Efficacy and Safety of Oxycodone/Naloxone Controlled-release Tablets (OXN) Compared to Placebo in Opioid-experienced Subjects With Moderate to Severe Chronic Low Back Pain

• Sponsor: Purdue Pharma LP (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01358526
• Collaborator: (none)
• Enrollment: 1,095
• Locations: 151
• Arms: 2
• Duration (Months): 18.1
• Patients Per Site: 7.3
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The primary objective of this study is to assess the efficacy and safety of OXN compared to placebo in opioid-experienced subjects with moderate to severe pain due to chronic low back pain who require around-the-clock opioid therapy.

Condition or Disease	Intervention/Treatment	Phase
Low Back Pain	Drug: Oxycodone/Naloxone Controlled-release; Drug: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 1095 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-blind, Placebo-controlled, Multicenter Trial With an Enriched Study Design to Assess the Efficacy and Safety of Oxycodone/Naloxone Controlled-release Tablets (OXN) Compared to Placebo in Opioid-experienced Subjects With Moderate to Severe Pain Due to Chronic Low Back Pain Who Require Around-the-clock Opioid Therapy
• Study Start Date: May 1, 2011
• Actual Primary Completion Date: Oct 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: OXN Oxycodone/Naloxone Controlled-release Tablets (OXN)	Drug: Oxycodone/Naloxone Controlled-release; Oxycodone/Naloxone Controlled-release tablets (10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg) taken orally every 12 hours; Other Names: TARGINIQ ER
Placebo Comparator: Placebo Placebo tablets to match OXN	Drug: Placebo; Placebo tablets to match OXN taken orally every 12 hours

Outcome Measures

Primary Outcome Measures

1. The "Average Pain Over the Last 24 Hours" at Week 12 of the Double-blind Period [24 hours (Week 12)]

   The "average pain over the last 24 hours" score was collected using an 11-point numerical rating scale ranging from 0 to 10; where 0=no pain and 10=pain as bad as you can imagine.

Secondary Outcome Measures

1. The Sleep Disturbance Subscale of the MOS Sleep Scale at Weeks 4, 8, and 12 [Weeks 4, 8, and 12]

   The scale consists of 12 individual items (4 sleep disturbance, 2 sleep adequacy, 1 quantity of sleep, 3 somnolence, 1 snoring, 1 shortness of breath). Only Sleep Disturbance Subscale questions 1, 3, 7, and 8 were analyzed; scores range from 0 to 100, where higher scores indicate greater sleep disturbance.

2. Patient Global Impression of Change (PGIC) [Week 12]

   The PGIC observational scale was completed by the subject. Subjects were asked to assess the change in overall status relative to the start of the study. The scale has only 1 item, which measures global change of overall status by the subject on a 7-point scale (Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse), where 1 = very much improved and 7 = very much worse. The proportion of subjects responding "much improved" and "very much improved" was summarized by treatment group and compared between groups using an exact test.

Other Outcome Measures

1. Responder Analysis for Subjects With a ≥ 30% Reduction in Pain Compared to Baseline [Week 12]

   A subject's response to treatment was defined as the percentage reduction from the screening mean pain score to the "average pain over the last 24 hours" score for week 12 of the double-blind period.

2. Responder Analysis for Subjects With a ≥ 50% Reduction in Pain Compared to Baseline [Week 12]

   A subject's response to treatment was defined as the percentage reduction from the screening mean pain score to the "average pain over the last 24 hours" score for week 12 of the double-blind period.

Eligibility Criteria

Criteria

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

Inclusion Criteria include:

• Male and female subjects ≥ 18 years of age with moderate to severe, chronic low back pain (lasting at least several hours daily) as their predominant pain condition for at least 3 months prior to screening period;

• The back pain must be related to nonmalignant and nonneuropathic conditions and without radiation or with only proximal radiation (above the knee);

• Subjects must be on opioid analgesic therapy for low back pain which:

• Has been ongoing for at least 4 weeks prior to the screening visit and,

• Consists of a stable opioid regimen at a total average daily dose equivalent to 20 to 160 mg (inclusive) of morphine for the last 2 weeks prior to the screening visit. Subjects taking tramadol ≥ 100 mg daily on a stable regimen for the last 2 weeks prior to the screening visit will also meet this criterion;

