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

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

Population: Safety analysis set

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

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

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

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

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

Population: 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.

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

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

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

Population: Post-titration Safety Analysis set

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

Population: Post titration Safety Analysis set

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

Population: 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.

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

Population: Safety analysis set