Open-Label, Extension Study to Evaluate the Safety of Hydrocodone Bitartrate Extended-Release Tablets

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01922739
• Collaborator: (none)
• Enrollment: 182
• Locations: 61
• Arm: 1
• Duration (Months): 13
• Patients Per Site: 3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a 6-month, nonrandomized, open-label extension study to assess the long-term safety of hydrocodone bitartrate extended-release (ER) tablets in patients with moderate to severe chronic low back pain who require continuous opioid treatment for an extended period of time.

To be eligible for Study 3104, patients were required to have completed the entire double blind treatment period on study drug (either placebo or hydrocodone bitartrate ER tablets) through week 12 of Study 3103 (NCT01789970) and to have met the entry criteria for Study 3104.

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

Detailed Description

Eligible patients from Study 3103 (NCT01789970) were enrolled for participation in this extension study. For these patients, the final study visit in Study 3103 was visit 1 for this study (also referred to as the titration or adjustment baseline visit, depending on whether the patient was enrolled under the original or amended protocol, respectively). The original protocol was amended after 26 patients had been enrolled in the study. Those who were enrolled under the original protocol participated in a double-blind titration period of up to approximately 4 weeks followed by an open-label treatment period of 22 weeks. Those patients who were enrolled under the amended protocol participated in an open-label adjustment period of up to approximately 3 weeks followed by an open-label treatment period of 22 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 182 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A 6-Month, Open-Label, Extension Study to Evaluate the Safety of Hydrocodone Bitartrate Extended-Release Tablets (CEP-33237) at 15 to 90 mg Every 12 Hours for Relief of Moderate to Severe Pain in Patients With Chronic Low Back Pain Who Require Opioid Treatment for an Extended Period of Time
• Study Start Date: Jul 1, 2013
• Actual Primary Completion Date: Aug 1, 2014
• Actual Study Completion Date: Aug 1, 2014

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Hydrocodone ER Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.

Drug: Hydrocodone ER; Participants were instructed to take hydrocodone ER tablets orally with a glass of water on an empty stomach at least 1 hour before or 2 hours after eating.; Other Names: CEP-33237 Hydrocodone bitartrate extended-release tablets ; Drug: Placebo; During the double-blind titration period used in the original protocol, placebo tablets matching each dose of hydrocodone bitartrate ER tablets (active drug) were used to maintain the blind but not for purposes of comparison.

Outcome Measures

Primary Outcome Measures

1. Participants With Adverse Events [Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)]

   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. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. 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 Abnormal Laboratory Values [End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)]

   Data represents participants with potentially clinically significant abnormal serum chemistry, hematology and urinalysis values. Significance criteria: Blood urea nitrogen: >=10.71 mmol/L Creatinine: >=177 μmol/L Uric acid: M>=625, F>=506 μmol/L Aspartate aminotransferase (AST): >=3* upper limit of normal (ULN) Alkaline phosphatase: >=3* upper limit of normal (ULN) Gamma-glutamyl transpeptidase (GGT): >=3* upper limit of normal (ULN) Serum white blood cells: >=20 * 10^9/L Hemoglobin: M<=115, F<=95 g/dL Hematocrit: M<0.37, F<0.32 L/L Eosinophils: >=10.0 % Platelets: <=75 * 10^9/L Absolute neutrophils: <=1.0 * 10^9/L Urinalysis: Glucose, Ketones, and Total Protein: >=2 unit increase from baseline

3. Participants With Potentially Clinically Significant Abnormal Vital Signs Values [Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)]

   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. Participants With Shifts From Normal to Abnormal in Physical Examination Findings [End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)]

   The endpoint visit or early termination visit was an abbreviated exam. Endpoint refers to the last observation carried forward.