• Subjects must require continuation of opioid analgesic treatment in the range of 40 to 160 mg (inclusive) of morphine or its equivalent daily and be likely to benefit from chronic around-the-clock opioid therapy for the duration of the study;

• Subjects must have an average pain over the last 14 days score ≥ 5 (on an 11-point numerical rating scale [NRS]) at the screening visit, on their current opioid analgesic medication and, if applicable, nonopioid medication;

• Subjects must have an average pain over the last 24 hours score ≥ 5 (on an 11-point NRS) at the screening visit, on their current opioid analgesic medication and, if applicable, nonopioid medication;

• Subjects must be willing and able to be compliant with the protocol, capable of subjective evaluation, able to read and understand questionnaires, willing and able to use a diary per protocol, and read, understand, and sign the written informed consent in English.

Exclusion Criteria include:

• Female subjects who are pregnant (positive serum beta human chorionic gonadotropin [β hCG] test) or lactating;

• Subjects with any contraindication or any history of hypersensitivity to oxycodone, naloxone, or other opioids. This does not include subjects who have experienced common opioid side effects (e.g., nausea, constipation);

• Subjects with acute spinal cord compression, acute compression fracture, seronegative spondyloarthropathy, acute nerve root compression, cauda equina compression, fibromyalgia, reflex sympathetic dystrophy or causalgia (complex regional pain syndrome), diabetic amyotrophy, meningitis, discitis, or back pain due to secondary infection, tumor, or postherpetic neuralgia;

• Subjects with gout, unless controlled on stable suppressive treatment with colchicine or uric-acid-lowering therapy without any attacks for ≥ 2 years and the subject has not been using nonsteroidal anti-inflammatory drugs (NSAIDs) or COX-2 inhibitors on a regular basis;

• Subjects with pseudogout, psoriatic arthritis, active Lyme disease, rheumatoid arthritis or other inflammatory arthritis, or neuropathic pain conditions;

• Subjects who had surgical procedures directed towards the source of chronic low back pain within 6 months of the screening visit or planned during the study;

• Subjects with a history of opioid, alcohol, medication, or illicit drug abuse or addiction;

• Subjects who have received any investigational medication within 30 days of first dose of study drug;

• Subjects currently taking, or who have taken naloxone, naltrexone, methylnaltrexone, or alvimopan within 10 days before the screening visit;

• Subjects who have received study drug in a clinical study of oxycodone/naloxone controlled-release (OXN or ONU).

