

• Are female who are practicing abstinence or using a medically acceptable form of contraception or have been post-menopausal, biologically sterile, or surgically sterile for more than 1 year

• Willing and able to comply with all protocol required visits and assessments

Exclusion Criteria:

• Current cancer related pain or received chemotherapy with 6 months of screening

• Receiving opioid analgesic medication >10 mg MSE per day within 28 days of screening

• Subjects with a history of other chronic painful conditions

• Reflex sympathetic dystrophy or causalgia, acute spinal cord compression, cauda equina compression, acute nerve root compression, meningitis, or discitis

• Allergy or contraindications to any opioid or acetaminophen

• Surgical procedure for relief of pain with 6 months

• Hypokalemia or clinically unstable cardiac disease, including: unstable atrial fibrillation, symptomatic bradycardia, unstable congestive heart failure, or active myocardial ischemia

• QT interval corrected using Fridericia's formula (QTcF) of ≥450 milliseconds on the 12-lead electrocardiogram (ECG)

• History of long QT syndrome or a family member with this condition

• Moderate to severe hepatic impairment

• Moderate to severe renal impairment

• Current or past history of alcohol abuse

• Positive urine toxicology screen for drug of abuse

• History or abnormalities on physical exam, vital signs, electrocardiogram, or laboratory values

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Horizon Research Group, Inc./Alabama Orthopedic Clinic	Mobile	Alabama	United States	36608
2	Arizona Research Center	Phoenix	Arizona	United States	85023
3	Global Research	Anaheim	California	United States	92804
4	Catalina Research Institute, LLC	Chino	California	United States	91710
5	Synergy Clinical Research Center of Escondido	Escondido	California	United States	92025
6	Adam D. Karns MD	Los Angeles	California	United States	90036
7	Stamford Therapeutics Consortium	Stamford	Connecticut	United States	06905
8	Clinical Research of West Florida - Clearwater	Clearwater	Florida	United States	33765
9	Century Clinical Research, Inc.	Daytona Beach	Florida	United States	32117
10	Avail Clinical Research, LLC	Deland	Florida	United States	32720
11	Florida Health Center	Ft. Lauderdale	Florida	United States	33312
12	Eastern Research, Inc.	Hialeah	Florida	United States	33013
13	Florida Institute of Medical Research	Jacksonville	Florida	United States	32257
14	Drug Study Institute	Jupiter	Florida	United States	33458
15	Health Awareness, Inc.	Jupiter	Florida	United States	33458
16	NEMA Research, Inc.	Naples	Florida	United States	34108
17	Compass Research, LLC	Orlando	Florida	United States	32806
18	Peninsula Research	Ormond Beach	Florida	United States	32174
19	Gold Coast Research, L.L.C.	Plantation	Florida	United States	33317
20	Progressive Medical Research	Port Orange	Florida	United States	32127
21	Clinical Research of West Florida - Tampa	Tampa	Florida	United States	33603
22	National Pain Research Institute, LLC	Winter Park	Florida	United States	32789
23	Atlanta Research Center	Atlanta	Georgia	United States	30319
24	River Birch Research Alliance, LLC	Blue Ridge	Georgia	United States	30513
25	Drug Studies America	Marietta	Georgia	United States	30060
26	Georgia Institute for Clinical Research, LLC	Marietta	Georgia	United States	30060
27	Taylor Research, LLC	Marietta	Georgia	United States	30060
28	MediSphere Medical Research Center, LLC	Evansville	Indiana	United States	47714
29	Integrated Clinical Trial Services, Inc.	West Des Moines	Iowa	United States	50265
30	International Clinical Research Institute, Inc.	Overland Park	Kansas	United States	66210
31	Willis-Kinghton Physician Network/River Interventional Pain Specialist	Bossier City	Louisiana	United States	71111
32	Clinical Trials Management, LLC	Metairie	Louisiana	United States	70006
33	Best Clinical Trials, Inc.	New Orleans	Louisiana	United States	70115
34	River Cities Clinical Research Center	Shreveport	Louisiana	United States	71105
35	MedVadis Research Corp.	Watertown	Massachusetts	United States	02472
36	Great Lakes Research Group, Inc.	Bay City	Michigan	United States	48706
37	The Center for Clinical Trials	Biloxi	Mississippi	United States	39531
38	Office of Robert Kaplan, DO	Las Vegas	Nevada	United States	89119
39	Long Island Gastrointestinal Research Group	Great Neck	New York	United States	11023
40	Upstate Clinical Research Associates LLC	Williamsville	New York	United States	14221
41	PharmQuest, LLC	Greensboro	North Carolina	United States	27408
42	The Center for Clinical Research	Winston Salem	North Carolina	United States	27103
43	Plains Medical Clinic, LLC	Fargo	North Dakota	United States	58104
44	Clinical Inquest Center, Ltd.	Beavercreek	Ohio	United States	45432
45	New Horizons Clinical Research	Cincinnati	Ohio	United States	45242
46	Optimed Research, Ltd.	Columbus	Ohio	United States	43235
47	Prestige Clinical Research	Franklin	Ohio	United States	45005
48	Health Research Institute	Oklahoma City	Oklahoma	United States	73109
49	NPC Research	Oklahoma City	Oklahoma	United States	73109
50	Brandywine Clinical Research	Downingtown	Pennsylvania	United States	19335
51	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635
52	Health Concepts	Rapid City	South Dakota	United States	57702
53	FutureSearch Clinical Trials - Austin	Austin	Texas	United States	78731
54	KRK Medical Research	Dallas	Texas	United States	75230
55	FutureSearch Trials of Dallas, LP	Dallas	Texas	United States	75231
56	Advanced Clinical Research of Houston	Houston	Texas	United States	77062
57	Clinical Trial Network	Houston	Texas	United States	77074
58	Innovative Clinical Trials	San Antonio	Texas	United States	78229
59	Highland Clinical Research	Salt Lake City	Utah	United States	84124
60	Clinical Investigations Specialists, Inc.	Kenosha	Wisconsin	United States	53142