5. Shifts From Baseline to Endpoint (Treatment Period) in Electrocardiogram (ECG) Findings [Baseline (final visit for study 3103), End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)]

   A 12-lead ECG was conducted at the final visit for study 3103 which is used as baseline for this study, and at week 22 of the treatment period [or early termination]). A qualified physician at the study center was responsible for providing interpretation of the ECG. Endpoint refers to the last observation carried forward.

6. Participants With Clinically Significant (CS) Hearing Changes From Baseline to the Final Visit in Pure Tone Audiometry Test Results [Baseline was within two weeks of the final study visit in study 3103; during study exam was within two weeks of the end of trial visit for study 3104 (up to study week 26)]

   Pure tone audiometry was performed by trained personnel. Hearing loss was classified in degrees of hearing from normal to profound. This classification was determined by the hearing threshold (or the softest sound detected at a specific frequency). The exact ranges that classified hearing loss depended on the exact technique used during testing and on the patient's age. These values were provided by each audiology laboratory that performed the test. For serial audiograms, the criteria for a clinically significant hearing change were based on guidance from the American Speech Language Hearing Association (ASHA 1994, cited in [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. Change From Baseline to Weeks 2, 6, 10, 14, 18, 22 and Endpoint of the Treatment Period in Daily Worst Pain Intensity (WPI) Scores During the Previous 24 Hours for Each Visit [Baseline (Day 0 of Treatment Period), Weeks 2, 6, 10, 14, 18, 22 and Endpoint during the Open-Label Treatment Period]

   The WPI was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. At each visit, participants selected the number that best described their worst pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control. Endpoint refers to the last observation carried forward.

2. Change From Baseline to Weeks 2, 6, 10, 14, 18, 22 and Endpoint of the Treatment Period in Daily Average Pain Intensity (API) Scores During the Previous 24 Hours for Each Visit [Baseline (Day 0 of Treatment Period), Weeks 2, 6, 10, 14, 18, 22 and Endpoint during the Open-Label Treatment Period]

   The API was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described their average pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control. Endpoint refers to the last observation carried forward.

3. Percentage of Participants Withdrawn From the Study For Lack of Efficacy [Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)]

   Percentage of patients who withdrew from the study for lack of efficacy, as indicated on the early termination form of the case report form (CRF).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

1. Patients must have participated in and completed the entire double-blind treatment period on study drug through the final study visit (week 12) of study 3103.

NOTE: Patients who had a final on-treatment visit (i.e. prior to week 12) are not permitted to participate in study 3104.

1. The patient is able to speak English and is willing to provide written informed consent for study 3104, including re-signing a written opioid agreement, to participate in this study.

2. Women of childbearing potential (not surgically sterile or 2 years postmenopausal) must use a medically accepted method of contraception, 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. Acceptable methods of contraception include barrier method with spermicide, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected) in conjunction with a barrier method. NOTE: A woman will be considered surgically sterile if she has had a tubal ligation, hysterectomy, bilateral salpingo-oophorectomy or bilateral oophorectomy, or hysterectomy with bilateral salpingo-oophorectomy.

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

4. The patient must not participate in any other study involving an investigational agent (excluding those who participated in study 3103) while enrolled in the present study.

Exclusion Criteria:

1. The patient's current source of pain is different from the low back pain the patient was experiencing at entry into study 3103. NOTE: Any additional source of pain for a patient must be discussed with the medical monitor.

2. The patient has current evidence of alcohol or other substance abuse with the exception of nicotine or caffeine.

3. The patient has developed, during study 3103, a medical or psychiatric disease (including suicidality) that, in the opinion of the investigator, would compromise collected data.

4. The patient is expected to have surgery during the study.

5. The patient is pregnant or lactating.

6. The patient has developed an active malignancy (excluding basal cell carcinoma) during study 3103.

7. The patient has known human immunodeficiency virus (HIV).

8. 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.