Other protocol specific inclusion/exclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Orthopaedic Center, PC	Birmingham	Alabama	United States	35209
2	Alliance Clinical Research	Birmingham	Alabama	United States	35213
3	Winston Technology Research, LLC	Haleyville	Alabama	United States	35565
4	Monte Sano Clinical Research, LLC	Huntsville	Alabama	United States	35801
5	Research Facility	Mobile	Alabama	United States	36608
6	Radiant Research, Inc.	Chandler	Arizona	United States	85224
7	Dedicated Clinical Research	Phoenix	Arizona	United States	85020
8	Arizona Research Center	Phoenix	Arizona	United States	85023
9	Clinical Research Advantage, Inc./Tatum Highlands Medical Associates, PLLC	Phoenix	Arizona	United States	85050
10	Quality of Life Medical & Research Center, LLC	Tucson	Arizona	United States	85712
11	Ortho Surgeons	Little Rock	Arkansas	United States	72205
12	Orange County Research Institute	Anaheim	California	United States	92801
13	Physician Alliance Research Center	Anaheim	California	United States	92804
14	Advanced Pain Research Institute	Arcadia	California	United States	91007
15	Southbay Pharma Research	Buena Park	California	United States	90620
16	Providence Clinical Research	Burbank	California	United States	91505
17	Med Center	Carmichael	California	United States	95608
18	Advanced Pain Management and Rehabilitation Medical Group, Inc.	Castro Valley	California	United States	94546
19	Catalina Research Institute, LLC	Chino	California	United States	91710
20	Synergy Clinical Research of Escondido	Escondido	California	United States	92025
21	Valley Research	Fresno	California	United States	93720
22	RX Clinical Research, Inc.	Garden Grove	California	United States	92843
23	TriWest Research Associates	La Mesa	California	United States	91942
24	Pacific Coast Pain Management Center	Laguna Hills	California	United States	92637
25	South Orange County Surgical Medical Group	Laguna Hills	California	United States	92653
26	Clinical Trials Research	Lincoln	California	United States	95648
27	L.A. Pain and Wellness Institute	Los Angeles	California	United States	90017
28	Newport Beach Clinical Research Associates, Inc.	Newport Beach	California	United States	92663
29	Lotus Clinical Research	Pasadena	California	United States	91105
30	Northern California Clinical Research Center	Redding	California	United States	96001
31	Probe Clinical Research Corporation	Riverside	California	United States	92501
32	Northern California Research	Sacramento	California	United States	95821
33	Probe Clinical Research Corporation	Santa Ana	California	United States	92701
34	Denver Internal Medicine Group	Denver	Colorado	United States	80209
35	Front Range Clinical Research	Wheat Ridge	Colorado	United States	80033
36	New England Research Associates, LLC	Trumbull	Connecticut	United States	06611
37	Orthopedic Research Institute	Boynton Beach	Florida	United States	33472
38	Coastal Orthopedics & Pain Management	Bradenton	Florida	United States	34208
39	Southeast Clinical Research, LLC	Chiefland	Florida	United States	32626
40	Innovative Research of West Florida, Inc.	Clearwater	Florida	United States	33756
41	Clinical Research of West Florida, Inc.	Clearwater	Florida	United States	33765
42	Omega Research Consultants, LLC	Debary	Florida	United States	32713
43	S & W Clinical Research	Fort Lauderdale	Florida	United States	33306
44	Southeastern Integrated Medical, PL	Gainesville	Florida	United States	32607
45	Health Care Family Rehab & Research Center	Hialeah	Florida	United States	33012
46	Eastern Research, Inc.	Hialeah	Florida	United States	33013
47	Southeast Clinical Research, LLC	Jacksonville	Florida	United States	32216
48	Florida Institute of Medical Research	Jacksonville	Florida	United States	32257
49	Drug Study Institute	Jupiter	Florida	United States	33458
50	Pharma Care Research, Inc.	Miami	Florida	United States	33144
51	Advanced Pharma CR, LLC	Miami	Florida	United States	33175
52	Compass Research, LLC	Orlando	Florida	United States	32806
53	Peninsula Research, Inc.	Ormond Beach	Florida	United States	32174
54	Sarasota Clinical Research, LLC	Sarasota	Florida	United States	34232
55	Sarasota Pain Medicine Research	Sarasota	Florida	United States	34238
56	Vita Research Solutions & Medical Center, Inc.	Tamarac	Florida	United States	33319
57	Stedman Clinical Trials	Tampa	Florida	United States	33613
58	Advanced Research Institute, Inc.	Trinity	Florida	United States	34655
59	Palm Beach Research Center	West Palm Beach	Florida	United States	33409
60	National Pain Research Institute, LLC	Winter Park	Florida	United States	32789
61	Independent Neurodiagnostic Clinic	Atlanta	Georgia	United States	30327
62	In-Quest Medical Research, LLC	Duluth	Georgia	United States	30096
63	Georgia Institute for Clinical Research, LLC	Marietta	Georgia	United States	30060
64	Research Facility	Marietta	Georgia	United States	30060
65	Better Health Clinical Research, Inc.	Newnan	Georgia	United States	30265
66	SouthCoast Medical Group	Savannah	Georgia	United States	31406
67	Georgia Clinical Research, LLC	Snellville	Georgia	United States	30078
68	The Pain Center	Boise	Idaho	United States	83702
69	Clinical Investigation Specialists, Inc.	Gurnee	Illinois	United States	60031
70	Destiny Clinical Research, LLC	Evansville	Indiana	United States	47714
71	MediSphere Medical Research Center, LLC	Evansville	Indiana	United States	47714
72	Northwest Indiana Center for Clinical Research	Valparaiso	Indiana	United States	46383
73	International Clinical Research Institute, Inc.	Leawood	Kansas	United States	66211
74	Clinical Trials Technology, Inc. CTT Consultants, Inc.	Prairie Village	Kansas	United States	66206
75	The Pain Treatment Center of the Bluegrass	Lexington	Kentucky	United States	40503
