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

• Sponsor: BioDelivery Sciences International (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01675167
• Collaborator: (none)
• Enrollment: 815
• Locations: 66
• Arms: 2
• Duration (Months): 21
• Patients Per Site: 12.3
• Patients Per Site Per Month: 0.6

Study Details

Study Description

Brief Summary

The purpose of the study is to determine if buprenorphine hydrochloride (HCl) buccal film is effective in treating opioid-experienced 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: 815 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-Experienced Subjects With Chronic Lower Back Pain Requiring Opioid Analgesia
• Study Start Date: Sep 1, 2012
• Actual Primary Completion Date: Jun 1, 2014
• Actual Study Completion Date: Jun 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Buccal Film 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 150-900 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 numeric rating scale (NRS) ranging from 0 (no pain) to 10 (worst pain imaginable).

2. Number of Subjects With Opioid Rescue Medication Use [Week 1 to Week 12]

   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 "optimum" 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 Outcome 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).

8. Medical Outcomes Score Sleep Subscale - Quantity of Sleep/Optimal Sleep [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 quantity of sleep dimension is the average number of hours of sleep per night reported and optimal sleep is when the number of hours of sleep is ≥7.

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 ATC opioid analgesic medication equivalent to ≥30 mg and ≤160 mg morphine sulfate equivalents (MSE) per day for ≥4 weeks. (Additional as needed [PRN] analgesic rescue medications permitted on top of the stable daily maintenance dose of ≥30 mg MSE opioid analgesic, but must be included in the total daily MSE calculation and in combination with the stable daily maintenance dose not to exceed 160 mg MSE per day)

• Stable health, as determine by Principal Investigator

• Females are practicing abstinence, using a medically acceptable form of contraception, or 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 within 6 months of screening

• Subjects with 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 of any opioid or acetaminophen

