A Study to Assess the Abuse Potential of Hydrocodone Extended-Release Tablet in Recreational Opioid Users

A Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Assess the Abuse Potential of the Hydrocodone Bitartrate Extended-Release Tablet in Healthy, Nondependent, Recreational Opioid Users

The purpose of this study is to assess the relative abuse potential of the hydrocodone bitartrate extended-release tablet compared to immediate-release hydrocodone bitartrate.

Hydrocodone bitartrate is a semisynthetic opioid analgesic and antitussive. Hydrocodone is widely used for various indications similar to those of codeine, primarily for relief of moderate to moderately severe pain. For the treatment of pain in the United States, hydrocodone is currently available only as an immediate-release (IR) product in combination with other medications such as acetaminophen or ibuprofen. The extended-release (ER) formulation tested in this study is designed to be resistant to dose dumping with alcohol or rapid release of hydrocodone after tampering.

The study will consist of 3 phases: A, B,and C. Phase A is the screening phase where subject eligibility will be confirmed (Visit 1). Subjects who are eligible will enter Phase B, a double-blind, 2-period crossover design (Visit 2) followed by Phase C, a double-blind 4-period crossover design (Visits 3 through 6).

Phase B is the randomized, double-blind, placebo-controlled, 2-treatment, 2- period crossover portion of the study which is designed to ensure that the subject can tolerate a 45-mg dose of hydrocodone and that the subject can discriminate between the effect of hydrocodone and the effect of placebo. Subjects will arrive at the study center on the day prior to the first study drug administration and remain at the study center for a minimum of 24 hours after the second study drug administration in phase B. After a review of the inclusion/exclusion criteria and check-in procedures (including a Naloxone Challenge),eligible subjects will be randomly assigned to one of 2 treatment sequences. For subjects who qualify to continue into phase C, there will be a minimum 7-day washout period between the second dose in phase B and the first dose in phase C.

Phase C is the randomized, double-blind, triple-dummy, placebo-controlled, 4-period crossover portion of the study. Subjects will arrive at the study center the day prior to each study drug administration in phase C and remain at the study center through 72 hours after study drug administration in each period. Eligible subjects will be randomly assigned to 1 of 4 treatment groups. Each dose in phase C will be separated by a minimum 14 day washout period.

All subjects (including those who withdraw from the study) will be asked to return to the study center for a follow-up visit approximately 48 to 72 hours after discharge from the study center following their final dose of study drug.

Inclusion Criteria:

• Written informed consent is obtained.
• The subject speaks and writes in English.
• The subject is not physically dependent on opioids as demonstrated by successful completion of a naloxone challenge; ie, subject does not exhibit signs or symptoms of opioid withdrawal (as assessed by a Clinical Opiate Withdrawal Scale score of <5) following administration of intravenous naloxone in the Naloxone Challenge.
• The subject has a history of recreational opioid use to achieve a "high" at least 10 times in the last year and at least on 1 occasion within the 12 weeks before screening. Subjects who abuse multiple drugs should express a preference for opioids.
• The subject is aged 18 through 50 years with a minimum body weight of 50 kg and a body mass index (BMI) of 18.0 through 32.0 kg/m2.
• The subject is in good health as determined by medical and psychiatric history, physical examination, ECG, serum chemistry, hematology, urinalysis, and serology.
• The subject, if a woman, is surgically sterile or 2 years postmenopausal, or if of childbearing potential, is currently using a medically accepted method of contraception and agrees to continue use of this method for the duration of the study (and for 30 days after participation in the study). Acceptable methods of contraception include abstinence, or an intrauterine device (known to have a failure rate of less than 1% per year).
• The subject must have a negative urine drug screen (except for tetrahydrocannabinol) and a negative alcohol test at screening. NOTE: If a subject tests negative for tetrahydrocannabinol at screening, the test result at baseline must be negative for the subject to be considered for enrollment in the study.
• The subject is willing to comply with study restrictions and remain at the study center for the duration of each treatment period during the study.