76	Louisiana Research Associates, Inc.	New Orleans	Louisiana	United States	70114
77	Research Facility	New Orleans	Louisiana	United States	70115
78	Mid-Atlantic Medical Research Centers	Hollywood	Maryland	United States	20636
79	MidAtlantic Pain Medicine Center	Pikesville	Maryland	United States	21208
80	Beacon Clinical Research, LLC	Brockton	Massachusetts	United States	02301
81	ActivMed Practices and Research	Haverhill	Massachusetts	United States	01830
82	Medvadis Research Corporation	Watertown	Massachusetts	United States	02472-3930
83	Great Lakes Research Group, Inc.	Bay City	Michigan	United States	48706
84	Great Lakes Family Care	Cadillac	Michigan	United States	49601
85	Great Lakes Research Group, Inc.	Pinconning	Michigan	United States	48650
86	Medex Healthcare Research, Inc.	Saint Louis	Missouri	United States	63117
87	Mercy Health Research	St. Louis	Missouri	United States	63141
88	Sundance Clinical Research, LLC	St. Louis	Missouri	United States	63141
89	Meridian Clinical Research, LLC	Omaha	Nebraska	United States	68134
90	Research Facility	Las Vegas	Nevada	United States	89109
91	South Jersey Medical Associates, P.A.	Blackwood	New Jersey	United States	08012
92	University of Medicine & Dentistry of New Jersey - School of Osteopathic Medicine (UMDNJ)	Stratford	New Jersey	United States	08084
93	Five Towns Neuroscience Research/Five Towns Neurology	Cedarhurst	New York	United States	11516
94	Long Island Gastrointestinal Research Group, LLP	Great Neck	New York	United States	11023
95	Medex Healthcare Research, Inc.	New York	New York	United States	10022
96	Research Across America	New York	New York	United States	10022
97	Upstate Clinical Research Associates, LLC	Williamsville	New York	United States	14221
98	Gaffney Health Services	Charlotte	North Carolina	United States	28205
99	Box Arthritis & Rheumatology of the Carolinas, PLLC	Charlotte	North Carolina	United States	28210
100	PharmQuest	Greensboro	North Carolina	United States	27408
101	Peters Medical Research	High Point	North Carolina	United States	27262
102	Plains Medical Clinic, LLC	Fargo	North Dakota	United States	58104
103	Clinical Inquest Center Ltd.	Beavercreek	Ohio	United States	45432
104	Community Research	Cincinnati	Ohio	United States	45227
105	Columbus Clinical Research, Inc.	Columbus	Ohio	United States	43213
106	Hometown Urgent Care and Research	Dayton	Ohio	United States	45432
107	Prestige Clinical Research	Franklin	Ohio	United States	45005
108	Hometown Urgent Care and Research	Springfield	Ohio	United States	45504
109	J L Clinical Research	Tiffin	Ohio	United States	44883
110	Bone Joint and Spine Surgeons, Inc.	Toledo	Ohio	United States	43623
111	Pharmacotherapy Research Associates, Inc.	Zanesville	Ohio	United States	43701
112	Neuropsychiatric Center and NPC Research	Oklahoma City	Oklahoma	United States	73109-3834
113	Health Research Institute	Oklahoma City	Oklahoma	United States	73109
114	Paradigm Research Professionals, LLC	Oklahoma City	Oklahoma	United States	73112
115	Bend Memorial Clinic	Bend	Oregon	United States	97701
116	Pain Consultants of Oregon	Eugene	Oregon	United States	97401
117	Willamette Valley Clinical Studies	Eugene	Oregon	United States	97404
118	Sunstone Medical Research, LLC	Medford	Oregon	United States	97504
119	Allegheny Pain Management, PC	Altoona	Pennsylvania	United States	16602
120	Paramount Clinical Research	Bridgeville	Pennsylvania	United States	15017
121	Altoona Center for Clinical Research	Duncansville	Pennsylvania	United States	16635
122	The Clinical Trial Center, LLC	Jenkintown	Pennsylvania	United States	19046
123	Central Pennsylvania Clinical Research	Mechanicsburg	Pennsylvania	United States	17055
124	CRI Worldwide, LLC	Philadelphia	Pennsylvania	United States	19139
125	Dairyland Medical Center	Red Lion	Pennsylvania	United States	17356
126	New England Center for Clinical Research, Inc	Cranston	Rhode Island	United States	02920
127	Hartwell Research Group, LLC	Anderson	South Carolina	United States	29621
128	Greenville Pharmaceutical Research, Inc.	Greenville	South Carolina	United States	29615
129	Internal Medicine of Greer	Greer	South Carolina	United States	29650
130	Meridian Clinical Research	Dakota Dunes	South Dakota	United States	57049
131	Health Concepts Wellness Center	Rapid City	South Dakota	United States	57702
132	Integrity Clinical Research, LLC	Huntingdon	Tennessee	United States	38344
133	FutureSearch Trials of Neurology	Austin	Texas	United States	78731
134	Austin Center for Clinical Research	Austin	Texas	United States	78756
135	Corpus Christi Pain Medicine	Corpus Christi	Texas	United States	78415
136	FutureSearch Trials of Dallas	Dallas	Texas	United States	75231
137	Pineloch Medical Clinic	Houston	Texas	United States	77062
138	Clinical Trial Network	Houston	Texas	United States	77074
139	Southwest Clinical Trials	Houston	Texas	United States	77074
140	Protenium Clinical Research, LLC	Hurst	Texas	United States	76054
141	TEAM Research of Central Texas	Killeen	Texas	United States	76543
142	West Texas Medical Associates	San Angelo	Texas	United States	76904
143	Sun Research Institute	San Antonio	Texas	United States	78215
144	Research Facility	Bountiful	Utah	United States	84010
145	Summit Pain Management	Murray	Utah	United States	84107
146	Alpine Medical Group	Salt Lake City	Utah	United States	84102
147	Highland Clinical Research	Salt Lake City	Utah	United States	84124
148	Virginia Research Center	Midlothian	Virginia	United States	23114
149	Hilltop Medical Center	Virginia Beach	Virginia	United States	23454
150	Independence Family Medicine	Virginia Beach	Virginia	United States	23455
151	Universal Research Group	Tacoma	Washington	United States	98405

