Clinical trial NCT01999114: 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
Official title: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: ECG Effects
Keywords: Healthy subjects
Opioid
Transdermal
ECG
Lead sponsor: Purdue Pharma LP
Sponsor class: INDUSTRY
First posted: 2013-12-03
Enrollment: 328
Sex: ALL
Minimum age (years): 18
Maximum age (years): 55
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: 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.

Primary outcomes:
measure: 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)
timeFrame: Baseline to Day 6
measure: 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)
timeFrame: Baseline to Day 13
measure: 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)
timeFrame: Baseline to Day 17
Secondary outcomes:
measure: QTcF and QTcB for Historical Purposes, PR Interval, QRS Interval, and Uncorrected QT Interval
timeFrame: Baseline to Day 6
measure: Heart Rate (HR)
timeFrame: Baseline to Day 6
measure: QTcF and QTcB for Historical Purposes, PR Interval, QRS Interval, and Uncorrected QT Interval
timeFrame: Baseline to Day 13
measure: Heart Rate (HR)
timeFrame: Baseline to Day 13
measure: QTcF and QTcB for Historical Purposes, PR Interval, QRS Interval, and Uncorrected QT Interval
timeFrame: Baseline to Day 17
measure: Heart Rate (HR)
timeFrame: Baseline to Day 17
measure: ECG Morphology
timeFrame: Baseline to Day 6
measure: ECG Morphology
timeFrame: Baseline to Day 13
measure: ECG Morphology
timeFrame: Baseline to Day 17
Other outcomes:
Locations:
city: Austin
country: United States
facility: PPD Phase I Clinic
state: Texas
Study officials:
References:
citation: Harris SC, Morganroth J, Ripa SR, Thorn MD, Colucci S. Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials. Postgrad Med. 2017 Jan;129(1):69-80. doi: 10.1080/00325481.2017.1270156.