Study to Evaluate the Long-Term Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) in Patients Who Require Opioid Treatment for an Extended Period of Time

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01223365
• Collaborator: (none)
• Enrollment: 330
• Locations: 54
• Arm: 1
• Duration (Months): 23
• Patients Per Site: 6.1
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The primary objective of this study is to evaluate the safety of hydrocodone extended-release tablets when used over a 12-month period in patients with chronic pain, as assessed by adverse events, clinical laboratory results, vital signs measurements, electrocardiogram results, physical examination findings, pure tone audiometry, and concomitant medication usage.

Condition or Disease	Intervention/Treatment	Phase
Chronic Pain	Drug: Hydrocodone ER	Phase 3

Detailed Description

This was a Phase 3, open-label, nonrandomized study that consisted of a screening period, an open label titration period, and a 52 week, long term, open-label treatment period in patients with chronic pain. Patients were eligible to participate in this study if they had completed study C33237/3079 (NCT01240863) (these patients are hereafter referred to as rollover patients) or if they had not participated in study 3079 (these patients are hereafter referred to as either new opioid naïve or new opioid experienced patients).

Study Design

• Study Type: Interventional
• Actual Enrollment: 330 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 12-Month, Open-Label Study to Evaluate the Long-Term Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) at 15 to 90 mg Every 12 Hours in Patients Who Require Opioid Treatment for an Extended Period of Time
• Study Start Date: Oct 1, 2010
• Actual Primary Completion Date: Sep 1, 2012
• Actual Study Completion Date: Sep 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Hydrocodone ER Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of extended-release hydrocodone tablets at dosages of 15, 30, 45, 60, or 90 mg orally every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at the successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.

Drug: Hydrocodone ER; Hydrocodone bitartrate extended-release tablets were administered at doses of 15, 30, 45, 60, and 90 mg orally every 12 hours. During the open-label titration period, doses were adjusted until a stable pain control was achieved. In general, the dose of hydrocodone extended release tablets could be adjusted for efficacy or tolerability, as necessary, at any time during the open-label treatment period; however, participants were required to visit the study center before increasing the dose of study drug.; Other Names: CEP-33237 Hydrocodone bitartrate extended-release

Outcome Measures

Primary Outcome Measures

1. Participants With Adverse Experiences [Day 1 of open-label titration period - Week 52 of the open-label treatment period]

   An adverse event (AE) was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.

2. Participants With Potentially Clinically Significant (PCS) Abnormal Laboratory Values During the Open-Label Treatment Period by Participant Status [Day 1 - Week 52 of the open-label treatment period]

   Data represents participants with PCS abnormal serum chemistry, hematology and urinalysis values. Significance criteria: alanine aminotransferase (ALT): >=3 times the upper limit of normal (ULN). Normal range is 6-43 U/L aspartate aminotransferase (AST): >=3 times ULN. Normal range is 9-36 U/L blood urea nitrogen (BUN): >=10.71 mmol/L creatinine: >=177 μmol/L uric acid: M>=625, F>=506 μmol/L white blood cell count: <=3.0*10^9/L hemoglobin: M<=115, F<=95 g/dL hematocrit: M<0.37, F<0.32 L/L urine blood (hemoglobin): >=2 unit increase from baseline urine glucose: >=2 unit increase from baseline

3. Participants With Potentially Clinically Significant Abnormal Vital Signs Values by Participant Status [Day 1 of open-label titration period - Week 52 of the open-label treatment period]

   Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria Pulse - high: >=120 and increase of >= 15 beats/minute from baseline Pulse - low: <=50 and decrease of >=15 beats/minute Systolic blood pressure - high: >=180 and increase >=20 mmHg Systolic blood pressure - low: <=90 and decrease >=20 mmHg Diastolic blood pressure - high: >=105 and increase of >=15 mmHg Diastolic blood pressure - low: <=50 and decrease of >=15 mmHg

4. Shifts in Electrocardiogram (ECG) Findings From Baseline to Overall Study by Participant Status [Baseline for new participants was between Day -7 and -14 (the study 3080 screening visit); baseline for rollover participants was the last ECG in study 3079. During study ECGs were performed on weeks 24 and 52 of the open-label treatment period]

   A 12-lead ECG was conducted at screening, week 24, and week 52 or at the last postbaseline observation. For rollover participants, the ECG performed at the final visit of study 3079 served as the 1st ECG in study 3080. A qualified physician was responsible for interpreting the ECG. Any ECG finding that was judged by the investigator as a clinically meaningful change (worsening) compared with baseline was considered an adverse event. For overall results, the worst postbaseline finding for the participant was summarized. Results below are formatted as Baseline ECG result - Overall ECG result.

5. Participants With Clinically Significant (CS) Hearing Changes From Baseline in Pure Tone Audiometry Test Results by Patient Status [Baseline for new participants was between Day -7 and -14 (study 3080 screening visit); baseline for rollover participants was the baseline test in study 3079. During study covers both open-label titration and 52-week treatment periods]

   Pure tone audiometry was performed by trained personnel. During the test, the patient wore headphones and was seated in a quiet room; trained personnel manipulated the audiometry equipment to test the patient's hearing. For serial audiograms, the criteria for a clinically significant (CS) hearing change were based on the guidance from the American Speech-Language Hearing Association (ASHA) 1994 (Konrad-Martin et al 2005). These criteria included the following: greater than 20 decibels (dB) pure tone threshold shift at 1 frequency; greater than 10 dB shift at 2 consecutive test frequencies; or threshold response shifting to "no response" at 3 consecutive test frequencies.

Secondary Outcome Measures

1. Participant Global Assessment (PGA) of the Method of Pain Control by Participant Status [Baseline for new participants was Day 1, i.e. the first day of open-label titration. Baseline for rollover participants was the baseline in study 3079. Week 4 (end of titration, start of open-label treatment), Week 52, last visit up to Week 52]

   The PGA of the method of pain control consisted of a asking patients a single question to assess their method of pain control during the previous 24 hours as either poor, fair, good, or excellent (Rothman et al 2009).