Sponsors and Collaborators

• Purdue Pharma LP

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• TARGINIQ ER Labeling

Publications

None provided.

• Responsible Party: Purdue Pharma LP
• ClinicalTrials.gov Identifier: NCT01358526
• Other Study ID Numbers: ONU3701
• First Posted: May 23, 2011
• Last Update Posted: Nov 11, 2015
• Last Verified: Oct 1, 2015

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

Study Results

Participant Flow

Recruitment Details	First subject first visit: 25-May-2011; Last subject last visit: 15-Oct-2012. The study was conducted at 132 medical/research sites in the United States.
Pre-assignment Detail	Opioid-experienced subjects with moderate to severe pain due to chronic low back pain, who required around-the-clock opioid therapy.

Arm/Group Title	Open-label Titration OXN	OXN Group	Placebo Group
Arm/Group Description	The open-label titration was designed to identify a stable, effective, and tolerable dose of OXN for each subject.	Oxycodone/Naloxone Controlled-release Tablets (OXN) Oxycodone/Naloxone Controlled-release: Oxycodone/Naloxone Controlled-release tablets (10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg) taken orally every 12 hours	Placebo tablets to match OXN Placebo: Placebo tablets to match OXN taken orally every 12 hours
Period Title: Open-label Titration Period
STARTED	1095	0	0
COMPLETED	601	0	0
NOT COMPLETED	494	0	0
Period Title: Open-label Titration Period
STARTED	0	298	302
COMPLETED	0	218	181
NOT COMPLETED	0	80	121