Sponsors and Collaborators

• BioDelivery Sciences International

Investigators

• Study Director: M. Todd Kirby, PhD, Endo Pharmaceuticals

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: BioDelivery Sciences International
• ClinicalTrials.gov Identifier: NCT01633944
• Other Study ID Numbers: EN3409-308
• First Posted: Jul 6, 2012
• Last Update Posted: Feb 27, 2017
• Last Verified: Jan 1, 2017

• Keywords provided by BioDelivery Sciences International: CLBP; Chronic Low Back Pain; Chronic Pain; Back Pain
• Additional relevant MeSH terms: Back Pain; Low Back Pain; Buprenorphine

Study Results

Participant Flow

Pre-assignment Detail	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.

Arm/Group Title	OL Buprenorphine HCl Buccal Film	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	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	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	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Period Title: Open-label Titration Phase
STARTED	752	0	0
COMPLETED	462	0	0
NOT COMPLETED	290	0	0
Period Title: Open-label Titration Phase
STARTED	0	230	232
COMPLETED	0	176	174
NOT COMPLETED	0	54	58

Baseline Characteristics

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film	Total
Arm/Group Description	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	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase	Total of all reporting groups
Overall Participants	209	211	420
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	180 86.1%	186 88.2%	366 87.1%
>=65 years	29 13.9%	25 11.8%	54 12.9%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52.0	49.0	51.0
Gender (Count of Participants)
Female	107 51.2%	124 58.8%	231 55%
Male	102 48.8%	87 41.2%	189 45%
Region of Enrollment (participants) [Number]
United States	209 100%	211 100%	420 100%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Week 12 in Average Daily Pain Intensity Scores
Description	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).
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	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	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Measure Participants	209	211
Mean (Standard Deviation) [units on a scale]	0.94 (1.846)	1.59 (2.040)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DB Buprenorphine HCl Buccal Film, DB Placebo Film
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	-0.67
	Confidence Interval	(2-Sided) 95%; -1.07 to -0.26
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Participants With Response to Treatment (Responder) Using NRS Scale
Description	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).
Time Frame	Prior to open-label titration to Week 12 in double-blind treatment

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	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	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Measure Participants	209	211
Responders with ≥30% pain reduction	131 62.7%	99 46.9%
Responders with ≥50% pain reduction	86 41.1%	69 32.7%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	DB Buprenorphine HCl Buccal Film, DB Placebo Film
	Comments	Responders with ≥30% pain reduction
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0012
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by stratum (dose level)

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	DB Buprenorphine HCl Buccal Film, DB Placebo Film
	Comments	Responders with ≥50% pain reduction
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0754
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by stratum (dose level)

3. Secondary Outcome

Title	Number of Subjects With Rescue Medication Use
Description	Use of analgesic rescue medication recorded in subject diary.
Time Frame	Week 1 to Week 12 in double-blind treatment

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	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	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Measure Participants	209	211
Week 1	123 58.9%	140 66.4%
Week 2	112 53.6%	132 62.6%
Week 3	85 40.7%	107 50.7%
Week 4	81 38.8%	98 46.4%
Week 5	76 36.4%	92 43.6%
Week 6	74 35.4%	94 44.5%
Week 7	73 34.9%	85 40.3%
Week 8	64 30.6%	85 40.3%
Week 9	67 32.1%	82 38.9%
Week 10	60 28.7%	81 38.4%
Week 11	62 29.7%	72 34.1%
Week 12	56 26.8%	72 34.1%