2. Participants by Risk Category for Aberrant Drug Misuse Based on the Total Score in the Screener and Opioid Assessment for Patients With Pain - Revised (SOAPP-R) [End of Open-label Titration Period. Weeks 4 and 24 of the Open-label Treatment Period]

   SOAPP-R is a clinician-rated scale used to assess each patient's risk of developing aberrant drug use behaviors while on long term opioid therapy. SOAPP-R consists of 24 questions that address 8 concepts: substance abuse history, medication related behaviors, antisocial behaviors/history, psychosocial problems, psychiatric history, physician patient relationship factors, emotional attachment to pain medications, and personal care and lifestyle issues (Butler et al 2008). Each question is answered using a 5 point Likert-like scale, with 0=never, 1=seldom, 2=sometimes, 3=often, and 4=very often for a total range of 0-96. The higher the overall score, the greater the probability the patient is at risk for displaying aberrant behaviors consistent with drug use. An overall score of 18 or higher is considered positive for predicting aberrant drug related behavior, therefore the reported risk categories are <18 and <=18. Results indicate timeframe followed by risk cat

3. Addiction Behavior Checklist (ABC) Total Scores During Both the Open-Label Titration and Open-Label Treatment Periods by Participant Status [Baseline for new participants was Day 1 of open-label titration; rollover participants baseline was in study 3079. End of Open-label Titration: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 40, 44, 48, 52 and last visit up to week 52]

   The ABC was a clinician rated scale that consisted of a brief (21 item) questionnaire designed to track behaviors characteristic of addiction related to prescription opioid medications in chronic pain populations. Items were focused on observable behaviors noted both during and between clinic visits. Each affirmative response was counted as 1 point, and points were added to calculate the total score. All but 1 of the 21 items (the provider's impression) was used in calculating the total score, consequently resulting in scores ranging from 0 to 20 (0=no addiction-related behaviors seen and higher scores indicating an increasing number of addition-related behaviors seen). Participants with a total score of 3 or greater were classified as exhibiting inappropriate opioid use during the study.

4. Current Opioid Misuse Measure (COMM) Scores During Both the Open-Label Titration and Open-Label Treatment Periods by Participant Status [Baseline for new participants was Day 1 of open-label titration; rollover participants baseline was in study 3079. End of Open-label Titration Period. Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 40, 44, 48, 52 and last visit up to week 52]

   The COMM was a clinician-rated scale developed as a brief self-report measure of current aberrant drug-related behavior for patients with chronic pain who were already on long-term opioid therapy. A total score was calculated as the sum of the 17 questions. The total score ranged from 0 to 68. A score of 0 indicates no aberrant drug-related behaviors were seen. Patients with a total score of 9 or greater were classified as exhibiting aberrant drug-related behavior.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• The patient must be willing and able to successfully self-administer the study drug, comply with study restrictions, and return to the clinic for scheduled study visits as specified in this protocol.

• The patient has either completed Cephalon study 3079 or has chronic pain of at least 3 months duration prior to entering this study associated with any of the following conditions: diabetic peripheral neuropathy, postherpetic neuralgia, traumatic injury, complex regional pain syndrome, back pain, neck pain, osteoarthritis, or rheumatoid arthritis. Patients with other painful conditions may qualify for the study with permission from the Cephalon medical monitor or designee.

• Those patients who completed the 12-week, double-blind, placebo-controlled, randomized study (study 3079) and are willing to re-titrate study drug to an effective dose of hydrocodone extended-release tablets are eligible to enter this study.

• The patient is able to speak English, willing to provide written informed consent, and sign a written opioid agreement, to participate in this study.

• The patient is 18 through 80 years of age (inclusive) at the time of entering this or the previous study (study 3079).

• Women of childbearing potential (not surgically sterile or 2 years postmenopausal), must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after participation in the study, and have a negative pregnancy test at screening.

Exclusion Criteria:

• Patients who were enrolled in study 3079 but did not complete the 12-week, double-blind, placebo-controlled, randomized study may not be enrolled into this study.

• The patient has known or suspected hypersensitivities, allergies, or other contraindications to the study drug or its excipients.

• The patient has a recent history (within 5 years) or current evidence of alcohol or other substance abuse.

• The patient has a medical or psychiatric condition/disease that, in the opinion of the investigator, would compromise collected data.

• The patient is taking a total (i.e., including around-the clock [ATC] and rescue medications) of more than 135 mg/day of oxycodone or equivalent for 14 days prior to screening.

• The patient has a history of suicidality.

• The patient has a diagnosis of chronic headache or migraine as the primary painful condition under study.

• The patient is expected to have surgery during the study and it is anticipated that the surgery will alleviate the patient's pain.

• The patient is pregnant or lactating.

• The patient has active malignancy.

• The patient has human immunodeficiency virus (HIV).

• In the judgment of the investigator, the patient has any clinically significant deviation from normal in the physical examination and/or clinical laboratory test values.

• The patient has cardiopulmonary disease that would, in the opinion of the investigator, significantly increase the risk of treatment with potent synthetic opioids.

• The patient has participated in a study involving an investigational drug in the previous 30 days (excluding those who participated in study 3079).

• The patient has received a monoamine oxidase inhibitor (MAOI) within 14 days before the first treatment with study drug.

• The patient has any other medical condition or is receiving concomitant medication/therapy (e.g., regional nerve block) that would, in the opinion of the investigator, compromise the patient's safety or compliance with the study protocol, or compromise collected data.

• The patient is involved in active litigation in regard to the chronic pain currently being treated.

• The patient has a positive urine drug screen (UDS) for an illicit substance or medication not prescribed by the physician currently treating the chronic pain.

