Buprenorphine Transdermal System (BTDS) in Subjects With Moderate to Severe Chronic Low Back Pain

• Sponsor: Purdue Pharma LP (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00490919
• Collaborator: (none)
• Enrollment: 539
• Locations: 86
• Arms: 2
• Duration (Months): 16
• Patients Per Site: 6.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The objective of this study is to determine the analgesic efficacy and safety of Buprenorphine Transdermal System (BTDS) 10 and 20 compared to placebo in opioid-naïve subjects with moderate to severe chronic low back pain. The double-blind treatment intervention duration is 12 weeks, during which time supplemental analgesic medication (immediate-release oxycodone for the first 6 days post-randomization and acetaminophen or ibuprofen for the remainder of the double-blind phase) will be provided to all subjects in addition to study drug.

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

Detailed Description

Buprenorphine is a synthetic opioid analgesic with over 25 years of international clinical experience indicating it to be safe and effective in a variety of therapeutic settings for the relief of moderate to severe pain. BTDS is a transdermal system formulation that is designed to deliver a consistent and a steady dose of buprenorphine over a 7-day period with limited blood concentration fluctuation.

Study Design

• Study Type: Interventional
• Actual Enrollment: 539 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Multi-center, Randomized, Double-blind, Placebo-controlled With Open Label run-in Study Assessing Efficacy, Tolerability, Safety of BTDS 10 or 20 Compared to Placebo in Opioid-naïve Subjects With Moderate to Severe, Chronic Low Back Pain
• Study Start Date: Jun 1, 2007
• Actual Primary Completion Date: Jul 1, 2008
• Actual Study Completion Date: Oct 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Double-blind BTDS 10 or 20 Buprenorphine transdermal system 10 or 20 mcg/h applied for 7-day wear	Drug: Buprenorphine transdermal system; Buprenorphine transdermal system 10 or 20 mcg/h worn for 7 days; Other Names: Butrans™
Placebo Comparator: Double-blind Placebo TDS Placebo transdermal system to match BTDS patches, applied for 7 days	Drug: Placebo; transdermal system (placebo) worn for 7 days

Outcome Measures

Primary Outcome Measures

1. Average Pain Over the Last 24 Hours Scores at Week 12 of the Double-blind Phase. [Prerandomization phase consisted of a 6-10 day screening period and a <27 day open-label run-in period; and a 12-week double-blind phase.]

   Pain was assessed on an 11-point numerical scale ranging from 0 = no pain to 10 = pain as bad as you can imagine.

Secondary Outcome Measures

1. The Mean Daily Number of Tablets of Nonopioid Supplemental Analgesic Medications Taken During Weeks 2 Through 12 of the Double-blind Phase [weeks 2-12]

   Nonopioid supplemental analgesic tablets were sponsor-supplied acetaminophen or ibuprofen.

2. The Sleep Disturbance Subscale in the Medical Outcome Study (MOS) Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase [Weeks 4, 8, 12 of double-blind phase]

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

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects with moderate to severe chronic low back pain (lasting several hours daily) as their predominant pain condition for at least 3 months prior to screening,

• Subjects treated within the 14 days prior to screening with nonopioid therapy only, or with therapy including opioids at a dose of <5 mg oxycodone (or equivalent) per day,

• Subjects whose low back pain is not adequately controlled with non-opioid analgesic medication and who the Investigator feels are appropriate candidates for around-the-clock opioid therapy

Exclusion Criteria:

• Subjects who had a surgical procedure directed towards the source of back pain within 6 months of screening or planned during the study conduct period,

• Subjects who are allergic to buprenorphine or who had a history of allergies to other opioids,

• Subjects who have allergies or other contraindications to transdermal delivery systems or patch adhesives.

