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

Study Overview
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Brief Summary
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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.

Official Title
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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

Conditions
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ECG Effects

Intervention / Treatment
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* Drug: Buprenorphine transdermal patch
* Drug: Naltrexone tablet
* Drug: Placebos (for TDS and for naltrexone and for moxifloxacin)
* Drug: Moxifloxacin tablet


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 55 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: BTDS<br>Buprenorphine transdermal patches 10, 40 (2 x 20), and 80 (4 x 20) mcg/hr | Drug: Buprenorphine transdermal patch<br>* Buprenorphine patch applied transdermally<br>* Other names: Butrans;|
| Experimental: BTDS with naltrexone<br>Buprenorphine transdermal patches 10, 40 (2 x 20), and 80 (4 x 20) mcg/hr and naltrexone 50 mg tablets | Drug: Buprenorphine transdermal patch<br>* Buprenorphine patch applied transdermally<br>* Other names: Butrans;Drug: Naltrexone tablet<br>* Naltrexone tablet; 1 tablet taken orally every 12 hours<br>* Other names: ReVia;|
| Active Comparator: Naltrexone<br>Naltrexone 50 mg tablets | Drug: Naltrexone tablet<br>* Naltrexone tablet; 1 tablet taken orally every 12 hours<br>* Other names: ReVia;|
| Placebo Comparator: Placebo<br>Matching placebo for transdermal patches and/or naltrexone tablets and/or moxifloxacin tablets | Drug: Placebos (for TDS and for naltrexone and for moxifloxacin)<br>* Matching placebos<br>|
| Active Comparator: Moxifloxacin<br>Moxifloxacin 400-mg tablets | Drug: Moxifloxacin tablet<br>* Moxifloxacin tablet; 1 tablet taken orally on Days 6, 13 and 17<br>* Other names: Avelox®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The Maximum Time-matched Change From Baseline in QT Data Corrected for Heart Rate (QTc), Placebo-corrected, Based on an Individual Correction (QTcI) Method (ΔΔQTcI) | The effects of 10 mcg/hr buprenorphine (Day 6) delivered by BTDS alone, or by BTDS dosed with naltrexone, and naltrexone alone on cardiac repolarization, were assessed based on the corrected QT interval since HR inversely affects QT duration. The time-matched analysis was conducted as the primary endpoint as recommended by ICH E14, with the 2-sided 90% confidence interval for each treatment at each time point showing the placebo- and baseline-corrected (ΔΔ) analysis for QTcI. The effect of BTDS 10 on QT intervals was compared with the moxifloxacin-positive control after placebo and baseline correction. | Baseline to Day 6 | 
| The Maximum Time-matched Change From Baseline in QT Data Corrected for Heart Rate (QTc), Placebo-corrected, Based on an Individual Correction (QTcI) Method (ΔΔQTcI) | The effects of 40 mcg/hr buprenorphine (Day 13) delivered by BTDS alone, or by BTDS dosed with naltrexone, and naltrexone alone on cardiac repolarization, were assessed based on the corrected QT interval since HR inversely affects QT duration. The time-matched analysis was conducted as the primary endpoint as recommended by ICH E14, with the 2-sided 90% confidence interval for each treatment at each time point showing the placebo- and baseline-corrected (ΔΔ) analysis for QTcI. The effect of BTDS 40 on QT intervals was compared with the moxifloxacin-positive control after placebo and baseline correction. | Baseline to Day 13 | 
| The Maximum Time-matched Change From Baseline in QT Data Corrected for Heart Rate (QTc), Placebo-corrected, Based on an Individual Correction (QTcI) Method (ΔΔQTcI) | The effects of 80 mcg/hr buprenorphine (Day 17) delivered by BTDS alone, or by BTDS dosed with naltrexone, and naltrexone alone on cardiac repolarization, were assessed based on the corrected QT interval since HR inversely affects QT duration. The time-matched analysis was conducted as the primary endpoint as recommended by ICH E14, with the 2-sided 90% confidence interval for each treatment at each time point showing the placebo- and baseline-corrected (ΔΔ) analysis for QTcI. The effect of BTDS 80 on QT intervals was compared with the moxifloxacin-positive control after placebo and baseline correction. | Baseline to Day 17 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| QTcF and QTcB for Historical Purposes, PR Interval, QRS Interval, and Uncorrected QT Interval | Mean change from baseline for the BTDS 10 mcg/hr dose on Day 6, presented as time-averaged mean change from baseline for BTDS only, BTDS with naltrexone, naltrexone alone, moxifloxacin, and placebo. | Baseline to Day 6 | 