• The investigator feels that the patient is not suitable for the study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Horizon Research Group, LLC	Mobile	Alabama	United States
2	Physician Alliance Research Center	Anaheim	California	United States
3	Adam D. Karns, MD	Beverly Hills	California	United States
4	Associated Pharmaceutical Research Center, Inc.	Buena Park	California	United States
5	Providence Clinical Research	Burbank	California	United States
6	Research Center of Fresno, Inc.	Fresno	California	United States
7	Pacific Coast Pain Management Center	Laguna Hills	California	United States
8	South Orange County Surgical Medical Group	Laguna Hills	California	United States
9	Accelovance, Inc.	San Diego	California	United States
10	Bayview Research Group, LLC	Valley Village	California	United States
11	Clinical Research of West Florida, Inc.	Clearwater	Florida	United States
12	Avail Clinical Research, LLC	DeLand	Florida	United States
13	Compass Research, LLC	Orlando	Florida	United States
14	Sarasota Pain Medicine Research LLC	Sarasota	Florida	United States
15	Gold Coast Research LLC	Weston	Florida	United States
16	Drug Studies America	Marietta	Georgia	United States
17	Georgia Institute for Clinical Research, LLC	Marietta	Georgia	United States
18	Taylor Research, LLC	Marietta	Georgia	United States
19	Better Health Clinical Research, Inc.	Newnan	Georgia	United States
20	Millennium Pain Center	Bloomington	Illinois	United States
21	Rehabilitation Associates of Indiana	Indianapolis	Indiana	United States
22	International Clinical Research, Inc.	Overland Park	Kansas	United States
23	Community Research	Crestview Hills	Kentucky	United States
24	Willis Knighton River Cities Clinical Research Center	Shreveport	Louisiana	United States
25	MidAtlantic Pain Medicine Center	Pikesville	Maryland	United States
26	Beacon Clinical Research, LLC	Brockton	Massachusetts	United States
27	HealthCare Research	Florissant	Missouri	United States
28	Sundance Clinical Research, LLC	Saint Louis	Missouri	United States
29	Meridian Clinical Research	Omaha	Nebraska	United States
30	Clinical Research Center of Nevada	Las Vegas	Nevada	United States
31	Advanced Pain Consultants	Voorhees	New Jersey	United States
32	Upstate Clinical Research Associates	Williamsville	New York	United States
33	Wake Research Associates	Raleigh	North Carolina	United States
34	Sterling Research Group, Ltd.	Cincinnati	Ohio	United States
35	Columbus Clinical Research	Columbus	Ohio	United States
36	SP Research	Oklahoma City	Oklahoma	United States
37	Pain Research of Oregon	Eugene	Oregon	United States
38	Summit Research Network Inc.	Portland	Oregon	United States
39	Brandywine Clinical Research	Downingtown	Pennsylvania	United States
40	AMH Feasterville Family Health Care Center	Feasterville-Trevose	Pennsylvania	United States
41	Tipton Medical and Diagnostic Center	Tipton	Pennsylvania	United States
42	Clinical Research Center of Reading, LLP	West Reading	Pennsylvania	United States
43	Omega Medical Research	Warwick	Rhode Island	United States
44	Greenville Pharmaceutical Research	Greenville	South Carolina	United States
45	Trident Institute of Medical Research, LLC	North Charleston	South Carolina	United States
46	S. Carolina Pharmaceutical Research	Spartanburg	South Carolina	United States
47	KRK Medical Research	Dallas	Texas	United States
48	Radiant Research	Dallas	Texas	United States
49	Renaissance Clinical Research & Hypertension of Texas, PLLC	Dallas	Texas	United States
50	Medstar Clinical Research	Houston	Texas	United States
51	Benchmark Research	San Angelo	Texas	United States
52	DCT-Sugarland, LLC dba Discovery Clinical Trials	Sugar Land	Texas	United States
53	Hillcrest Family Health Centers	Waco	Texas	United States
54	Aspen Clinical Research, LLC	Orem	Utah	United States

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Sponsor's Medical Expert, MD, Cephalon

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT01223365
• Other Study ID Numbers: C33237/3080
• First Posted: Oct 19, 2010
• Last Update Posted: Jun 5, 2017
• Last Verified: May 1, 2017

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: moderate to severe pain; diabetic peripheral neuropathy; postherpetic neuralgia; traumatic injury; complex regional pain syndrome; back pain; neck pain; osteoarthritis; rheumatoid arthritis
• Additional relevant MeSH terms: Chronic Pain; Hydrocodone

Study Results

Participant Flow

Recruitment Details	365 patients with chronic pain were screened for enrollment into this study: 25 patients were excluded on the basis of exclusion criteria, 6 withdrew consent, 2 were lost to follow up before the baseline visit, 1 patient did not meet an inclusion criteria, and 1 patient had an opioid violation because of self increasing analgesic medication.
Pre-assignment Detail	330 enrolled patients came from 61 centers in the US: 166 rolled-over from study 3079, 52 were new opioid-naïve participants and 112 were new opioid-experienced participants. One enrolled patient was withdrawn before taking any study drug.

Arm/Group Title	Hydrocodone ER
Arm/Group Description	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at the successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Period Title: Open-label Titration Period
STARTED	330
Safety Analysis Set	329
Achieved Stable Pain Relief	294
COMPLETED	291
NOT COMPLETED	39
Period Title: Open-label Titration Period
STARTED	291
COMPLETED	189
NOT COMPLETED	102

Baseline Characteristics

Arm/Group Title	Hydrocodone ER
Arm/Group Description	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at th3 successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Overall Participants	330
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	54.4 (11.51)
Sex: Female, Male (Count of Participants)
Female	197 59.7%
Male	133 40.3%
Race/Ethnicity, Customized (Count of Participants)
White	260 78.8%
Black	66 20%
Asian	2 0.6%
Pacific Islander	1 0.3%
Other	1 0.3%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	10 3%
Non-Hispanic and non-Latino	319 96.7%
Unknown	1 0.3%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	95.6 (23.97)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.7 (10.57)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	33.1 (7.38)
Type of Pain (Count of Participants)
Low back pain	113 34.2%
Back pain	103 31.2%
Osteoarthritis	82 24.8%
Diabetic peripheral neuropathy	12 3.6%
Postherpetic neuralgia	0 0%
Traumatic injury	3 0.9%
Neck pain	10 3%
Complex regional pain syndrome	3 0.9%
Rheumatoid arthritis	2 0.6%
Other	2 0.6%
Duration Since Diagnosis (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	12.3 (9.54)
Duration on Opioid Therapy (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.4 (5.27)

