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

Study Overview
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Brief Summary
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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.

Detailed Description
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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).

Official Title
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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

Conditions
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Chronic Pain

Intervention / Treatment
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* Drug: Hydrocodone ER


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hydrocodone ER<br>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<br>* 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.<br>* Other names: Hydrocodone bitartrate extended-release;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Adverse Experiences | 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. | Day 1 of open-label titration period - Week 52 of the open-label treatment period | 
| Participants With Potentially Clinically Significant (PCS) Abnormal Laboratory Values During the Open-Label Treatment Period by Participant Status | 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 | Day 1 - Week 52 of the open-label treatment period | 
| Participants With Potentially Clinically Significant Abnormal Vital Signs Values by Participant Status | 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 | Day 1 of open-label titration period - Week 52 of the open-label treatment period | 
| Shifts in Electrocardiogram (ECG) Findings From Baseline to Overall Study by Participant Status | 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. | 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 | 
| Participants With Clinically Significant (CS) Hearing Changes From Baseline in Pure Tone Audiometry Test Results by Patient Status | 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. | 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 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participant Global Assessment (PGA) of the Method of Pain Control by Participant Status | 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). | 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 | 
| 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) | 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 | End of Open-label Titration Period. Weeks 4 and 24 of the Open-label Treatment Period | 
| Addiction Behavior Checklist (ABC) Total Scores During Both the Open-Label Titration and Open-Label Treatment Periods by Participant Status | 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. | 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 | 
| Current Opioid Misuse Measure (COMM) Scores During Both the Open-Label Titration and Open-Label Treatment Periods by Participant Status | 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. | 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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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moderate to severe pain, diabetic peripheral neuropathy, postherpetic neuralgia, traumatic injury, complex regional pain syndrome, back pain, neck pain, osteoarthritis, rheumatoid arthritis