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

10. The patient is receiving a monoamine oxidase inhibitor (MAOI).

• Other exclusion criteria apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Teva Investigational Site 10412	Birmingham	Alabama	United States
2	Teva Investigational Site 10426	Mobile	Alabama	United States
3	Teva Investigational Site 10436	Montgomery	Alabama	United States
4	Teva Investigational Site 10363	Phoenix	Arizona	United States
5	Teva Investigational Site 10366	Phoenix	Arizona	United States
6	Teva Investigational Site 10437	Tucson	Arizona	United States
7	Teva Investigational Site 10358	Anaheim	California	United States
8	Teva Investigational Site 10408	Bell Gardens	California	United States
9	Teva Investigational Site 10425	Carmichael	California	United States
10	Teva Investigational Site 10390	Cerritos	California	United States
11	Teva Investigational Site 10429	El Cajon	California	United States
12	Teva Investigational Site 10423	Escondido	California	United States
13	Teva Investigational Site 10391	Huntington Park	California	United States
14	Teva Investigational Site 10370	Los Angeles	California	United States
15	Teva Investigational Site 10392	Sherman Oaks	California	United States
16	Teva Investigational Site 10398	Thousand Oaks	California	United States
17	Teva Investigational Site 10428	Torrance	California	United States
18	Teva Investigational Site 10361	Walnut Creek	California	United States
19	Teva Investigational Site 10369	DeLand	Florida	United States
20	Teva Investigational Site 10379	Fort Lauderdale	Florida	United States
21	Teva Investigational Site 10365	Jacksonville	Florida	United States
22	Teva Investigational Site 10445	Leesburg	Florida	United States
23	Teva Investigational Site 10362	Orlando	Florida	United States
24	Teva Investigational Site 10381	Ormond Beach	Florida	United States
25	Teva Investigational Site 10357	Plantation	Florida	United States
26	Teva Investigational Site 10435	Royal Palm Beach	Florida	United States
27	Teva Investigational Site 10432	Columbus	Georgia	United States
28	Teva Investigational Site 10383	Marietta	Georgia	United States
29	Teva Investigational Site 10385	Marietta	Georgia	United States
30	Teva Investigational Site 10444	Newnan	Georgia	United States
31	Teva Investigational Site 10431	Meridian	Idaho	United States
32	Teva Investigational Site 10743	Meridian	Idaho	United States
33	Teva Investigational Site 10411	Chicago	Illinois	United States
34	Teva Investigational Site 10440	Newburgh	Indiana	United States
35	Teva Investigational Site 10419	New Orleans	Louisiana	United States
36	Teva Investigational Site 10359	Shreveport	Louisiana	United States
37	Teva Investigational Site 10389	Fall River	Massachusetts	United States
38	Teva Investigational Site 10388	Bay City	Michigan	United States
39	Teva Investigational Site 10397	Biloxi	Mississippi	United States
40	Teva Investigational Site 10406	Hazelwood	Missouri	United States
41	Teva Investigational Site 10401	Saint Louis	Missouri	United States
42	Teva Investigational Site 10376	Omaha	Nebraska	United States
43	Teva Investigational Site 10399	Las Vegas	Nevada	United States
44	Teva Investigational Site 10409	Berlin	New Jersey	United States
45	Teva Investigational Site 10439	Buffalo	New York	United States
46	Teva Investigational Site 10410	New York	New York	United States
47	Teva Investigational Site 10414	Winston-Salem	North Carolina	United States
48	Teva Investigational Site 10446	Oklahoma City	Oklahoma	United States
49	Teva Investigational Site 10430	Duncansville	Pennsylvania	United States
50	Teva Investigational Site 10386	Mechanicsburg	Pennsylvania	United States
51	Teva Investigational Site 10373	Tipton	Pennsylvania	United States
52	Teva Investigational Site 10405	Austin	Texas	United States
53	Teva Investigational Site 10364	Dallas	Texas	United States
54	Teva Investigational Site 10372	Dallas	Texas	United States
55	Teva Investigational Site 10371	Houston	Texas	United States
56	Teva Investigational Site 10377	Lake Jackson	Texas	United States
57	Teva Investigational Site 10374	Plano	Texas	United States
58	Teva Investigational Site 10378	San Antonio	Texas	United States
59	Teva Investigational Site 10402	Salt Lake City	Utah	United States
60	Teva Investigational Site 10420	Bellevue	Washington	United States
61	Teva Investigational Site 10433	Everett	Washington	United States

Sponsors and Collaborators

• Teva Branded Pharmaceutical Products R&D, Inc.