• Surgical procedure for relief of pain within 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	Parkway Medical Center	Birmingham	Alabama	United States	35215
2	Haleyville Clinical Research LLC	Haleyville	Alabama	United States	35565
3	Horizon Research Group. Inc / Alabama Orthopedice	Mobile	Alabama	United States	36608
4	Arizona Research Center	Phoenix	Arizona	United States	85023
5	Global Research	Anaheim	California	United States	92804
6	Catalina Research Institute, LLC	Chino	California	United States	91710
7	Synergy Clinical Research Center of Escondido	Escondido	California	United States	92025
8	RX Clinical Research, Inc.	Garden Grove	California	United States	92843
9	Adam D. Karns, MD	Los Angeles	California	United States	90036
10	Stamford Therapeutics Consortium	Stamford	Connecticut	United States	06905
11	Century Clinic Research	Daytona Beach	Florida	United States	32117
12	Avail Clinical Research, LLC	Deland	Florida	United States	32720
13	Florida Health Center	Ft. Lauderdale	Florida	United States	33312
14	Eastern Research, Inc.	Hialeah	Florida	United States	33013
15	Florida Institute of Medical Research	Jacksonville	Florida	United States	32257
16	Drug Study Institute	Jupiter	Florida	United States	33458
17	Health Awareness, Inc.	Jupiter	Florida	United States	33458
18	FPA Clinical Research	Kissimmee	Florida	United States	34741
19	Try Research, Inc.	Maitland	Florida	United States	32751
20	NEMA Research, Inc.	Naples	Florida	United States	34108
21	Compass Research, LLC	Orlando	Florida	United States	32806
22	Peninsula Research, Inc.	Ormond Beach	Florida	United States	32174
23	Gold Coast Research, LLC	Plantation	Florida	United States	33317
24	Progressive Medical Research	Port Orange	Florida	United States	32127
25	Clinical Research of West Florida, Inc.	Tampa	Florida	United States	33603
26	Palm Beach Research Center	West Palm Beach	Florida	United States	33409
27	National Pain Research Institute, LLC	Winter Park	Florida	United States	32789
28	Atlanta Research Center	Atlanta	Georgia	United States	30319
29	River Birch Research Alliance, LLC	Blue Ridge	Georgia	United States	30513
30	Drug Studies America	Marietta	Georgia	United States	30060
31	Georgia Institute for Clinical Research, LLC	Marietta	Georgia	United States	30060
32	Taylor Research, LLC	Marietta	Georgia	United States	30060
33	Georgia Pain & Spine Care & Better Health Clinical Research	Newnan	Georgia	United States	30265
34	Clinical Investigations Specialists, Inc.	Gurnee	Illinois	United States	60031
35	MediSphere Medical Research, LLC	Evansville	Indiana	United States	47714
36	Integrated Clinical Trial Services, Inc	West Des Moines	Iowa	United States	50265
37	International Clinical Research Institute, Inc.	Overland Park	Kansas	United States	66210
38	Willis-Kinghton Physician Network / River Cities International Pain Specialist	Bossier City	Louisiana	United States	71111
39	Clinical Trials Management, LLC	Metairie	Louisiana	United States	70006
40	Best Clinical Trials, LLC	New Orleans	Louisiana	United States	70115
41	River Cities Clinical Research Center	Shreveport	Louisiana	United States	71105
42	MedVadis Research Corp.	Watertown	Massachusetts	United States	02472
43	Great Lakes Research Group, Inc.	Bay City	Michigan	United States	48706
44	The Center for Clinical Trials	Biloxi	Mississippi	United States	39531
45	Office of Robert Kaplan, DO	Las Vegas	Nevada	United States	89119
46	Comprehensive Clinical Research	Berlin	New Jersey	United States	08009
47	Long Island Gastrointestinal Research Group	Great Neck	New York	United States	11023
48	Upstate Clinical Research Associates	Williamsville	New York	United States	14221
49	PharmQuest, LLC	Greensboro	North Carolina	United States	27408
50	The Center for Clinical Research	Winston-Salem	North Carolina	United States	27103
51	Plains Medical Clinic, LLC	Fargo	North Dakota	United States	58104
52	Clinical Inquest Center, Ltd	Beavercreek	Ohio	United States	45432
53	New Horizons Health Research	Cincinnati	Ohio	United States	45242
54	Prestige Clinical Research	Franklin	Ohio	United States	45005
55	Health Research Institute	Oklahoma City	Oklahoma	United States	73109
56	Neuropsychiatric Research Center Research	Oklahoma City	Oklahoma	United States	73109
57	Brandywine Clinical Research	Downingtown	Pennsylvania	United States	19335
58	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635
59	Health Concepts	Rapid City	South Dakota	United States	57702
60	FutureSearch Clinical Trials	Austin	Texas	United States	78731
61	KRK Medical Research	Dallas	Texas	United States	75230
62	Future Search Trials of Dallas, LP	Dallas	Texas	United States	75231
63	Advanced Clinical Research of Houston	Houston	Texas	United States	77062
64	Clinical Trial Network	Houston	Texas	United States	77074
65	Innovative Clinical Trials	San Antonio	Texas	United States	78229
66	Highland Clinical Research	Salt Lake City	Utah	United States	84124

Sponsors and Collaborators

• BioDelivery Sciences International

Investigators

• Study Director: Andrew Finn, PharmD, BioDelivery Sciences International, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: BioDelivery Sciences International
• ClinicalTrials.gov Identifier: NCT01675167
• Other Study ID Numbers: EN3409-307
• First Posted: Aug 29, 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 1656 subjects screened, 938 subjects entered an analgesic taper phase and 1 subject was eligible to bypass the analgesic taper phase; a total of 815 subjects progressed to the open-label (OL) titration phase. Subjects who completed the open-label titration phase (511) 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, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for up to 8 weeks in the open-label titration period	Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Period Title: Open-label Titration Phase
STARTED	815	0	0
COMPLETED	511	0	0
NOT COMPLETED	304	0	0
Period Title: Open-label Titration Phase
STARTED	0	254	257
COMPLETED	0	206	147
NOT COMPLETED	0	48	110