Outcome Measures

1. Primary Outcome

Title	Participants With Adverse Experiences
Description	An adverse event (AE) was defined in the protocol as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Relation of AE to treatment was determined by the investigator. Serious AEs include death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, OR an important medical event that jeopardized the patient and required medical intervention to prevent the previously listed serious outcomes.
Time Frame	Day 1 of open-label titration period - Week 52 of the open-label treatment period

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	New Opioid Naïve Subpopulation	New Opioid Experienced Subpopulation	Rollover Subpopulation	Total Hydrocodone ER
Arm/Group Description	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid naïve (ie, those who were taking less than 10 mg/day of oxycodone or equivalent for the 14 days immediately before screening).	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid experienced (ie, those who were taking 10 mg/day or more of oxycodone or equivalent, but not more than 135 mg/day, including around-the-clock medication and rescue medications, for the 14 days immediately before screening).	The subpopulation of participants who completed study C33237/3079 (NCT01240863) and 'rolled over' to participate in this study.	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at a successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Measure Participants	52	112	165	329
Any adverse event	51 15.5%	98 NaN	135 NaN	284 NaN
Treatment-related adverse event	41 12.4%	69 NaN	63 NaN	173 NaN
Death	0 0%	1 NaN	1 NaN	2 NaN
Serious adverse event	4 1.2%	16 NaN	7 NaN	27 NaN
Withdrawals from treatment due to adverse event	18 5.5%	24 NaN	20 NaN	62 NaN

2. Primary Outcome

Title	Participants With Potentially Clinically Significant (PCS) Abnormal Laboratory Values During the Open-Label Treatment Period by Participant Status
Description	Data represents participants with PCS abnormal serum chemistry, hematology and urinalysis values. Significance criteria: alanine aminotransferase (ALT): >=3 times the upper limit of normal (ULN). Normal range is 6-43 U/L aspartate aminotransferase (AST): >=3 times ULN. Normal range is 9-36 U/L blood urea nitrogen (BUN): >=10.71 mmol/L creatinine: >=177 μmol/L uric acid: M>=625, F>=506 μmol/L white blood cell count: <=3.0*10^9/L hemoglobin: M<=115, F<=95 g/dL hematocrit: M<0.37, F<0.32 L/L urine blood (hemoglobin): >=2 unit increase from baseline urine glucose: >=2 unit increase from baseline
Time Frame	Day 1 - Week 52 of the open-label treatment period

Outcome Measure Data

Analysis Population Description

Posttitration Safety Analysis set. The posttitration safety analysis set included all patients who successfully completed the open label titration period and received 1 or more doses of study drug treatment in the open label treatment period.

Arm/Group Title	New Opioid Naïve Subpopulation	New Opioid Experienced Subpopulation	Rollover Subpopulation	Total Hydrocodone ER
Arm/Group Description	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid naïve (ie, those who were taking less than 10 mg/day of oxycodone or equivalent for the 14 days immediately before screening).	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid experienced (ie, those who were taking 10 mg/day or more of oxycodone or equivalent, but not more than 135 mg/day, including around-the-clock medication and rescue medications, for the 14 days immediately before screening).	The subpopulation of participants who completed study C33237/3079 (NCT01240863) and 'rolled over' to participate in this study.	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at a successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Measure Participants	42	92	157	291
ALT	0 0%	2 NaN	1 NaN	3 NaN
AST	0 0%	2 NaN	0 NaN	2 NaN
BUN	0 0%	3 NaN	5 NaN	8 NaN
Creatinine	0 0%	1 NaN	1 NaN	2 NaN
Uric acid	1 0.3%	4 NaN	3 NaN	8 NaN
White blood cell count	0 0%	1 NaN	0 NaN	1 NaN
Hemoglobin	1 0.3%	3 NaN	3 NaN	7 NaN
Hematocrit	2 0.6%	6 NaN	6 NaN	14 NaN
Urine blood	1 0.3%	4 NaN	2 NaN	7 NaN
Urine glucose	2 0.6%	2 NaN	5 NaN	9 NaN

3. Primary Outcome

Title	Participants With Potentially Clinically Significant Abnormal Vital Signs Values by Participant Status
Description	Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria Pulse - high: >=120 and increase of >= 15 beats/minute from baseline Pulse - low: <=50 and decrease of >=15 beats/minute Systolic blood pressure - high: >=180 and increase >=20 mmHg Systolic blood pressure - low: <=90 and decrease >=20 mmHg Diastolic blood pressure - high: >=105 and increase of >=15 mmHg Diastolic blood pressure - low: <=50 and decrease of >=15 mmHg
Time Frame	Day 1 of open-label titration period - Week 52 of the open-label treatment period

Outcome Measure Data

Analysis Population Description

Safety analysis set. One rollover participant did not have vital signs values.