Investigators

• Study Director: Teva Medical Expert, MD, Teva Branded Pharmaceutical Products R&D, Inc.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Teva Branded Pharmaceutical Products R&D, Inc.
• ClinicalTrials.gov Identifier: NCT01922739
• Other Study ID Numbers: C33237/3104
• First Posted: Aug 14, 2013
• Last Update Posted: Nov 9, 2021
• Last Verified: Nov 1, 2021

• Keywords provided by Teva Branded Pharmaceutical Products R&D, Inc.: low back pain; hydrocodone bitartrate; opioids
• Additional relevant MeSH terms: Back Pain; Low Back Pain; Hydrocodone

Study Results

Participant Flow

Recruitment Details	A total of 183 patients with moderate to severe chronic low back pain completed Study 3103 and were screened and eligible for enrollment into this study. One patient chose not to participate prior to enrollment.
Pre-assignment Detail	Of the 182 participants who enrolled into Study 3104, 26 participants enrolled under the original protocol and 156 participants enrolled under the amended protocol.

Arm/Group Title	Hydrocodone ER
Arm/Group Description	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.
Period Title: Titration/Adjustment Period
STARTED	182
Safety Analysis Set	182
COMPLETED	170
NOT COMPLETED	12
Period Title: Titration/Adjustment Period
STARTED	170
Treatment SAS and FAS	170
COMPLETED	136
NOT COMPLETED	34

Baseline Characteristics

Arm/Group Title	Hydrocodone ER - Opioid Naive	Hydrocodone ER - Opioid Experienced	Total
Arm/Group Description	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-experienced participants were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.	Total of all reporting groups
Overall Participants	109	73	182
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	49.9 (13.30)	55.8 (12.37)	52.3 (13.22)
Sex: Female, Male (Count of Participants)
Female	60 55%	40 54.8%	100 54.9%
Male	49 45%	33 45.2%	82 45.1%
Age Group (Count of Participants)
<=65 years	94 86.2%	53 72.6%	147 80.8%
>65 years	15 13.8%	20 27.4%	35 19.2%
Race (Count of Participants)
White	69 63.3%	58 79.5%	127 69.8%
Black	27 24.8%	12 16.4%	39 21.4%
Asian	9 8.3%	1 1.4%	10 5.5%
American Indian or Alaskan Native	2 1.8%	1 1.4%	3 1.6%
Pacific Islander	1 0.9%	0 0%	1 0.5%
Other	1 0.9%	1 1.4%	2 1.1%
Ethnicity (Count of Participants)
Hispanic or Latino	24 22%	4 5.5%	28 15.4%
Non-Hispanic and non-Latino	85 78%	69 94.5%	154 84.6%
Weight (kg) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg]	94.2 (24.56)	94.2 (25.07)	94.2 (24.69)
Height (cm) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [cm]	169.3 (10.77)	172.1 (11.18)	170.4 (10.99)
Body Mass Index (kg/m^2) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [kg/m^2]	32.9 (8.41)	31.8 (8.27)	32.5 (8.35)
Duration Since Diagnosis of Chronic Low Back Pain (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	10.7 (10.33)	12.8 (11.43)	11.6 (10.80)
Duration on Opioid Therapy (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	2.1 (4.72)	4.8 (4.06)	3.2 (4.65)
Worst Pain Intensity (WPI) Score (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	3.7 (1.71)	4.6 (2.13)	4.1 (1.92)
Average Pain Intensity (API) (units on a scale) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [units on a scale]	2.6 (1.41)	3.0 (1.78)	2.7 (1.57)