Baseline Characteristics

Arm/Group Title	OXN Group	Placebo Group	Total
Arm/Group Description	Oxycodone/Naloxone Controlled-release Tablets (OXN) Oxycodone/Naloxone Controlled-release: Oxycodone/Naloxone Controlled-release tablets (10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg) taken orally every 12 hours	Placebo tablets to match OXN Placebo: Placebo tablets to match OXN taken orally every 12 hours	Total of all reporting groups
Overall Participants	298	302	600
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	53.5 (11.69)	53.0 (10.97)	53.2 (11.33)
Sex: Female, Male (Count of Participants)
Female	162 54.4%	176 58.3%	338 56.3%
Male	136 45.6%	126 41.7%	262 43.7%
Race/Ethnicity, Customized (participants) [Number]
White	229 76.8%	233 77.2%	462 77%
Black or African American	53 17.8%	61 20.2%	114 19%
Asian	8 2.7%	3 1%	11 1.8%
American Indian or Alaska Native	1 0.3%	3 1%	4 0.7%
Other	7 2.3%	2 0.7%	9 1.5%

Outcome Measures

1. Primary Outcome

Title	The "Average Pain Over the Last 24 Hours" at Week 12 of the Double-blind Period
Description	The "average pain over the last 24 hours" score was collected using an 11-point numerical rating scale ranging from 0 to 10; where 0=no pain and 10=pain as bad as you can imagine.
Time Frame	24 hours (Week 12)

Outcome Measure Data

Analysis Population Description

The full analysis population for efficacy (N = 600) was the group of subjects who were randomized and received at least 1 dose of double-blind study drug

Arm/Group Title	OXN Group	Placebo Group
Arm/Group Description	Oxycodone/Naloxone Controlled-release Tablets (OXN) Oxycodone/Naloxone Controlled-release: Oxycodone/Naloxone Controlled-release tablets (10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg) taken orally every 12 hours	Placebo tablets to match OXN Placebo: Placebo tablets to match OXN taken orally every 12 hours
Measure Participants	298	302
Mean (Standard Error) [units on a scale (0 - 10)]	3.86 (0.116)	4.32 (0.115)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OXN Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0055
	Comments	A gate-keeping strategy and a Bonferroni-Holm method was used to control the family-wise (primary and secondary efficacy analysis) error rate at the 5% level.
	Method	Mixed Models Analysis
	Comments	Mixed-model repeated measures analysis of pain data using a pattern mixture model framework
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	0.45
	Confidence Interval	(2-Sided) 95%; 0.13 to 0.77
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 0.163
	Estimation Comments

2. Secondary Outcome

Title	The Sleep Disturbance Subscale of the MOS Sleep Scale at Weeks 4, 8, and 12
Description	The scale consists of 12 individual items (4 sleep disturbance, 2 sleep adequacy, 1 quantity of sleep, 3 somnolence, 1 snoring, 1 shortness of breath). Only Sleep Disturbance Subscale questions 1, 3, 7, and 8 were analyzed; scores range from 0 to 100, where higher scores indicate greater sleep disturbance.
Time Frame	Weeks 4, 8, and 12

Outcome Measure Data

Analysis Population Description

The full analysis population for efficacy (N = 600) was the group of subjects who were randomized and received at least 1 dose of double-blind study drug

Arm/Group Title	OXN Group	Placebo Group
Arm/Group Description	Oxycodone/Naloxone Controlled-release Tablets (OXN) Oxycodone/Naloxone Controlled-release: Oxycodone/Naloxone Controlled-release tablets (10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg) taken orally every 12 hours	Placebo tablets to match OXN Placebo: Placebo tablets to match OXN taken orally every 12 hours
Measure Participants	298	302
Week 4	32.5	38.0
Week 8	30.8	36.8
Week 12	31.1	36.4

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OXN Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0191
	Comments
	Method	Mixed Models Analysis
	Comments	Mixed-model repeated measures analysis
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	5.3
	Confidence Interval	(2-Sided) 95%; 0.9 to 9.8
	Parameter Dispersion	Type: Standard Error of the Mean; Value: 2.26
	Estimation Comments	Mean difference (final values) is the treatment comparison estimated using mixed model repeated measures analysis with effect for treatment, time (weeks 4, 8, 12), treatment by time interaction, and prerandomization value. Subject is a random effect.