Other protocol-specific inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Research Facility	Anniston	Alabama	United States	36207
2	Coastal Clinical Research, Inc.	Mobile	Alabama	United States	36608
3	Radiant Research; Phoenix Southeast	Chandler	Arizona	United States	85225
4	Arizona Research Center Inc.	Phoenix	Arizona	United States	85023
5	Research Facility	Phoenix	Arizona	United States	85029
6	Research Facility	Phoenix	Arizona	United States	85032
7	Research Facility	Anaheim	California	United States	92801
8	Lovelace Scientific Resources, Inc.	Beverly Hills	California	United States	90211
9	Research Facility	Carmichael	California	United States	95608
10	Advance Care Medical Group	City of Industry	California	United States	91748
11	Research Facility	Downey	California	United States	90241
12	Research Facility	Foothill Ranch	California	United States	92610
13	Research Facility	Sacramento	California	United States	95831
14	Research Facility	San Luis Obispo	California	United States	93405
15	Research Facility	Littleton	Colorado	United States	80128
16	Research Facility	Stamford	Connecticut	United States	06905
17	Clinical Research of West Florida	Clearwater	Florida	United States	33765
18	Research Facility	Clearwater	Florida	United States	33765
19	University Clinical Research	Deland	Florida	United States	32720
20	Arthritis Associates of S. FL	Delray Beach	Florida	United States	33484
21	Research Facility	Ft. Myers	Florida	United States	33907
22	Century Clinical Research, Inc.	Holly Hill	Florida	United States	32117-2257
23	Research Facility	Jupiter	Florida	United States	33458-7200
24	Research Facility	Largo	Florida	United States	33770
25	Research Facility	Merritt Island	Florida	United States	32953
26	Pharmax Research Clinic	Miami	Florida	United States	33126
27	Research Facility	Orlando	Florida	United States	32806
28	Research Facility	Plantation	Florida	United States	33324
29	Research Facility	Port Orange	Florida	United States	32127
30	Clinical Research of West Flor	Tampa	Florida	United States	33603
31	Research Facility	Tampa	Florida	United States	33613
32	Research Facility	West Palm Beach	Florida	United States	33409
33	Independent Neurodiagnostic Clinic	Atlanta	Georgia	United States	30327
34	Research Facility	Dawsonville	Georgia	United States	30534
35	Druid Oaks Health Center	Decatur	Georgia	United States	30033
36	Research Facility	Marietta	Georgia	United States	30060
37	Research Facility	Marietta	Georgia	United States	30066
38	Research Facility	Honolulu	Hawaii	United States	96814-4526
39	Research Facility	Boise	Idaho	United States	83702
40	Rehabilitation Association of IN	Indianapolis	Indiana	United States	46250
41	Research Facility	Overland Park	Kansas	United States	66211
42	CTT Consultants, Inc.	Prairie Village	Kansas	United States	66206
43	Dolby Research, LLC	Baton Rouge	Louisiana	United States	70809
44	Research Facility	New Orleans	Louisiana	United States	70114
45	Research Facility	New Orleans	Louisiana	United States	70115
46	Research Facility	Shreveport	Louisiana	United States	71103
47	Research Facility	Brockton	Massachusetts	United States	02301
48	East Coast Clinical Research	Haverhill	Massachusetts	United States	01830-6141
49	Research Facility	Springfield	Massachusetts	United States	01103
50	Research Facility	Bay City	Michigan	United States	48706
51	Research Facility	Biloxi	Mississippi	United States	39531
52	Research Facility	Florissant	Missouri	United States	63031
53	Research Facility	St. Louis	Missouri	United States	63117
54	Research Facility	St. Louis	Missouri	United States	63141
55	Sports Med Consultants, PC	St. Louis	Missouri	United States	63141
56	Research Facility	Henderson	Nevada	United States	89014
57	Research Facility	Las Vegas	Nevada	United States	89123
58	Lovelace Scientific Resources	Albuquerque	New Mexico	United States	87108
59	Research Facility	New York	New York	United States	10004
60	Research Facility	New York	New York	United States	10022
61	Research Facility	Charlotte	North Carolina	United States	28209
62	Research Facility	Greensboro	North Carolina	United States	27401
63	Research Facility	Morgantown	North Carolina	United States	28655
64	Community Research	Cincinatti	Ohio	United States	45245
65	Research Facility	Cincinnati	Ohio	United States	45242
66	Research Facility	Columbus	Ohio	United States	43213
67	Research Facility	Columbus	Ohio	United States	43235
68	Research Facility	Toledo	Ohio	United States	43623
69	Research Facility	Oklahoma City	Oklahoma	United States	73109
70	Research Facility	Eugene	Oregon	United States	97404
71	Research Facility	Medford	Oregon	United States	97504-8311
72	Research Facility	Altoona	Pennsylvania	United States	16602
73	Research Facility	Chicora	Pennsylvania	United States	16025
74	Research Facility	Duncansville	Pennsylvania	United States	16635
75	Research Facility	Mechanicsburg	Pennsylvania	United States	17055
76	Research Facility	West Reading	Pennsylvania	United States	19611
77	New England Center for Clinical Research	Cranston	Rhode Island	United States	02920
78	Anderson Family Care, PA	Anderson	South Carolina	United States	29621
79	KRK Medical Research	Dallas	Texas	United States	75230
80	Research Facility	Killeen	Texas	United States	76543
81	Research Facility	Plano	Texas	United States	75093
82	Research Facility	San Antonio	Texas	United States	78205-1116
83	Research Facility	San Antonio	Texas	United States	78229
84	Research Facility	Sugarland	Texas	United States	77479
85	Research Facility	Salt Lake City	Utah	United States	84106
86	Research Facility	Roanoke	Virginia	United States	24018