Outcome Measures

1. Primary Outcome

Title	Participants With Adverse Events
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. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. 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 the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set for the Titration/Adjustment period; Post-Titration/Post-Adjustment Safety Analysis Set for the Open-Label Treatment Period

Arm/Group Title	Placebo: Double-Blind Titration Period	Hydrocodone ER: Double-Blind Titration Period	Placebo: Open-Label Adjustment Period	Hydrocodone ER: Open-Label Adjustment Period	Hydrocodone ER: Open-Label Treatment Period
Arm/Group Description	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. As defined in the original protocol, participants who received placebo during the double-blind treatment period in Study 3103 took hydrocodone bitartrate ER tablets (and matching placebo) every 12 hours titrated to an effective dosage over approximately 4 weeks.	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. As defined in the original protocol, participants who received hydrocodone ER during the double-blind treatment period in Study 3103 took hydrocodone ER tablets and matching placebo every 12 hours titrated to an effective dosage over approximately 4 weeks.	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. As defined in the amended protocol, participants who received placebo during the double-blind treatment period in Study 3103 took hydrocodone ER every 12 hours titrated to an effective dosage over approximately 3 weeks.	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. As defined in the amended protocol, participants who received hydrocodone ER during the double-blind treatment period in Study 3103 took hydrocodone ER every 12 hours titrated to an effective dosage over approximately 3 weeks.	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful during the Titration/Adjustment period for managing their pain. The Open-Label Treatment Period lasted 22 weeks.
Measure Participants	10	16	68	88	170
Any AE	4 3.7%	2 2.7%	34 18.7%	25 NaN	88 NaN
Severe AE	0 0%	0 0%	1 0.5%	2 NaN	11 NaN
Treatment-related AE	3 2.8%	2 2.7%	21 11.5%	10 NaN	26 NaN
Deaths	0 0%	0 0%	0 0%	0 NaN	0 NaN
Serious AE	0 0%	0 0%	0 0%	1 NaN	10 NaN
Withdrawals from treatment due to AE	1 0.9%	0 0%	2 1.1%	1 NaN	5 NaN

2. Primary Outcome

Title	Participants With Potentially Clinically Significant Abnormal Laboratory Values
Description	Data represents participants with potentially clinically significant abnormal serum chemistry, hematology and urinalysis values. Significance criteria: Blood urea nitrogen: >=10.71 mmol/L Creatinine: >=177 μmol/L Uric acid: M>=625, F>=506 μmol/L Aspartate aminotransferase (AST): >=3* upper limit of normal (ULN) Alkaline phosphatase: >=3* upper limit of normal (ULN) Gamma-glutamyl transpeptidase (GGT): >=3* upper limit of normal (ULN) Serum white blood cells: >=20 * 10^9/L Hemoglobin: M<=115, F<=95 g/dL Hematocrit: M<0.37, F<0.32 L/L Eosinophils: >=10.0 % Platelets: <=75 * 10^9/L Absolute neutrophils: <=1.0 * 10^9/L Urinalysis: Glucose, Ketones, and Total Protein: >=2 unit increase from baseline
Time Frame	End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set includes all participants who took at least one dose of study drug and who had at least 1 post-baseline efficacy assessment. Participants with a post-baseline result for each test are counted as part of the number of participants analyzed for that test.