Baseline Characteristics

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film	Total
Arm/Group Description	Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Total of all reporting groups
Overall Participants	243	248	491
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	211 86.8%	206 83.1%	417 84.9%
>=65 years	32 13.2%	42 16.9%	74 15.1%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	53.0	55.0	54.0
Gender (Count of Participants)
Female	130 53.5%	136 54.8%	266 54.2%
Male	113 46.5%	112 45.2%	225 45.8%
Region of Enrollment (participants) [Number]
United States	243 100%	248 100%	491 100%

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 19 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, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Measure Participants	243	248
Mean (Standard Deviation) [units on a scale]	0.88 (1.785)	1.92 (1.867)

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	<.00001
	Comments	P value was adjusted using weighted z-test (CHW).
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-0.98
	Confidence Interval	(2-Sided) 95%; -1.32 to -0.64
	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 numeric rating scale (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 19 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, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Measure Participants	243	248
Responders with ≥30% pain reduction	156 64.2%	76 30.6%
Responders with ≥50% pain reduction	96 39.5%	42 16.9%

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	<.0001
	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	<.0001
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Stratified by Stratum (Dose Level)

3. Secondary Outcome

Title	Number of Subjects With Opioid Rescue Medication Use
Description	Use of analgesic rescue medication recorded in subject diary
Time Frame	Week 1 to 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 19 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, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Measure Participants	243	248
Week 1 (n=242, 246)	215 88.5%	228 91.9%
Week 2 (n=234, 204)	202 83.1%	185 74.6%
Week 3 (n=229, 189)	197 81.1%	172 69.4%
Week 4 (n=229, 179)	191 78.6%	164 66.1%
Week 5 (n=222, 162)	186 76.5%	147 59.3%
Week 6 (n=219, 161)	185 76.1%	146 58.9%
Week 7 (n=213, 154)	178 73.3%	140 56.5%
Week 8 (n=210, 152)	177 72.8%	137 55.2%
Week 9 (n=207, 146)	173 71.2%	129 52%
Week 10 (n=205, 145)	172 70.8%	130 52.4%
Week 11 (n=203, 144)	172 70.8%	130 52.4%
Week 12 (n=201, 141)	166 68.3%	128 51.6%

4. Secondary Outcome

Title	Time to Optimal Dose of Open-label Study Medication
Description	Overall time to reach the "optimum" 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 HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for up to 8 weeks in the open-label titration period
Measure Participants	511
Mean (Standard Deviation) [days]	24.5 (11.70)

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 19 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, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Measure Participants	243	248
Number [percentage of participants]	9.9 4.1%	29.4 11.9%

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 (19). Includes only participants with PGIC assessment at week 12 (n=231 buprenorphine and n=230 placebo).

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Measure Participants	231	230
Mean (Standard Deviation) [units on a scale]	4.5 (1.86)	3.2 (1.98)

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 (19). Includes only participants with RMDQ assessment at week 12 (n=225 buprenorphine and n=231 placebo).

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Measure Participants	225	231
Mean (Standard Deviation) [units on a scale]	0.5 (5.03)	1.6 (5.63)

8. Secondary Outcome

Title	Change From Baseline to Week 12 in Medical Outcome 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 (19). Includes only participants with MOS assessment at week 12 (n=231 buprenorphine and n=230 placebo).

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Measure Participants	231	230
Sleep problems index	-0.36 (7.857)	-1.37 (8.359)
Sleep disturbance	-0.93 (10.739)	-3.54 (12.038)
Somnolence	0.20 (12.927)	-0.38 (15.301)
Sleep adequacy	0.13 (17.924)	3.61 (18.326)
Snoring	0.87 (18.630)	-2.78 (15.945)
Awaken short of breath or headache	0.52 (17.288)	-4.26 (19.628)

9. Secondary Outcome

Title	Medical Outcomes Score Sleep Subscale - Quantity of Sleep/Optimal Sleep
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 quantity of sleep dimension is the average number of hours of sleep per night reported and optimal sleep is when the number of hours of sleep is ≥7.
Time Frame	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 (19). Includes only participants with MOS assessment at week 12 (n=231 buprenorphine and n=230 placebo).