3. Secondary Outcome

Title	Patient Global Impression of Change (PGIC)
Description	The PGIC observational scale was completed by the subject. Subjects were asked to assess the change in overall status relative to the start of the study. The scale has only 1 item, which measures global change of overall status by the subject on a 7-point scale (Very much improved, Much improved, Minimally improved, No change, Minimally worse, Much worse, Very much worse), where 1 = very much improved and 7 = very much worse. The proportion of subjects responding "much improved" and "very much improved" was summarized by treatment group and compared between groups using an exact test.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The full analysis population for efficacy (N = 600) was the group of subjects who were randomized and received at least 1 dose of double-blind study drug

Arm/Group Title	OXN Group	Placebo Group
Arm/Group Description	Oxycodone/Naloxone Controlled-release Tablets (OXN) Oxycodone/Naloxone Controlled-release: Oxycodone/Naloxone Controlled-release tablets (10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg) taken orally every 12 hours	Placebo tablets to match OXN Placebo: Placebo tablets to match OXN taken orally every 12 hours
Measure Participants	298	302
Number [participants (responders)]	153 51.3%	109 36.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OXN Group, Placebo Group
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	Comments	The proportion of subjects responding "much improved" and "very much improved" was summarized by treatment group and compared between groups using an exact test
	Method	Fisher Exact
	Comments

4. Other Pre-specified Outcome

Title	Responder Analysis for Subjects With a ≥ 30% Reduction in Pain Compared to Baseline
Description	A subject's response to treatment was defined as the percentage reduction from the screening mean pain score to the "average pain over the last 24 hours" score for week 12 of the double-blind period.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The full analysis population for efficacy (N = 600) was the group of subjects who were randomized and received at least 1 dose of double-blind study drug

Arm/Group Title	OXN Group	Placebo Group
Arm/Group Description	Oxycodone/Naloxone Controlled-release Tablets (OXN) Oxycodone/Naloxone Controlled-release: Oxycodone/Naloxone Controlled-release tablets (10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg) taken orally every 12 hours	Placebo tablets to match OXN Placebo: Placebo tablets to match OXN taken orally every 12 hours
Measure Participants	298	302
Number [participants (responders)]	164 55%	124 41.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OXN Group, Placebo Group
	Comments	Proportion of subjects with a response to treatment that is ≥ 30%
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0006
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test: responder as dependent variable, treatment as explanatory variable, dose at time of randomization as stratifying factor

5. Other Pre-specified Outcome

Title	Responder Analysis for Subjects With a ≥ 50% Reduction in Pain Compared to Baseline
Description	A subject's response to treatment was defined as the percentage reduction from the screening mean pain score to the "average pain over the last 24 hours" score for week 12 of the double-blind period.
Time Frame	Week 12

Outcome Measure Data

Analysis Population Description

The full analysis population for efficacy (N = 600) was the group of subjects who were randomized and received at least 1 dose of double-blind study drug

Arm/Group Title	OXN Group	Placebo Group
Arm/Group Description	Oxycodone/Naloxone Controlled-release Tablets (OXN) Oxycodone/Naloxone Controlled-release: Oxycodone/Naloxone Controlled-release tablets (10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg) taken orally every 12 hours	Placebo tablets to match OXN Placebo: Placebo tablets to match OXN taken orally every 12 hours
Measure Participants	298	302
Number [participants (responders)]	109 36.6%	75 24.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	OXN Group, Placebo Group
	Comments	Proportion of subjects with a response to treatment that is ≥ 50%
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0018
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Cochran-Mantel-Haenszel test: responder as dependent variable, treatment as explanatory variable, dose at time of randomization as stratifying factor