Arm/Group Title	Hydrocodone ER
Arm/Group Description	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.
Measure Participants	170
Blood urea nitrogen	5 4.6%
Creatinine	1 0.9%
Uric acid	5 4.6%
AST	1 0.9%
Alkaline phosphatase	1 0.9%
GGT	7 6.4%
Serum white blood cells	1 0.9%
Hemoglobin	4 3.7%
Hematocrit	5 4.6%
Eosinophils	1 0.9%
Platelets	1 0.9%
Absolute neutrophils	1 0.9%
Urine glucose	4 3.7%
Urine ketones	1 0.9%
Urine total protein	1 0.9%

3. Primary Outcome

Title	Participants With Potentially Clinically Significant Abnormal Vital Signs Values
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 the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)

Outcome Measure Data

Analysis Population Description

The Full Analysis Set includes all participants who took at least one dose of study drug and who had at least 1 post-baseline efficacy assessment. Participants with a post-baseline vital sign result are counted as part of the number of participants analyzed.

Arm/Group Title	Hydrocodone ER
Arm/Group Description	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.
Measure Participants	178
Pulse - high	1 0.9%
Pulse - low	1 0.9%
Systolic blood pressure - high	1 0.9%
Systolic blood pressure - low	3 2.8%
Diastolic blood pressure - high	1 0.9%
Diastolic blood pressure - low	2 1.8%

4. Primary Outcome

Title	Participants With Shifts From Normal to Abnormal in Physical Examination Findings
Description	The endpoint visit or early termination visit was an abbreviated exam. Endpoint refers to the last observation carried forward.
Time Frame	End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)

Outcome Measure Data

Analysis Population Description

Post-Titration Safety Analysis Set

Arm/Group Title	Hydrocodone ER
Arm/Group Description	Participants were administered hydrocodone ER tablets orally at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both versions of protocol 3104 followed the titration/adjustment period with a open-label treatment period of 22 weeks.
Measure Participants	170
Normal at baseline - Abnormal at Endpoint	20 18.3%
Abnormal findings reported as adverse events	7 6.4%

5. Primary Outcome

Title	Shifts From Baseline to Endpoint (Treatment Period) in Electrocardiogram (ECG) Findings
Description	A 12-lead ECG was conducted at the final visit for study 3103 which is used as baseline for this study, and at week 22 of the treatment period [or early termination]). A qualified physician at the study center was responsible for providing interpretation of the ECG. Endpoint refers to the last observation carried forward.
Time Frame	Baseline (final visit for study 3103), End of trial visit (up to week 22 of Open-label Treatment Period which is up to week 26 including the titration/adjustment period)

Outcome Measure Data

Analysis Population Description

Post-Titration Safety Analysis Set. Includes participants who have both baseline and endpoint data.

Arm/Group Title	Hydrocodone ER - Opioid Naive	Hydrocodone ER - Opioid Experienced	Hydrocodone ER
Arm/Group Description	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-experienced participants were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both were followed by an open-label treatment period of 22 weeks.
Measure Participants	97	60	157
Baseline normal - Endpoint normal	26 23.9%	19 26%	45 24.7%
Baseline normal - Endpoint abnormal	18 16.5%	11 15.1%	29 15.9%
Baseline abnormal - Endpoint normal	11 10.1%	8 11%	19 10.4%
Baseline abnormal - Endpoint abnormal	42 38.5%	22 30.1%	64 35.2%

6. Primary Outcome

Title	Participants With Clinically Significant (CS) Hearing Changes From Baseline to the Final Visit in Pure Tone Audiometry Test Results
Description	Pure tone audiometry was performed by trained personnel. Hearing loss was classified in degrees of hearing from normal to profound. This classification was determined by the hearing threshold (or the softest sound detected at a specific frequency). The exact ranges that classified hearing loss depended on the exact technique used during testing and on the patient's age. These values were provided by each audiology laboratory that performed the test. For serial audiograms, the criteria for a clinically significant hearing change were based on guidance from the American Speech Language Hearing Association (ASHA 1994, cited in [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 was within two weeks of the final study visit in study 3103; during study exam was within two weeks of the end of trial visit for study 3104 (up to study week 26)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	Hydrocodone ER - Opioid Naive	Hydrocodone ER - Opioid Experienced	Hydrocodone ER
Arm/Group Description	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-experienced participants were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both were followed by an open-label treatment period of 22 weeks.
Measure Participants	109	73	182
Count of Participants [Participants]	11 10.1%	7 9.6%	18 9.9%