| Heart Rate (HR) | Mean change from baseline for the BTDS 10 mcg/hr dose on Day 6, presented as time-averaged mean change from baseline for BTDS only, BTDS with naltrexone, naltrexone alone, moxifloxacin, and placebo. | Baseline to Day 6 | 
| QTcF and QTcB for Historical Purposes, PR Interval, QRS Interval, and Uncorrected QT Interval | Mean change from baseline for the BTDS 40 mcg/hr dose on Day 13, presented as time-averaged mean change from baseline for BTDS only, BTDS with naltrexone, naltrexone alone, moxifloxacin, and placebo. | Baseline to Day 13 | 
| Heart Rate (HR) | Mean change from baseline for the BTDS 40 mcg/hr dose on Day 13, presented as time-averaged mean change from baseline for BTDS only, BTDS with naltrexone, naltrexone alone, moxifloxacin, and placebo. | Baseline to Day 13 | 
| QTcF and QTcB for Historical Purposes, PR Interval, QRS Interval, and Uncorrected QT Interval | Mean change from baseline for the BTDS 80 mcg/hr dose on Day 17, presented as time-averaged mean change from baseline for BTDS only, BTDS with naltrexone, naltrexone alone, moxifloxacin, and placebo. | Baseline to Day 17 | 
| Heart Rate (HR) | Mean change from baseline for the BTDS 80 mcg/hr dose on Day 17, presented as time-averaged mean change from baseline for BTDS only, BTDS with naltrexone, naltrexone alone, moxifloxacin, and placebo. | Baseline to Day 17 | 
| ECG Morphology | Morphological analyses were performed with regard to the digital ECG waveform interpretation as defined by a central ECG laboratory's cardiologist blinded to the study treatment. Changes from baseline to each day of treatment were evaluated separately. Any T-U wave complex that suggested an abnormal form compatible with an effect on cardiac repolarization was noted. New ECG morphological onset changes were presented as the percentage of subjects meeting the new criterion (new meant not present on any baseline ECG and became present on at least 1 on-treatment ECG) for the following variables: Second degree heart block Third degree heart block Complete right bundle branch block (RBBB) Complete left bundle branch block (LBBB) ST segment changes (elevation and depression separately) T-wave abnormalities (negative T waves only) Myocardial infarction (MI) pattern Any new abnormal U waves | Baseline to Day 6 | 
| ECG Morphology | Morphological analyses were performed with regard to the digital ECG waveform interpretation as defined by a central ECG laboratory's cardiologist blinded to the study treatment. Changes from baseline to each day of treatment were evaluated separately. Any T-U wave complex that suggested an abnormal form compatible with an effect on cardiac repolarization was noted. New ECG morphological onset changes were presented as the percentage of subjects meeting the new criterion (new meant not present on any baseline ECG and became present on at least 1 on-treatment ECG) for the following variables: Second degree heart block Third degree heart block Complete right bundle branch block (RBBB) Complete left bundle branch block (LBBB) ST segment changes (elevation and depression separately) T-wave abnormalities (negative T waves only) Myocardial infarction (MI) pattern Any new abnormal U waves | Baseline to Day 13 | 
| ECG Morphology | Morphological analyses were performed with regard to the digital ECG waveform interpretation as defined by a central ECG laboratory's cardiologist blinded to the study treatment. Changes from baseline to each day of treatment were evaluated separately. Any T-U wave complex that suggested an abnormal form compatible with an effect on cardiac repolarization was noted. New ECG morphological onset changes were presented as the percentage of subjects meeting the new criterion (new meant not present on any baseline ECG and became present on at least 1 on-treatment ECG) for the following variables: Second degree heart block Third degree heart block Complete right bundle branch block (RBBB) Complete left bundle branch block (LBBB) ST segment changes (elevation and depression separately) T-wave abnormalities (negative T waves only) Myocardial infarction (MI) pattern Any new abnormal U waves | Baseline to Day 17 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Healthy subjects, Opioid, Transdermal, ECG