Arm/Group Title	New Opioid Naïve Subpopulation	New Opioid Experienced Subpopulation	Rollover Subpopulation	Total Hydrocodone ER
Arm/Group Description	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid naïve (ie, those who were taking less than 10 mg/day of oxycodone or equivalent for the 14 days immediately before screening).	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid experienced (ie, those who were taking 10 mg/day or more of oxycodone or equivalent, but not more than 135 mg/day, including around-the-clock medication and rescue medications, for the 14 days immediately before screening).	The subpopulation of participants who completed study C33237/3079 (NCT01240863) and 'rolled over' to participate in this study.	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at a successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Measure Participants	52	112	164	328
Pulse - high	0 0%	2 NaN	0 NaN	2 NaN
Pulse - low	1 0.3%	0 NaN	5 NaN	6 NaN
Systolic blood pressure - high	1 0.3%	0 NaN	2 NaN	3 NaN
Systolic blood pressure - low	0 0%	4 NaN	7 NaN	11 NaN
Diastolic blood pressure - high	3 0.9%	0 NaN	3 NaN	6 NaN
Diastolic blood pressure - low	1 0.3%	2 NaN	3 NaN	6 NaN

4. Primary Outcome

Title	Shifts in Electrocardiogram (ECG) Findings From Baseline to Overall Study by Participant Status
Description	A 12-lead ECG was conducted at screening, week 24, and week 52 or at the last postbaseline observation. For rollover participants, the ECG performed at the final visit of study 3079 served as the 1st ECG in study 3080. A qualified physician was responsible for interpreting the ECG. Any ECG finding that was judged by the investigator as a clinically meaningful change (worsening) compared with baseline was considered an adverse event. For overall results, the worst postbaseline finding for the participant was summarized. Results below are formatted as Baseline ECG result - Overall ECG result.
Time Frame	Baseline for new participants was between Day -7 and -14 (the study 3080 screening visit); baseline for rollover participants was the last ECG in study 3079. During study ECGs were performed on weeks 24 and 52 of the open-label treatment period

Outcome Measure Data

Analysis Population Description

Post-titration Safety analysis set. Only those participants with both baseline and visit electrocardiogram findings were summarized.

Arm/Group Title	New Opioid Naïve Subpopulation	New Opioid Experienced Subpopulation	Rollover Subpopulation	Total Hydrocodone ER
Arm/Group Description	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid naïve (ie, those who were taking less than 10 mg/day of oxycodone or equivalent for the 14 days immediately before screening).	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid experienced (ie, those who were taking 10 mg/day or more of oxycodone or equivalent, but not more than 135 mg/day, including around-the-clock medication and rescue medications, for the 14 days immediately before screening).	The subpopulation of participants who completed study C33237/3079 (NCT01240863) and 'rolled over' to participate in this study.	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at a successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Measure Participants	41	89	150	280
Normal baseline - Normal overall	18 5.5%	33 NaN	43 NaN	94 NaN
Normal baseline - Abnormal overall	8 2.4%	17 NaN	35 NaN	60 NaN
Abnormal baseline - Normal overall	0 0%	7 NaN	18 NaN	25 NaN
Abnormal baseline - Abnormal overall	15 4.5%	32 NaN	54 NaN	101 NaN

5. Primary Outcome

Title	Participants With Clinically Significant (CS) Hearing Changes From Baseline in Pure Tone Audiometry Test Results by Patient Status
Description	Pure tone audiometry was performed by trained personnel. During the test, the patient wore headphones and was seated in a quiet room; trained personnel manipulated the audiometry equipment to test the patient's hearing. For serial audiograms, the criteria for a clinically significant (CS) hearing change were based on the guidance from the American Speech-Language Hearing Association (ASHA) 1994 (Konrad-Martin et al 2005). These criteria included the following: greater than 20 decibels (dB) pure tone threshold shift at 1 frequency; greater than 10 dB shift at 2 consecutive test frequencies; or threshold response shifting to "no response" at 3 consecutive test frequencies.
Time Frame	Baseline for new participants was between Day -7 and -14 (study 3080 screening visit); baseline for rollover participants was the baseline test in study 3079. During study covers both open-label titration and 52-week treatment periods

Outcome Measure Data

Analysis Population Description

Safety analysis set. The endpoint value is from the post-titration safety set (n=42, 92, 157, 291)

Arm/Group Title	New Opioid Naïve Subpopulation	New Opioid Experienced Subpopulation	Rollover Subpopulation	Total Hydrocodone ER
Arm/Group Description	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid naïve (ie, those who were taking less than 10 mg/day of oxycodone or equivalent for the 14 days immediately before screening).	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid experienced (ie, those who were taking 10 mg/day or more of oxycodone or equivalent, but not more than 135 mg/day, including around-the-clock medication and rescue medications, for the 14 days immediately before screening).	The subpopulation of participants who completed study C33237/3079 (NCT01240863) and 'rolled over' to participate in this study.	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at a successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Measure Participants	52	112	165	329
>=1 CS value during study	10 3%	30 NaN	36 NaN	76 NaN
>=1 CS value during open-label titration period	4 1.2%	14 NaN	4 NaN	22 NaN
>=1 CS value at endpoint	2 0.6%	8 NaN	13 NaN	23 NaN

6. Secondary Outcome

Title	Participant Global Assessment (PGA) of the Method of Pain Control by Participant Status
Description	The PGA of the method of pain control consisted of a asking patients a single question to assess their method of pain control during the previous 24 hours as either poor, fair, good, or excellent (Rothman et al 2009).
Time Frame	Baseline for new participants was Day 1, i.e. the first day of open-label titration. Baseline for rollover participants was the baseline in study 3079. Week 4 (end of titration, start of open-label treatment), Week 52, last visit up to Week 52

Outcome Measure Data

Analysis Population Description

Full analysis set included all patients in the safety analysis set who had at least 1 postbaseline efficacy assessment. Participants contributing to each time point are listed in the time point label.

