The Effect of Buprenorphine Delivered by Buprenorphine Transdermal System (BTDS) at Doses up to 80 Micrograms/Hour (mcg/hr) and Naltrexone on Electrocardiogram (ECG) Intervals in Healthy Volunteers

A Randomized, Triple-blind, Placebo- and Positive-Controlled, Parallel Group Study of the Effect of Buprenorphine Delivered by the Buprenorphine Transdermal System (BTDS) at Doses up to 80 mcg/Hour and Naltrexone on ECG Intervals in Healthy Adult Subjects

The purpose of this study is to evaluate the ECG effects of 10, 40, and 80 mcg/hr buprenorphine delivered by BTDS alone, or by BTDS dosed with naltrexone, relative to placebo in healthy male and female subjects.

Inclusion Criteria:

• Provide written informed consent.
• Males and females aged 18 to 55, inclusive.
• Body weight ranging from 50 to 100 kilograms (kg) (110 to 220 lbs) and body mass index (BMI) ranging from 18 to 30 (kg/m2), inclusive.
• Healthy and free of significant abnormal findings as determined by medical history, physical examination, clinical laboratory values, vital signs, and resting 12-lead ECG.
• Females of child-bearing potential must be using an adequate and reliable method of contraception (ie, barrier with additional spermicidal foam or jelly, intra-uterine device, hormonal contraception). Females who are postmenopausal must have been postmenopausal ≥ 1 year and have elevated serum follicle stimulating hormone (FSH).
• Willing to eat the food supplied during the study.
• Willing to refrain from strenuous exercise during the entire study. Subjects will not begin a new exercise program nor participate in any unusually strenuous physical exertion.
• All 8 anatomical transdermal system (TDS) application sites (upper back, upper chest, upper outer arm, or lateral thorax) must be acceptable for study use.

Exclusion Criteria:

• Females who are pregnant (positive beta human chorionic gonadotropin test) or lactating.

• Current or recent (within 5 years) history of drug or alcohol abuse.

• History or any current conditions that might interfere with drug absorption (transdermal or gastrointestinal), distribution, metabolism or excretion.

• Use of an opioid-containing medication in the past 30 days preceding the initial dose in this study.

• Known allergy to buprenorphine, any excipient of BTDS, opioids, psychotropic or hypnotic drugs, and/or moxifloxacin or any member of the quinolone class drugs.

• Any history of frequent nausea or emesis regardless of etiology.

• Any history of seizures or head trauma with sequelae.

• Participation in a clinical drug study during the 30 days preceding the initial dose in this study.

• Any significant illness during the 30 days preceding the initial dose in this study.

• Use of any medication including thyroid hormonal therapy (hormonal contraception and hormonal replacement therapy in the form of estrogen with or without progestin is allowed), vitamins, herbal and/or mineral supplements during the 7 days preceding the initial dose.

• Any personal or family history of prolonged QT interval or disorders of cardiac rhythm.

• Abnormal cardiac conditions including hypertension.

• Abnormal cardiac condition denoted by any of the following:

  • QTcF interval > 450 milliseconds (msec)
  • PR interval > 240 msec or QRS > 110 msec
  • Evidence of second- or third-degree atrioventricular (AV) block
  • Pathological Q-waves (defined as Q-wave >40 msec or depth > 0.5 mV)
  • Evidence of ventricular pre-excitation, complete left bundle branch block, right bundle branch block (RBBB), or incomplete RBBB
  • With a resting heart rate outside the range of 45 to 85 beats per minute (bpm)

• Abnormalities on physical examination, vital signs, ECG, or clinical laboratory values, unless those abnormalities were judged clinically insignificant by the investigator.

• Oxygen saturation (SpO2) ≤ 94% as measured by pulse oximetry.

• Refusal to abstain from caffeine or xanthine containing beverages entirely during confinement.

• Refusal to abstain from consumption of alcoholic beverages 48 hours prior to initial study drug administration and any time during study.

• History of smoking or use of nicotine products within 45 days of study drug administration or a positive urine cotinine test

• Blood or blood products donated within 30 days prior to study drug administration or anytime during the study.

• Positive results of urine drug screen or alcohol screen.

• Positive results of hepatitis B surface antigen (HBsAg), hepatitis C antibody (anti-HCV).

• Positive naloxone challenge test.

• Presence of Gilbert's Syndrome, or any known hepatobiliary abnormalities.

• The investigator believes the subject to be unsuitable for reason(s) not specifically stated in the exclusion criteria.

• Subjects who have allergies or other contraindications to transdermal systems or patch adhesives.

• Clinically significant history of allergic reaction to wound dressings or elastoplast.

• Subjects with a dermatological disorder at any relevant patch application site that precludes proper placement and/or rotation of patch.

• Taking antihistamines within 72 hours prior to dosing or systemic or topical corticosteroids within 3 weeks prior to dosing.

• Subjects will not allow hair to be removed at the proposed patch application site which may prevent proper placement of the patch.

• Subjects for whom a proper assessment of possible application site reactions would be confounded by local skin conditions.