4. Secondary Outcome

Title	Time to Optimal Dose of Open-label Study Medication
Description	Overall time to reach the "optimal" dose of study medication required to progress to double-blind treatment.
Time Frame	Up to 8 weeks in open-label titration

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	OL Buprenorphine HCl Buccal Film
Arm/Group Description	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
Measure Participants	462
Mean (Standard Deviation) [days]	17.1 (7.77)

5. Secondary Outcome

Title	Percentage of Participants With Treatment Failure in the Double-blind Treatment Phase (up to 12 Weeks)
Description	Treatment failure is defined as study discontinuation due to lack of efficacy or discontinuation due to adverse events in the double-blind treatment phase.
Time Frame	Baseline to treatment failure or end of double-blind treatment phase (up to 12 weeks)

Outcome Measure Data

Analysis Population Description

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.

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	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	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Measure Participants	209	211
Number [percentage of participants]	9.6 4.6%	14.2 6.7%

6. Secondary Outcome

Title	Patient Global Impression of Change
Description	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)
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	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	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Measure Participants	198	194
Mean (Standard Deviation) [units on a scale]	4.5 (1.75)	3.9 (1.99)

7. Secondary Outcome

Title	Change From Baseline to Week 12 in Roland Morris Disability Questionnaire
Description	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.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	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	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Measure Participants	193	189
Mean (Standard Deviation) [units on a scale]	0.6 (5.37)	1.2 (5.75)

8. Secondary Outcome

Title	Change From Baseline to Week 12 in Medical Outcomes Score Sleep Subscale
Description	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).
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

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).

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	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	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
Measure Participants	199	194
Sleep problems index	-0.23 (8.274)	0.10 (8.480)
Sleep disturbance	-1.43 (12.405)	-1.68 (12.515)
Somnolence	0.90 (15.823)	0.14 (17.381)
Sleep adequacy	1.71 (19.204)	6.19 (19.285)

Adverse Events

Time Frame	From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 24 weeks)
Adverse Event Reporting Description	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)
Arm/Group Title	OL Buprenorphine HCl Buccal Film		DB Buprenorphine HCl Buccal Film		DB Placebo Film
Arm/Group Description	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		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		Placebo buccal film, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment phase
All Cause Mortality
	OL Buprenorphine HCl Buccal Film		DB Buprenorphine HCl Buccal Film		DB Placebo Film
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	OL Buprenorphine HCl Buccal Film		DB Buprenorphine HCl Buccal Film		DB Placebo Film
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/749 (0.5%)		3/229 (1.3%)		1/232 (0.4%)
Cardiac disorders
Atrial fibrillation	0/749 (0%)	0	1/229 (0.4%)	1	0/232 (0%)	0
Gastrointestinal disorders
Ileus	0/749 (0%)	0	0/229 (0%)	0	1/232 (0.4%)	1
Small intestinal obstruction	0/749 (0%)	0	1/229 (0.4%)	1	0/232 (0%)	0
Infections and infestations
Osteomyelitis	1/749 (0.1%)	1	0/229 (0%)	0	0/232 (0%)	0
Pneumonia	1/749 (0.1%)	1	0/229 (0%)	0	0/232 (0%)	0
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/749 (0%)	0	1/229 (0.4%)	1	0/232 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Lung cancer metastatic	1/749 (0.1%)	1	0/229 (0%)	0	0/232 (0%)	0
Nervous system disorders
Cerebrovascular accident	1/749 (0.1%)	1	0/229 (0%)	0	0/232 (0%)	0
Skin and subcutaneous tissue disorders
Dry gangrene	1/749 (0.1%)	1	0/229 (0%)	0	0/232 (0%)	0
Other (Not Including Serious) Adverse Events
	OL Buprenorphine HCl Buccal Film		DB Buprenorphine HCl Buccal Film		DB Placebo Film
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	443/749 (59.1%)		43/229 (18.8%)		31/232 (13.4%)
Gastrointestinal disorders
Constipation	97/749 (13%)	105	9/229 (3.9%)	9	6/232 (2.6%)	6
Nausea	373/749 (49.8%)	669	23/229 (10%)	32	17/232 (7.3%)	23
Vomiting	58/749 (7.7%)	62	9/229 (3.9%)	10	1/232 (0.4%)	1
Nervous system disorders
Dizziness	48/749 (6.4%)	52	4/229 (1.7%)	4	1/232 (0.4%)	1
Headache	60/749 (8%)	62	5/229 (2.2%)	5	8/232 (3.4%)	9
Somnolence	52/749 (6.9%)	56	2/229 (0.9%)	2	1/232 (0.4%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

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.