Arm/Group Title	New Opioid Naïve Subpopulation	New Opioid Experienced Subpopulation	Rollover Subpopulation	Total Hydrocodone ER
Arm/Group Description	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid naïve (ie, those who were taking less than 10 mg/day of oxycodone or equivalent for the 14 days immediately before screening).	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid experienced (ie, those who were taking 10 mg/day or more of oxycodone or equivalent, but not more than 135 mg/day, including around-the-clock medication and rescue medications, for the 14 days immediately before screening).	The subpopulation of participants who completed study C33237/3079 (NCT01240863) and 'rolled over' to participate in this study.	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at a successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Measure Participants	42	92	157	291
Baseline: Poor	18 5.5%	10 NaN	49 NaN	77 NaN
Baseline: Fair	14 4.2%	55 NaN	71 NaN	140 NaN
Baseline: Good	1 0.3%	18 NaN	29 NaN	48 NaN
Baseline: Excellent	1 0.3%	3 NaN	3 NaN	7 NaN
Week 4: Poor	2 0.6%	1 NaN	2 NaN	5 NaN
Week 4: Fair	5 1.5%	17 NaN	27 NaN	49 NaN
Week 4: Good	20 6.1%	54 NaN	94 NaN	168 NaN
Week 4: Excellent	13 3.9%	15 NaN	27 NaN	55 NaN
Week 52: Poor	0 0%	2 NaN	2 NaN	4 NaN
Week 52: Fair	3 0.9%	9 NaN	18 NaN	30 NaN
Week 52: Good	17 5.2%	36 NaN	62 NaN	115 NaN
Week 52: Excellent	8 2.4%	10 NaN	21 NaN	39 NaN
Endpoint: Poor	3 0.9%	6 NaN	8 NaN	17 NaN
Endpoint: Fair (n=42, 92, 157, 291)	7 2.1%	21 NaN	27 NaN	55 NaN
Endpoint: Good	21 6.4%	52 NaN	93 NaN	166 NaN
Endpoint: Excellent	11 3.3%	13 NaN	29 NaN	53 NaN

7. Secondary Outcome

Title	Participants by Risk Category for Aberrant Drug Misuse Based on the Total Score in the Screener and Opioid Assessment for Patients With Pain - Revised (SOAPP-R)
Description	SOAPP-R is a clinician-rated scale used to assess each patient's risk of developing aberrant drug use behaviors while on long term opioid therapy. SOAPP-R consists of 24 questions that address 8 concepts: substance abuse history, medication related behaviors, antisocial behaviors/history, psychosocial problems, psychiatric history, physician patient relationship factors, emotional attachment to pain medications, and personal care and lifestyle issues (Butler et al 2008). Each question is answered using a 5 point Likert-like scale, with 0=never, 1=seldom, 2=sometimes, 3=often, and 4=very often for a total range of 0-96. The higher the overall score, the greater the probability the patient is at risk for displaying aberrant behaviors consistent with drug use. An overall score of 18 or higher is considered positive for predicting aberrant drug related behavior, therefore the reported risk categories are <18 and <=18. Results indicate timeframe followed by risk cat
Time Frame	End of Open-label Titration Period. Weeks 4 and 24 of the Open-label Treatment Period

Outcome Measure Data

Analysis Population Description

Safety analysis set

Arm/Group Title	New Opioid Naïve Subpopulation	New Opioid Experienced Subpopulation	Rollover Subpopulation	Total Hydrocodone ER
Arm/Group Description	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid naïve (ie, those who were taking less than 10 mg/day of oxycodone or equivalent for the 14 days immediately before screening).	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid experienced (ie, those who were taking 10 mg/day or more of oxycodone or equivalent, but not more than 135 mg/day, including around-the-clock medication and rescue medications, for the 14 days immediately before screening).	The subpopulation of participants who completed study C33237/3079 (NCT01240863) and 'rolled over' to participate in this study.	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at a successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Measure Participants	52	112	165	329
End of Open-Label Titration: >=18	0 0%	0 NaN	0 NaN	0 NaN
End of Open-Label Titration: <18	0 0%	0 NaN	2 NaN	2 NaN
Week 4: >=18	1 0.3%	12 NaN	3 NaN	16 NaN
Week 4: <18	39 11.8%	73 NaN	134 NaN	246 NaN
Week 24: >=18	0 0%	0 NaN	0 NaN	0 NaN
Week 24: <18	0 0%	0 NaN	1 NaN	1 NaN

8. Secondary Outcome

Title	Addiction Behavior Checklist (ABC) Total Scores During Both the Open-Label Titration and Open-Label Treatment Periods by Participant Status
Description	The ABC was a clinician rated scale that consisted of a brief (21 item) questionnaire designed to track behaviors characteristic of addiction related to prescription opioid medications in chronic pain populations. Items were focused on observable behaviors noted both during and between clinic visits. Each affirmative response was counted as 1 point, and points were added to calculate the total score. All but 1 of the 21 items (the provider's impression) was used in calculating the total score, consequently resulting in scores ranging from 0 to 20 (0=no addiction-related behaviors seen and higher scores indicating an increasing number of addition-related behaviors seen). Participants with a total score of 3 or greater were classified as exhibiting inappropriate opioid use during the study.
Time Frame	Baseline for new participants was Day 1 of open-label titration; rollover participants baseline was in study 3079. End of Open-label Titration: Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 40, 44, 48, 52 and last visit up to week 52