7. Secondary Outcome

Title	Change From Baseline to Weeks 2, 6, 10, 14, 18, 22 and Endpoint of the Treatment Period in Daily Worst Pain Intensity (WPI) Scores During the Previous 24 Hours for Each Visit
Description	The WPI was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. At each visit, participants selected the number that best described their worst pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control. Endpoint refers to the last observation carried forward.
Time Frame	Baseline (Day 0 of Treatment Period), Weeks 2, 6, 10, 14, 18, 22 and Endpoint during the Open-Label Treatment Period

Outcome Measure Data

Analysis Population Description

Full Analysis Set includes participants who had at least one post-baseline efficacy assessment. Participants contributing to each time point are counted as part of the number of participants analyzed for that test.

Arm/Group Title	Hydrocodone ER - Opioid Naive	Hydrocodone ER - Opioid Experienced	Hydrocodone ER
Arm/Group Description	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.	Participants were administered extended-release hydrocodone tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-experienced participants were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.	Participants were administered extended-release hydrocodone tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both were followed by an open label treatment period of 22 weeks.
Measure Participants	106	64	170
Week 2	0.0 (1.23)	0.2 (1.28)	0.1 (1.25)
Week 6	0.1 (1.63)	0.1 (1.76)	0.1 (1.68)
Week 10)	0.0 (1.70)	0.0 (1.68)	0.0 (1.69)
Week 14	-0.4 (1.70)	-0.2 (1.82)	-0.3 (1.74)
Week 18	-0.3 (1.73)	-0.4 (1.95)	-0.3 (1.81)
Week 22	-0.1 (1.91)	-0.2 (1.90)	-0.1 (1.90)
Endpoint	0.0 (1.87)	0.1 (1.96)	0.0 (1.90)

8. Secondary Outcome

Title	Change From Baseline to Weeks 2, 6, 10, 14, 18, 22 and Endpoint of the Treatment Period in Daily Average Pain Intensity (API) Scores During the Previous 24 Hours for Each Visit
Description	The API was recorded daily by participants in an electronic diary using an 11-point numerical rating scale (NRS-11), a Likert-type scale in which 0=no pain and 10=the worst pain imaginable. Participants selected the number that best described their average pain intensity over the last 24 hours. Negative change from baseline scores indicate improvement in pain control. Endpoint refers to the last observation carried forward.
Time Frame	Baseline (Day 0 of Treatment Period), Weeks 2, 6, 10, 14, 18, 22 and Endpoint during the Open-Label Treatment Period

Outcome Measure Data

Analysis Population Description

Full Analysis Set includes participants who had at least one post-baseline efficacy assessment. Participants contributing to each time point are counted as part of the number of participants analyzed for that test.

Arm/Group Title	Hydrocodone ER - Opioid Naive	Hydrocodone ER - Opioid Experienced	Hydrocodone ER
Arm/Group Description	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-naïve participants were defined as those who were taking tramadol or less than 10 mg per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. Opioid-experienced participants were defined as those who were taking 10 mg or more per day of oxycodone, or equivalent (including around-the-clock and rescue medication) for the 14 days before screening in the C33237/3103 (NCT01789970) study.	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both were followed by an open-label treatment period of 22 weeks.
Measure Participants	106	64	170
Week 2	-0.1 (0.95)	0.1 (1.18)	0.0 (1.05)
Week 6	0.1 (1.34)	0.0 (1.52)	0.1 (1.41)
Week 10	-0.1 (1.45)	-0.1 (1.43)	-0.1 (1.44)
Week 14	-0.3 (1.27)	-0.2 (1.54)	-0.2 (1.37)
Week 18	-0.2 (1.35)	-0.4 (1.57)	-0.3 (1.44)
Week 22	-0.2 (1.54)	-0.3 (2.03)	-0.3 (1.74)
Endpoint	-0.1 (1.55)	0.1 (2.20)	0.0 (1.82)