Arm/Group Title	DB Buprenorphine HCl Buccal Film	DB Placebo Film
Arm/Group Description	Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 μg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period	Placebo buccal film applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind treatment period
Measure Participants	231	230
Quantity of Sleep/Optimal Sleep ≥7	75 30.9%	81 32.7%
Quantity of Sleep/Optimal Sleep <7	156 64.2%	149 60.1%

Adverse Events

Time Frame	From informed consent at screening through 14 days after last dose in the double-blind treatment phase (up to 26 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, 150, 300, 450, 600, 750, or 900 µg, applied to the buccal mucosa every 12 hours for up to 8 weeks in the open-label titration period		Buprenorphine HCl buccal film, 150, 300, 450, 600, 750, or 900 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind titration period		Placebo buccal film, 150, 300, 450, 600, 750, or 900 µg, applied to the buccal mucosa every 12 hours for 12 weeks in the double-blind titration period
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	14/810 (1.7%)		4/254 (1.6%)		4/256 (1.6%)
Cardiac disorders
Angina pectoris	1/810 (0.1%)	2	0/254 (0%)	0	0/256 (0%)	0
Atrial flutter	0/810 (0%)	0	0/254 (0%)	0	1/256 (0.4%)	1
Coronary artery disease	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Myocardial infarction	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Tachycardia	0/810 (0%)	0	0/254 (0%)	0	1/256 (0.4%)	1
Gastrointestinal disorders
Abdominal pain upper	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Ileus	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Pancreatitis relapsing	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
General disorders
Chest pain	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Impaired healing	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Non-cardiac chest pain	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Hepatobiliary disorders
Cholecystitis	0/810 (0%)	0	1/254 (0.4%)	1	0/256 (0%)	0
Infections and infestations
Abscess limb	0/810 (0%)	0	0/254 (0%)	0	1/256 (0.4%)	1
Cellulitis	1/810 (0.1%)	1	1/254 (0.4%)	1	2/256 (0.8%)	2
Kidney infection	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Pneumonia	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Pneumonia staphylococcal	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Injury, poisoning and procedural complications
Arthropod bite	0/810 (0%)	0	0/254 (0%)	0	1/256 (0.4%)	1
Pulmonary contusion	0/810 (0%)	0	1/254 (0.4%)	1	0/256 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Nervous system disorders
Dysarthria	0/810 (0%)	0	1/254 (0.4%)	1	0/256 (0%)	0
Transient ischaemic attack	0/810 (0%)	0	0/254 (0%)	0	1/256 (0.4%)	1
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (0%)	0
Vascular disorders
Venous insufficiency	1/810 (0.1%)	1	0/254 (0%)	0	0/256 (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	268/810 (33.1%)		42/254 (16.5%)		49/256 (19.1%)
Gastrointestinal disorders
Constipation	67/810 (8.3%)	73	7/254 (2.8%)	8	2/256 (0.8%)	2
Nausea	136/810 (16.8%)	167	19/254 (7.5%)	19	19/256 (7.4%)	19
Vomiting	54/810 (6.7%)	63	14/254 (5.5%)	15	6/256 (2.3%)	6
General disorders
Drug withdrawal syndrome	10/810 (1.2%)	10	9/254 (3.5%)	9	25/256 (9.8%)	25
Nervous system disorders
Dizziness	42/810 (5.2%)	47	2/254 (0.8%)	2	2/256 (0.8%)	2
Headache	54/810 (6.7%)	61	6/254 (2.4%)	6	8/256 (3.1%)	8
Somnolence	41/810 (5.1%)	54	0/254 (0%)	0	0/256 (0%)	0

Limitations/Caveats

[Not Specified]

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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.