Exclusion Criteria:

• The subject has any clinically significant uncontrolled medical conditions (treated or untreated).
• The subject has a clinically significant deviation from normal in the clinical laboratory values or ECG or physical examination findings, as determined by the investigator or the medical monitor.
• The subject is a poor metabolizer of cytochrome P450 (CYP2D6) substrates based on genotyping performed at screening.
• The subject currently or has habitually consumed, within the past 2 years, more than 28 units of alcohol per week for male subjects or 21 units of alcohol per week for female subjects, or has a history or current diagnosis of substance dependence as assessed using by the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR). NOTE: A unit of alcohol is equal to 1 ounce of hard liquor, 5 ounces of wine, or 8 ounces of beer.
• The subject has participated in, is currently participating in or is seeking treatment for substance-related disorders (excluding nicotine).
• The subject is a heavy smoker (>20 cigarettes per day), chews tobacco and/or is unable to abstain from smoking for 6 hours during any day, or abstain from caffeine intake for 20 hours during any day.
• The subject is a pregnant or lactating woman. (Any woman becoming pregnant during the study will be withdrawn from the study.)
• The subject has previously participated in a Cephalon-sponsored clinical study with the hydrocodone bitartrate extended-release tablet.
• The subject has any disorder that may interfere with drug absorption, distribution, metabolism, or excretion (including gastrointestinal surgery [appendectomy allowed]).
• The subject has a known sensitivity or idiosyncratic reaction to any compound present in hydrocodone or hydromorphone, their related compounds, or to any metabolites, to the solution used for reconstitution of the immediate-release product, or to any compound listed as being present in a study formulation or naloxone.
• The subject has received any investigational drug within 30 days or 5 half-lives (whichever is longer) before the first study drug administration in phase B.
• The subject has used any vitamins within 2 weeks before the first study drug administration in phase B or has used any systemic or topical prescription, or nonprescription medication (ie, over-the-counter [OTC] medications [except acetaminophen or ibuprofen]) within 2 weeks before the first study drug administration in phase B without evaluation and approval from the medical monitor.
• The subject has used herbal supplements within 2 weeks before the first study drug administration in phase B without evaluation and approval from the medical monitor.
• The subject has donated any plasma within 7 days prior to screening.
• The subject has donated any blood in excess of 450 mL within 56 days prior to screening.
• The subject has, after resting for 5 minutes, elevated blood pressure (defined as seated systolic blood pressure of equal to or more than 140 mm Hg and/or seated diastolic blood pressure of equal to or more than 90 mm Hg), or has hypotension (defined as seated systolic blood pressure of less than 90 mm Hg and/or seated diastolic blood pressure of less than 45 mm Hg). NOTE: No more than 2 rechecks of the subject's blood pressure are permitted at screening.
• The subject has, after resting for 5 minutes, a seated pulse outside the range of 45 to 90 bpm. NOTE: No more than 2 rechecks of the subject's pulse are permitted at screening.
• The subject has, after resting for 5 minutes, oxygen saturation less than 95%. NOTE: No more than 2 rechecks of the subject's SpO2 are permitted for eligibility purposes.
• The subject has a recent history of disclosed violence and/or disclosure of probation/parole.
• The subject has, within 2 weeks before the first dose of study drug in phase B, a clinically significant excessive consumption of coffee, tea, and/or other caffeine-containing beverage or food (ie, 1000 mg of caffeine or more per day, or 8 or more cups of coffee per day).
• The subject has, within 4 weeks before the first study drug administration in phase B, a clinically significant illness or, within 1 week before the first study drug administration in phase B, has any acute illness, or at screening or on the day before the first study drug administration in phase B, has symptoms of any clinically significant or acute illness.
• The subject is unlikely to comply with the study protocol or is unsuitable for any other reason, as judged by the investigator.
• The subject has a positive test result for hepatitis B surface antigen (HBsAg) or antibodies to hepatitis C.
• The subject has a known positive history of antibodies to human immunodeficiency virus (HIV) or HIV disease
• The subject has a clinical laboratory test value(s) outside the following range(s), or any other clinically significant laboratory abnormality as determined by an investigator or medical monitor:
• hemoglobin value less than 12 g/dL
• aspartate aminotransferase (AST) or alanine aminotransferase (ALT) value greater than twice the upper limit of the normal range (ULN)
• total bilirubin value of more than 25.7 μmol/L (1.5 mg/dL)