Outcome Measure Data

Analysis Population Description

Post-titration Safety Analysis set

Arm/Group Title	New Opioid Naïve Subpopulation	New Opioid Experienced Subpopulation	Rollover Subpopulation	Total Hydrocodone ER
Arm/Group Description	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid naïve (ie, those who were taking less than 10 mg/day of oxycodone or equivalent for the 14 days immediately before screening).	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid experienced (ie, those who were taking 10 mg/day or more of oxycodone or equivalent, but not more than 135 mg/day, including around-the-clock medication and rescue medications, for the 14 days immediately before screening).	The subpopulation of participants who completed study C33237/3079 (NCT01240863) and 'rolled over' to participate in this study.	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at a successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Measure Participants	42	92	157	291
Baseline	0.1 (0.40)	0.1 (0.46)	0.2 (0.60)	0.2 (0.53)
End of Titration	0.1 (0.22)	0.0 (0.15)	0.1 (0.38)	0.1 (0.31)
Week 4	0.2 (0.43)	0.2 (0.47)	0.1 (0.39)	0.1 (0.42)
Week 8	0.1 (0.41)	0.2 (0.42)	0.1 (0.38)	0.1 (0.40)
Week 12	0.2 (0.51)	0.2 (0.40)	0.1 (0.36)	0.1 (0.39)
Week 16	0.1 (0.34)	0.1 (0.29)	0.2 (0.56)	0.1 (0.47)
Week 20	0.2 (0.46)	0.1 (0.24)	0.2 (0.45)	0.1 (0.40)
Week 24	0.1 (0.26)	0.1 (0.31)	0.1 (0.41)	0.1 (0.36)
Week 28	0.1 (0.41)	0.1 (0.27)	0.1 (0.42)	0.1 (0.38)
Week 32	0.2 (0.60)	0.0 (0.25)	0.1 (0.42)	0.1 (0.41)
Week 36	0.1 (0.59)	0.1 (0.43)	0.1 (0.41)	0.1 (0.44)
Week 40	0.1 (0.31)	0.1 (0.25)	0.1 (0.46)	0.1 (0.38)
Week 44	0.1 (0.26)	0.1 (0.31)	0.1 (0.44)	0.1 (0.38)
Week 48	0.0 (0.19)	0.0 (0.13)	0.1 (0.41)	0.1 (0.32)
Week 52	0.1 (0.45)	0.1 (0.23)	0.1 (0.41)	0.1 (0.37)
Endpoint	0.2 (0.52)	0.2 (0.60)	0.2 (0.59)	0.2 (0.58)

9. Secondary Outcome

Title	Current Opioid Misuse Measure (COMM) Scores During Both the Open-Label Titration and Open-Label Treatment Periods by Participant Status
Description	The COMM was a clinician-rated scale developed as a brief self-report measure of current aberrant drug-related behavior for patients with chronic pain who were already on long-term opioid therapy. A total score was calculated as the sum of the 17 questions. The total score ranged from 0 to 68. A score of 0 indicates no aberrant drug-related behaviors were seen. Patients with a total score of 9 or greater were classified as exhibiting aberrant drug-related behavior.
Time Frame	Baseline for new participants was Day 1 of open-label titration; rollover participants baseline was in study 3079. End of Open-label Titration Period. Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36 40, 44, 48, 52 and last visit up to week 52

Outcome Measure Data

Analysis Population Description

Post titration Safety Analysis set

Arm/Group Title	New Opioid Naïve Subpopulation	New Opioid Experienced Subpopulation	Rollover Subpopulation	Total Hydrocodone ER
Arm/Group Description	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid naïve (ie, those who were taking less than 10 mg/day of oxycodone or equivalent for the 14 days immediately before screening).	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid experienced (ie, those who were taking 10 mg/day or more of oxycodone or equivalent, but not more than 135 mg/day, including around-the-clock medication and rescue medications, for the 14 days immediately before screening).	The subpopulation of participants who completed study C33237/3079 (NCT01240863) and 'rolled over' to participate in this study.	Participants were titrated (or re-titrated for roll-over participants) at escalating dosages of hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours until deemed successful for managing their pain during the open-label titration period. Once a successful dose was identified, participants entered the 52 week open-label treatment period in which hydrocodone ER was administered at a successful dose (15, 30, 45, 60, or 90 mg) every 12 hours.
Measure Participants	42	92	157	291
Baseline	5.1 (5.29)	5.4 (4.61)	3.7 (3.70)	4.4 (4.31)
End of Titration	3.8 (3.37)	4.0 (3.66)	2.1 (2.74)	3.0 (3.26)
Week 4	3.2 (3.06)	3.7 (3.70)	2.3 (2.83)	2.9 (3.21)
Week 8	2.4 (2.44)	3.9 (4.12)	2.4 (2.96)	2.8 (3.36)
Week 12	3.1 (3.12)	4.2 (3.99)	2.4 (2.71)	3.1 (3.28)
Week 16	2.4 (1.98)	4.0 (4.84)	2.3 (2.82)	2.9 (3.53)
Week 20	2.6 (2.49)	3.5 (3.78)	2.1 (2.80)	2.6 (3.13)
Week 24	2.6 (2.66)	3.9 (4.14)	2.4 (3.04)	2.9 (3.42)
Week 28	2.1 (2.10)	3.3 (3.66)	2.3 (2.91)	2.6 (3.09)
Week 32	2.3 (1.84)	2.8 (3.07)	2.0 (2.62)	2.3 (2.69)
Week 36	2.9 (2.44)	3.2 (3.35)	2.3 (3.30)	2.7 (3.22)
Week 40	2.8 (3.21)	3.0 (3.20)	2.1 (2.97)	2.5 (3.09)
Week 44	2.3 (1.90)	2.7 (2.86)	2.2 (3.41)	2.4 (3.06)
Week 48	2.4 (2.57)	3.0 (3.98)	2.3 (3.19)	2.5 (3.37)
Week 52	2.4 (2.39)	3.0 (3.30)	2.3 (3.05)	2.5 (3.04)
Endpoint	3.5 (3.74)	4.2 (4.41)	2.5 (3.25)	3.2 (3.78)