Sponsors and Collaborators

• Purdue Pharma LP

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Product Information

Publications

None provided.

• Responsible Party: Purdue Pharma LP
• ClinicalTrials.gov Identifier: NCT00490919
• Other Study ID Numbers: BUP3024
• First Posted: Jun 25, 2007
• Last Update Posted: Sep 10, 2012
• Last Verified: Sep 1, 2012

• Keywords provided by Purdue Pharma LP: Chronic pain; opioid; transdermal; Moderate to severe chronic low back pain
• Additional relevant MeSH terms: Back Pain; Low Back Pain; Buprenorphine

Study Results

Participant Flow

Recruitment Details	Study dates: 27-Jun-2007 (first patient first visit) to 24-Jul-2008 (last patient last visit), at 86 medical/research sites in the USA.
Pre-assignment Detail	The open-label run-in period (N = 1024 started) was designed to select subjects for randomization in the double-blind phase who met both tolerability and responsiveness criteria for either BTDS 10 or 20 (an enriched design).

Arm/Group Title	Open-label Run-in Period	Double-blind BTDS 10 or 20	Double-blind Placebo TDS
Arm/Group Description	The open-label run-in period (< 27 days) (N = 1024 started) was designed to select subjects for randomization who met both tolerability and responsiveness criteria for either BTDS 10 or 20 (an enriched design). Upon completion of the run-in period, 541 subjects were randomized and received treatment in the double-blind phase. Two subjects had no safety data after the randomization visit; therefore N = 539 for the randomized safety population.	Buprenorphine transdermal patch (BTDS) 10 mcg/h or 20 mcg/h applied for 7-day wear during the 12-week double-blind phase.	Matching placebo transdermal patch (placebo TDS) 10 or 20 mcg/h applied for 7-day wear during the 12-week double-blind phase.
Period Title: Open-label Run-in Period
STARTED	1024	0	0
COMPLETED	541	0	0
NOT COMPLETED	483	0	0
Period Title: Open-label Run-in Period
STARTED	0	256	283
COMPLETED	0	170	199
NOT COMPLETED	0	86	84

Baseline Characteristics

Arm/Group Title	Double-blind BTDS	Double-blind Placebo TDS	Total
Arm/Group Description	Buprenorphine transdermal patch 10 mcg/h or 20 mcg/h applied for 7-day wear during the 12-week double-blind phase	Matching placebo TDS 10 or 20 mcg/h applied for 7-day wear during the 12-week double-blind phase	Total of all reporting groups
Overall Participants	256	283	539
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	48.9 (12.50)	50.1 (13.31)	49.5 (12.93)
Sex: Female, Male (Count of Participants)
Female	133 52%	163 57.6%	296 54.9%
Male	123 48%	120 42.4%	243 45.1%

Outcome Measures

1. Primary Outcome

Title	Average Pain Over the Last 24 Hours Scores at Week 12 of the Double-blind Phase.
Description	Pain was assessed on an 11-point numerical scale ranging from 0 = no pain to 10 = pain as bad as you can imagine.
Time Frame	Prerandomization phase consisted of a 6-10 day screening period and a <27 day open-label run-in period; and a 12-week double-blind phase.

Outcome Measure Data

Analysis Population Description

The full analysis population (FAP) (N = 541) [539] consisted of subjects who were randomized and received at least 1 dose of the double-blind study drug. (Two subjects did not have safety data.)