Adverse Events

Time Frame	Adverse events (AEs) were reported from start of study participation through the period beyond study completion.
Adverse Event Reporting Description	AEs were learned of through spontaneous reports and/or subject interview, or were observed during physical examinations or other safety assessments. Ongoing AEs were followed until resolution or 30 days after last study drug dose. Serious AEs up to 30 days following the last study visit were followed until the AE or sequelae resolved or stabilized.
Arm/Group Title	Open-label Titration OXN		Double-blind Placebo		Double-blind OXN
Arm/Group Description	Oxycodone/Naloxone Controlled-release Tablets (OXN) Oxycodone/Naloxone Controlled-release: Oxycodone/Naloxone Controlled-release tablets (10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg) taken orally every 12 hours		Placebo tablets to match OXN Placebo: Placebo tablets to match OXN taken orally every 12 hours		Oxycodone/Naloxone Controlled-release Tablets (OXN) Oxycodone/Naloxone Controlled-release: Oxycodone/Naloxone Controlled-release tablets (10/5 mg, 20/10 mg, 30/15 mg, 40/20 mg) taken orally every 12 hours
All Cause Mortality
	Open-label Titration OXN		Double-blind Placebo		Double-blind OXN
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Open-label Titration OXN		Double-blind Placebo		Double-blind OXN
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/1095 (1%)		12/302 (4%)		19/298 (6.4%)
Cardiac disorders
Acute myocardial infarction	0/1095 (0%)		2/302 (0.7%)		0/298 (0%)
Angina pectoris	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Atrial fibrillation	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Gastrointestinal disorders
Abdominal pain	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Impaired gastric emptying	1/1095 (0.1%)		0/302 (0%)		0/298 (0%)
Nausea	1/1095 (0.1%)		0/302 (0%)		0/298 (0%)
Oesophageal stenosis	1/1095 (0.1%)		0/302 (0%)		0/298 (0%)
Rectal perforation	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Vomiting	1/1095 (0.1%)		0/302 (0%)		0/298 (0%)
General disorders
Non-cardiac chest pain	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Hepatobiliary disorders
Cholecystitis	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Cholecystitis acute	0/1095 (0%)		1/302 (0.3%)		0/298 (0%)
Cholelithiasis	0/1095 (0%)		1/302 (0.3%)		0/298 (0%)
Infections and infestations
Cellulitis	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Gallbladder empyema	0/1095 (0%)		1/302 (0.3%)		0/298 (0%)
Gangrene	0/1095 (0%)		1/302 (0.3%)		0/298 (0%)
Ludwig angina	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Pneumonia	0/1095 (0%)		1/302 (0.3%)		1/298 (0.3%)
Injury, poisoning and procedural complications
Gun shot wound	0/1095 (0%)		1/302 (0.3%)		0/298 (0%)
Overdose	1/1095 (0.1%)		0/302 (0%)		0/298 (0%)
Investigations
Drug screen positive	5/1095 (0.5%)		1/302 (0.3%)		9/298 (3%)
Hepatic enzyme increased	0/1095 (0%)		1/302 (0.3%)		0/298 (0%)
Metabolism and nutrition disorders
Dehydration	1/1095 (0.1%)		0/302 (0%)		0/298 (0%)
Hypokalaemia	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Musculoskeletal and connective tissue disorders
Arthritis	1/1095 (0.1%)		0/302 (0%)		0/298 (0%)
Systemic lupus erythematosus	0/1095 (0%)		1/302 (0.3%)		0/298 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Nervous system disorders
Syncope	0/1095 (0%)		0/302 (0%)		1/298 (0.3%)
Psychiatric disorders
Drug abuse	3/1095 (0.3%)		0/302 (0%)		0/298 (0%)
Renal and urinary disorders
Renal failure	0/1095 (0%)		1/302 (0.3%)		0/298 (0%)
Social circumstances
Substance abuse	0/1095 (0%)		2/302 (0.7%)		0/298 (0%)
Other (Not Including Serious) Adverse Events
	Open-label Titration OXN		Double-blind Placebo		Double-blind OXN
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	79/1095 (7.2%)		34/302 (11.3%)		41/298 (13.8%)
Gastrointestinal disorders
Nausea	79/1095 (7.2%)		14/302 (4.6%)		25/298 (8.4%)
Investigations
Drug screen positive	23/1095 (2.1%)		20/302 (6.6%)		19/298 (6.4%)

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.