Adverse Events

Time Frame	Day 1 of Open-label Titration period - Week 52 of the Open-label Treatment period
Arm/Group Title	New Opioid Naïve Subpopulation		New Opioid Experienced Subpopulation		Rollover Subpopulation
Arm/Group Description	The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid naïve (ie, those who were taking less than 10 mg/day of oxycodone or equivalent for the 14 days immediately before screening).		The subpopulation of participants who enrolled in this study without previous participation in study C33237/3079 (NCT01240863) and were categorized as opioid experienced (ie, those who were taking 10 mg/day or more of oxycodone or equivalent, but not more than 135 mg/day, including around-the-clock medication and rescue medications, for the 14 days immediately before screening).		The subpopulation of participants who completed study C33237/3079 (NCT01240863) and 'rolled over' to participate in this study.
All Cause Mortality
	New Opioid Naïve Subpopulation		New Opioid Experienced Subpopulation		Rollover Subpopulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	New Opioid Naïve Subpopulation		New Opioid Experienced Subpopulation		Rollover Subpopulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/52 (7.7%)		16/112 (14.3%)		7/165 (4.2%)
Blood and lymphatic system disorders
Thrombocytopenia	1/52 (1.9%)	1	0/112 (0%)	0	0/165 (0%)	0
Cardiac disorders
Cardiac arrest	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
Coronary artery disease	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Gastrointestinal disorders
Abdominal adhesions	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
Gastritis	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
Small intestinal obstruction	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
General disorders
Death	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Hepatobiliary disorders
Cholecystitis acute	1/52 (1.9%)	1	0/112 (0%)	0	0/165 (0%)	0
Infections and infestations
Appendicitis perforated	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Device related infection	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
Gastroenteritis	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Infected cyst	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Listeria sepsis	1/52 (1.9%)	1	0/112 (0%)	0	0/165 (0%)	0
Lobar pneumonia	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Pneumonia	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Pneumonia cryptococcal	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
Postoperative abscess	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Subcutaneous abscess	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Urosepsis	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Metabolism and nutrition disorders
Dehydration	1/52 (1.9%)	1	1/112 (0.9%)	1	0/165 (0%)	0
Diabetic ketoacidosis	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Hyperkalaemia	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
Musculoskeletal and connective tissue disorders
Osteoarthritis	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer metastatic	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
Colon neoplasm	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Prostate cancer	0/24 (0%)	0	1/44 (2.3%)	1	0/64 (0%)	0
Nervous system disorders
Hemiparesis	1/52 (1.9%)	1	0/112 (0%)	0	0/165 (0%)	0
Hypoaesthesia	1/52 (1.9%)	1	0/112 (0%)	0	0/165 (0%)	0
Lumbar radiculopathy	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
Sedation	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
Speech disorder	1/52 (1.9%)	1	0/112 (0%)	0	0/165 (0%)	0
Syncope	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Tremor	1/52 (1.9%)	1	0/112 (0%)	0	0/165 (0%)	0
Psychiatric disorders
Impulsive behaviour	1/52 (1.9%)	1	0/112 (0%)	0	0/165 (0%)	0
Panic attack	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Renal and urinary disorders
Renal failure	0/52 (0%)	0	0/112 (0%)	0	1/165 (0.6%)	1
Renal failure acute	1/52 (1.9%)	1	1/112 (0.9%)	1	0/165 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Pulmonary oedema	0/52 (0%)	0	1/112 (0.9%)	1	0/165 (0%)	0
Vascular disorders
Deep vein thrombosis	0/52 (0%)	0	2/112 (1.8%)	2	0/165 (0%)	0
Hypotension	1/52 (1.9%)	1	0/112 (0%)	0	0/165 (0%)	0
Other (Not Including Serious) Adverse Events
	New Opioid Naïve Subpopulation		New Opioid Experienced Subpopulation		Rollover Subpopulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	47/52 (90.4%)		83/112 (74.1%)		109/165 (66.1%)
Gastrointestinal disorders
Constipation	19/52 (36.5%)	22	35/112 (31.3%)	45	31/165 (18.8%)	43
Diarrhoea	2/52 (3.8%)	2	8/112 (7.1%)	9	13/165 (7.9%)	19
Nausea	16/52 (30.8%)	20	18/112 (16.1%)	25	28/165 (17%)	36
Vomiting	8/52 (15.4%)	9	7/112 (6.3%)	9	16/165 (9.7%)	17
General disorders
Fatigue	3/52 (5.8%)	3	7/112 (6.3%)	9	6/165 (3.6%)	6
Oedema peripheral	3/52 (5.8%)	3	6/112 (5.4%)	6	7/165 (4.2%)	8
Infections and infestations
Bronchitis	3/52 (5.8%)	3	8/112 (7.1%)	9	6/165 (3.6%)	8
Influenza	5/52 (9.6%)	7	5/112 (4.5%)	5	4/165 (2.4%)	5
Nasopharyngitis	4/52 (7.7%)	4	4/112 (3.6%)	5	10/165 (6.1%)	11
Sinusitis	0/52 (0%)	0	6/112 (5.4%)	11	11/165 (6.7%)	11
Upper respiratory tract infection	5/52 (9.6%)	5	6/112 (5.4%)	7	15/165 (9.1%)	16
Injury, poisoning and procedural complications
Fall	3/52 (5.8%)	3	9/112 (8%)	11	6/165 (3.6%)	9
Musculoskeletal and connective tissue disorders
Arthralgia	2/52 (3.8%)	2	10/112 (8.9%)	12	14/165 (8.5%)	15
Back pain	3/52 (5.8%)	3	7/112 (6.3%)	9	10/165 (6.1%)	13
Muscle spasms	1/52 (1.9%)	1	6/112 (5.4%)	6	8/165 (4.8%)	11
Nervous system disorders
Dizziness	4/52 (7.7%)	4	7/112 (6.3%)	11	6/165 (3.6%)	7
Headache	8/52 (15.4%)	11	20/112 (17.9%)	24	10/165 (6.1%)	12
Mental impairment	3/52 (5.8%)	3	1/112 (0.9%)	1	1/165 (0.6%)	1
Somnolence	9/52 (17.3%)	12	15/112 (13.4%)	16	11/165 (6.7%)	12
Psychiatric disorders
Insomnia	3/52 (5.8%)	3	6/112 (5.4%)	6	7/165 (4.2%)	8
Skin and subcutaneous tissue disorders
Pruritus	1/52 (1.9%)	1	7/112 (6.3%)	9	5/165 (3%)	5
Vascular disorders
Hypertension	4/52 (7.7%)	4	1/112 (0.9%)	1	4/165 (2.4%)	4

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

Sponsor has the right 60 days before submission for publication to review/provide comments. If the Sponsor's review shows that potentially patentable subject matter would be disclosed, publication or public disclosure shall be delayed for up to 90 additional days in order for the Sponsor, or Sponsor's designees, to file the necessary patent applications. In multicenter trials, each PI will postpone single center publications until after disclosure or publication of multicenter data.