Arm/Group Title	Double-blind BTDS	Double-blind Placebo TDS
Arm/Group Description	Buprenorphine transdermal patch 10 mcg/h or 20 mcg/h applied for 7-day wear during the 12-week double-blind phase	Matching placebo TDS 10 or 20 mcg/h applied for 7-day wear during the 12-week double-blind phase
Measure Participants	256	283
Screening	7.24 (1.263)	7.17 (1.223)
Prerandomization	2.57 (1.283)	2.56 (1.207)
Week 12 - Primary outcome	3.83 (2.738)	4.38 (2.690)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind BTDS, Double-blind Placebo TDS
	Comments	Missing average pain over the last 24 hours scores after treatment discontinuation were imputed using BOCF for adverse event-related withdrawals and LOCF for withdrawals due to other reasons.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0104
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed effects general linear model with repeated measures.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.58
	Confidence Interval	(2-Sided) 95%; -1.02 to -0.14
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.225
	Estimation Comments	Double-blind analysis (comparison between BTDS and placebo TDS) at week 12 of the double-blind phase.

2. Secondary Outcome

Title	The Mean Daily Number of Tablets of Nonopioid Supplemental Analgesic Medications Taken During Weeks 2 Through 12 of the Double-blind Phase
Description	Nonopioid supplemental analgesic tablets were sponsor-supplied acetaminophen or ibuprofen.
Time Frame	weeks 2-12

Outcome Measure Data

Analysis Population Description

Subjects in the full analysis population who took at least one dose of supplemental analgesic medication.

Arm/Group Title	Double-blind BTDS	Double-blind Placebo TDS
Arm/Group Description	Buprenorphine transdermal patch 10 mcg/h or 20 mcg/h applied for 7-day wear during the 12-week double-blind phase	Matching placebo TDS 10 or 20 mcg/h applied for 7-day wear during the 12-week double-blind phase
Measure Participants	137	180
Mean (Standard Error) [tablets]	0.620 (0.0658)	0.743 (0.0574)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind BTDS, Double-blind Placebo TDS
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.1586
	Comments	To address the issue of multiplicity and control the family-wise error rate, a gate-keeping strategy and a stepwise approach (Holms methodology) were used to evaluate the statistical significance of the secondary efficacy analyses.
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-0.124
	Confidence Interval	(2-Sided) 95%; -0.296 to 0.048
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.0874
	Estimation Comments	Mean comparison from weeks 2-12 of the double-blind phase.

3. Secondary Outcome

Title	The Sleep Disturbance Subscale in the Medical Outcome Study (MOS) Sleep Scale at Weeks 4, 8, and 12 of the Double-blind Phase
Description	The MOS Sleep Scale consists of 12 individual items (4 sleep disturbance, 2 sleep adequacy, 1 quantity of and optimal sleep, 3 somnolence, 1 snoring, and 1 shortness of breath) and takes 5 to 10 minutes to complete. Question 1 is scored on a scale of 1 to 5 and Questions 2 to 12 are scored on a scale of 1 to 6. The Sleep Disturbance Subscale score is derived from the scores to Questions 1, 3, 7 and 8, and ranges from 0 to 100, where higher scores indicate greater sleep disturbance.
Time Frame	Weeks 4, 8, 12 of double-blind phase

Outcome Measure Data

Analysis Population Description

The full analysis population (FAP) (N = 541) consisted of subjects who were randomized and received at least 1 dose of the double-blind study drug. 2 subjects did not have safety data (N = 539).

Arm/Group Title	Double-blind BTDS	Double-blind Placebo TDS
Arm/Group Description	Buprenorphine transdermal patch 10 mcg/h or 20 mcg/h applied for 7-day wear during the 12-week double-blind phase	Matching placebo TDS 10 or 20 mcg/h applied for 7-day wear during the 12-week double-blind phase
Measure Participants	256	283
Week 4	32.84 (25.552)	41.20 (26.813)
Week 8	35.63 (26.276)	39.87 (26.362)
Week 12	34.97 (26.871)	40.42 (26.675)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Double-blind BTDS, Double-blind Placebo TDS
	Comments	The primary comparison between groups was based on estimates and contrasts for the weeks 4, 8, and 12 mean values.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	.0062
	Comments	To address the issue of multiplicity and control the family-wise error rate, a gate-keeping strategy and a stepwise approach (Holms methodology) were used to evaluate the statistical significance of the secondary efficacy analyses.
	Method	Mixed Models Analysis
	Comments	Mixed effects general linear model with repeated measures.
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	-4.40
	Confidence Interval	(2-Sided) 95%; -7.55 to -1.25
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 1.605
	Estimation Comments	Treatment comparison over Weeks 4, 8, and 12.