9. Secondary Outcome

Title	Percentage of Participants Withdrawn From the Study For Lack of Efficacy
Description	Percentage of patients who withdrew from the study for lack of efficacy, as indicated on the early termination form of the case report form (CRF).
Time Frame	Day 1 of the Titration/Adjustment Period to Week 22 of the Treatment Period (total of 25-26 weeks)

Outcome Measure Data

Analysis Population Description

Safety Analysis Set

Arm/Group Title	Hydrocodone ER
Arm/Group Description	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. If enrolled under the original protocol, there was a double-blind titration period of four weeks to adjust the dose taken in study 3103 (NCT01789970). If enrolled under the amended protocol, there was an open-label adjustment period of three weeks to adjust the dose taken in study 3103 (NCT01789970). Both were followed by an open-label treatment period of 22 weeks.
Measure Participants	182
Number [percentage of participants]	2 1.8%

Adverse Events

Time Frame	Titration/Adjustment period: Day 1 up to Week 4 Open-label Treatment period: Week 4 to Week 26
Arm/Group Title	Hydrocodone ER - Titration/Adjustment Period		Hydrocodone ER - Open-Label Treatment Period
Arm/Group Description	Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful for managing their pain. The titration/adjustment period lasted 3-4 weeks.		Participants were administered hydrocodone ER tablets at dosages of 15, 30, 45, 60, or 90 mg every 12 hours at the dosage deemed successful during the Titration/Adjustment period for managing their pain. The Treatment Period lasted 22 weeks.
All Cause Mortality
	Hydrocodone ER - Titration/Adjustment Period		Hydrocodone ER - Open-Label Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Hydrocodone ER - Titration/Adjustment Period		Hydrocodone ER - Open-Label Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/182 (0.5%)		10/170 (5.9%)
Cardiac disorders
Acute myocardial infarction	0/182 (0%)	0	1/170 (0.6%)	1
Gastrointestinal disorders
Intestinal obstruction	1/182 (0.5%)	1	0/170 (0%)	0
General disorders
Chest pain	0/182 (0%)	0	1/170 (0.6%)	1
Hepatobiliary disorders
Cholangitis	0/182 (0%)	0	1/170 (0.6%)	1
Cholecystitis	0/182 (0%)	0	1/170 (0.6%)	1
Cholelithiasis	0/182 (0%)	0	1/170 (0.6%)	1
Cholestasis	0/182 (0%)	0	1/170 (0.6%)	1
Infections and infestations
Clostridium difficile infection	0/182 (0%)	0	1/170 (0.6%)	1
Staphylococcal infection	0/182 (0%)	0	1/170 (0.6%)	1
Urinary tract infection	0/182 (0%)	0	1/170 (0.6%)	1
Injury, poisoning and procedural complications
Road traffic accident	0/182 (0%)	0	1/170 (0.6%)	1
Investigations
Electrocardiogram T wave inversion	0/182 (0%)	0	1/170 (0.6%)	1
Renal and urinary disorders
Renal failure acute	0/182 (0%)	0	1/170 (0.6%)	1
Respiratory, thoracic and mediastinal disorders
Asthma	0/182 (0%)	0	1/170 (0.6%)	1
Pulmonary embolism	0/182 (0%)	0	1/170 (0.6%)	1
Other (Not Including Serious) Adverse Events
	Hydrocodone ER - Titration/Adjustment Period		Hydrocodone ER - Open-Label Treatment Period
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/182 (14.8%)		20/170 (11.8%)
Gastrointestinal disorders
Constipation	9/182 (4.9%)	9	12/170 (7.1%)	13
Nausea	19/182 (10.4%)	19	10/170 (5.9%)	12

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.