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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

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ClinicalTrials.gov Identifier: NCT01999114
Recruitment Status : Completed
First Posted : December 3, 2013
Results First Posted : November 5, 2018
Last Update Posted : November 5, 2018
Sponsor:
Information provided by (Responsible Party):
Purdue Pharma LP

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.

Condition or disease Intervention/treatment Phase
ECG Effects Drug: Buprenorphine transdermal patch Drug: Naltrexone tablet Drug: Placebos (for TDS and for naltrexone and for moxifloxacin) Drug: Moxifloxacin tablet Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 328 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple (Participant, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
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 Start Date : March 2012
Actual Primary Completion Date : October 2012
Actual Study Completion Date : October 2012


Arm Intervention/treatment
Experimental: BTDS
Buprenorphine transdermal patches 10, 40 (2 x 20), and 80 (4 x 20) mcg/hr
Drug: Buprenorphine transdermal patch
Buprenorphine patch applied transdermally
Other Name: Butrans

Experimental: BTDS with naltrexone
Buprenorphine transdermal patches 10, 40 (2 x 20), and 80 (4 x 20) mcg/hr and naltrexone 50 mg tablets
Drug: Buprenorphine transdermal patch
Buprenorphine patch applied transdermally
Other Name: Butrans

Drug: Naltrexone tablet
Naltrexone tablet; 1 tablet taken orally every 12 hours
Other Name: ReVia

Active Comparator: Naltrexone
Naltrexone 50 mg tablets
Drug: Naltrexone tablet
Naltrexone tablet; 1 tablet taken orally every 12 hours
Other Name: ReVia

Placebo Comparator: Placebo
Matching placebo for transdermal patches and/or naltrexone tablets and/or moxifloxacin tablets
Drug: Placebos (for TDS and for naltrexone and for moxifloxacin)
Matching placebos

Active Comparator: Moxifloxacin
Moxifloxacin 400-mg tablets
Drug: Moxifloxacin tablet
Moxifloxacin tablet; 1 tablet taken orally on Days 6, 13 and 17
Other Name: Avelox®




Primary Outcome Measures :
  1. 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) [ Time Frame: Baseline to Day 6 ]
    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.

  2. 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) [ Time Frame: Baseline to Day 13 ]
    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.

  3. 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) [ Time Frame: Baseline to Day 17 ]
    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.


Secondary Outcome Measures :
  1. QTcF and QTcB for Historical Purposes, PR Interval, QRS Interval, and Uncorrected QT Interval [ Time Frame: Baseline to Day 6 ]
    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.

  2. Heart Rate (HR) [ Time Frame: Baseline to Day 6 ]
    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.

  3. QTcF and QTcB for Historical Purposes, PR Interval, QRS Interval, and Uncorrected QT Interval [ Time Frame: Baseline to Day 13 ]
    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.

  4. Heart Rate (HR) [ Time Frame: Baseline to Day 13 ]
    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.

  5. QTcF and QTcB for Historical Purposes, PR Interval, QRS Interval, and Uncorrected QT Interval [ Time Frame: Baseline to Day 17 ]
    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.

  6. Heart Rate (HR) [ Time Frame: Baseline to Day 17 ]
    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.

  7. ECG Morphology [ Time Frame: Baseline to Day 6 ]

    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

  8. ECG Morphology [ Time Frame: Baseline to Day 13 ]

    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

  9. ECG Morphology [ Time Frame: Baseline to Day 17 ]

    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



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01999114


Locations
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United States, Texas
PPD Phase I Clinic
Austin, Texas, United States, 78744
Sponsors and Collaborators
Purdue Pharma LP

Additional Information:
Publications of Results:
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Responsible Party: Purdue Pharma LP
ClinicalTrials.gov Identifier: NCT01999114     History of Changes
Other Study ID Numbers: BUP1025
First Posted: December 3, 2013    Key Record Dates
Results First Posted: November 5, 2018
Last Update Posted: November 5, 2018
Last Verified: February 2018

Keywords provided by Purdue Pharma LP:
Healthy subjects
Opioid
Transdermal
ECG

Additional relevant MeSH terms:
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Buprenorphine
Naltrexone
Moxifloxacin
Norgestimate, ethinyl estradiol drug combination
Analgesics, Opioid
Narcotics
Central Nervous System Depressants
Physiological Effects of Drugs
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Narcotic Antagonists
Anti-Bacterial Agents
Anti-Infective Agents
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Contraceptives, Oral, Combined
Contraceptives, Oral
Contraceptive Agents, Female
Contraceptive Agents
Reproductive Control Agents
Alcohol Deterrents