Adverse Events

Time Frame	Adverse Events (AEs) that occurred after the signing of the informed consent up to end of study and 7 days after, discontinuation, or Serious AEs occurring up to 30 days following the last study visit were followed until the AE resolved or stabilized.
Adverse Event Reporting Description	AEs were obtained through spontaneous reports, subject interview, and subject diaries.
Arm/Group Title	Double-blind BTDS 10, 20		Double-blind Placebo TDS 10, 20		Open-label Run-in Period, BTDS 5, 10, 20
Arm/Group Description	Buprenorphine transdermal patch 10 mcg/h or 20 mcg/h applied for 7-day wear		Matching placebo TDS 10 or 20 applied for 7-day wear		Open-label BTDS 5, 10, 20 applied for 7-day wear
All Cause Mortality
	Double-blind BTDS 10, 20		Double-blind Placebo TDS 10, 20		Open-label Run-in Period, BTDS 5, 10, 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Double-blind BTDS 10, 20		Double-blind Placebo TDS 10, 20		Open-label Run-in Period, BTDS 5, 10, 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/256 (1.2%)		2/283 (0.7%)		4/1024 (0.4%)
Cardiac disorders
Acute myocardial infarction	0/256 (0%)	0	1/283 (0.4%)	1	0/1024 (0%)	0
Gastrointestinal disorders
Vomiting	0/256 (0%)	0	0/283 (0%)	0	1/1024 (0.1%)	1
Injury, poisoning and procedural complications
Skin laceration	0/256 (0%)	0	0/283 (0%)	0	1/1024 (0.1%)	1
Road traffic accident	1/256 (0.4%)	1	0/283 (0%)	0	1/1024 (0.1%)	1
Joint sprain	0/256 (0%)	0	0/283 (0%)	0	1/1024 (0.1%)	1
Metabolism and nutrition disorders
Dehydration	0/256 (0%)	0	0/283 (0%)	0	1/1024 (0.1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer metastatic	0/256 (0%)	0	0/283 (0%)	0	1/1024 (0.1%)	1
Nervous system disorders
Subarachnoid hemorrhage	0/256 (0%)	0	0/283 (0%)	0	1/1024 (0.1%)	1
Psychiatric disorders
Major depression	1/256 (0.4%)	1	0/283 (0%)	0	0/1024 (0%)	0
Homicidal thoughts	0/256 (0%)	0	1/283 (0.4%)	1	0/1024 (0%)	0
Anxiety	0/256 (0%)	0	1/283 (0.4%)	1	0/1024 (0%)	0
Suicidal ideation	0/256 (0%)	0	1/283 (0.4%)	1	0/1024 (0%)	0
Renal and urinary disorders
Renal failure acute	0/256 (0%)	0	0/283 (0%)	0	1/1024 (0.1%)	1
Social circumstances
Drug abuser	1/256 (0.4%)	1	0/283 (0%)	0	0/1024 (0%)	0
Other (Not Including Serious) Adverse Events
	Double-blind BTDS 10, 20		Double-blind Placebo TDS 10, 20		Open-label Run-in Period, BTDS 5, 10, 20
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/256 (20.3%)		63/283 (22.3%)		437/1024 (42.7%)
Gastrointestinal disorders
Nausea	32/256 (12.5%)		31/283 (11%)		240/1024 (23.4%)
Vomiting	11/256 (4.3%)		5/283 (1.8%)		77/1024 (7.5%)
Constipation	9/256 (3.5%)		3/283 (1.1%)		67/1024 (6.5%)
General disorders
Application site pruritus	11/256 (4.3%)		19/283 (6.7%)		87/1024 (8.5%)
Application site erythema	9/256 (3.5%)		14/283 (4.9%)		32/1024 (3.1%)
Application site rash	12/256 (4.7%)		7/283 (2.5%)		18/1024 (1.8%)
Nervous system disorders
Dizziness	10/256 (3.9%)		3/283 (1.1%)		102/1024 (10%)
Somnolence	4/256 (1.6%)		6/283 (2.1%)		84/1024 (8.2%)
Headache	14/256 (5.5%)		14/283 (4.9%)		100/1024 (9.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.