Healthy Volunteers
Conditions
Keywords
Healthy subjects, Opioid, Transdermal
Brief summary
The purpose of this study is to examine the effect of buprenorphine on QT interval corrected for heart rate (QTc) in healthy subjects.
Detailed description
Drugs in this opioid class have been associated with prolonging QT interval/QT interval corrected for heart rate (QTc).
Interventions
Buprenorphine transdermal patch 5, 10, 20, and 2 \* 20 mcg/h.
DRUGMatching placebo transdermal patch
Placebo transdermal patch to match BTDS 5, 10, 20, and 2 \* 20.
DRUGAvelox (moxifloxacin hydrochloride) tablet
Moxifloxacin 400 mg tablet; 1 tablet taken orally on days 6 and 13
Sponsors
Purdue Pharma LP
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Males and females 18 to 55 years of age, inclusive. * Body weight ranging from 50 to 100 kilograms (kg) and a body mass index (BMI) ≤ 30 kg/m2. * Healthy as determined by unremarkable medical history, physical examination, vital signs, laboratory evaluations, electrocardiogram (ECG), and a 24-hour screening ECG telemetry. * Willing to refrain from strenuous exercise or contact sports during the study. * Female subjects must be surgically sterile or at least 2 years postmenopausal, or using an effective contraceptive method (intrauterine device, hormonal contraceptive, or double-barrier method).
Exclusion criteria
* Any clinically significant illness during the 30 days prior to randomization. * Any history of allergy to buprenorphine, any excipient of BTDS, opioids, psychotropic or hypnotic drugs, and/or moxifloxacin or any member of the quinolone class of drugs. * A clinically significant history of allergic reaction to wound dressings or bandages. * Any medical or surgical conditions which might interfere with drug absorption (transdermal or gastrointestinal), distribution, metabolism, or excretion. * Abnormalities on physical examination, vital signs, ECG, or clinical laboratory values, unless those abnormalities are judged to be clinically insignificant by the Investigator. * Any cardiovascular disorders, including hypertension. * Oxygen saturation (SpO2) ≤ 94% as measured by pulse oximetry. * Any personal or family history of prolonged QT interval or disorders of cardiac rhythm. * Abnormal cardiac condition denoted by any of the following: * QT interval ≥ 450 milliseconds (msec). * PR interval \> 240 msec or ≤ 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 preexcitation, complete left bundle branch block, right bundle branch block (RBBB), or incomplete RBBB. * A resting heart rate outside the range of 50 to 85 beats per minute (bpm). Other protocol-specific exclusion/inclusion criteria may apply.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Comparison of BTDS to Placebo Transdermal System (TDS): the Average Difference From Baseline Using QT Corrected From Within-subject Data (QTci) on Day 13 | Baseline to Day 13 | Observed time from start of the QRS complex to end of the T wave (QT), and the time between the 2 R waves (RR) data for each of 4 electrocardiographs (ECGs) over an approximate 10-minute interval at each nominal time point. The average QT and QTc data over the 2 pretreatment days were used as the baseline. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected from within-subject data (QTci) msec. |
| The Comparison of Moxifloxacin to Placebo Transdermal System (TDS): the Average Difference From Baseline Using QT Interval Corrected From Within-subject Data (QTci) on Day 13 | Baseline to Day 13 | Observed time from start of the QRS complex to end of the T wave (QT), and the time between the 2 R waves (RR) data for each of 4 electrocardiographs (ECGs) over an approximate 10-minute interval at each nominal time point. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected from within-subject data (QTci) msec. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Average Differences From Baseline Between BTDS and Placebo by Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13 | Baseline to Day 6 and Day 13 | QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc (QT interval corrected for heart rate) data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected by Bazett's method (QTcB) msec. |
| The Average Differences From Baseline Between Moxifloxacin and Placebo of Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13 | Baseline to Day 6 and Day 13 | QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected by Bazett's method (QTcB) msec. |
| The Average Differences Between BTDS vs Placebo From Baseline by Interval Corrected From Within-subject Data (QTci) on Day 6 | Baseline to Day 6 | QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected from within-subject data (QTci) msec. |
| The Average Differences From Baseline Between Moxifloxacin and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13 | Baseline to Day 6 and Day 13 | QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc (interval corrected for heart rate) data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected by Fridericia's method (QTcF) msec. |
| The Average Differences From Baseline Between BTDS and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13 | Baseline to Day 6 and Day 13 | QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc (interval corrected for heart rate) data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected by Fridericia's method (QTcF) msec. |
| The Average Differences Between Moxifloxacin vs Placebo From Baseline by Interval Corrected From Within-subject Data (QTci) on Day 6 | Baseline to Day 6 | QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected from within-subject data (QTci) msec. |
Countries
United States
Participant flow
Recruitment details
02-Jul-2004 (first patient first visit) to 16-Dec-2004 (last patient last visit) at 1 site in the US (Austin, TX.)
Pre-assignment details
During the initial screening visit, subjects were assessed for study eligibility through medical history, physical examination, vital signs, oxygen saturation, conventional 12-lead ECG, and laboratory tests. The investigator at the site examined the ECG telemetry to determine the subjects' eligibility.
Participants by arm
| Arm | Count |
|---|---|
| BTDS Buprenorphine transdermal patches 5, 10, 20, and 2 \* 20 mcg/h. | 44 |
| Placebo Matching placebo transdermal patches. | 44 |
| Moxifloxacin Positive control: One 400 mg moxifloxacin tablet (Avelox®) by mouth on days 6 and 13 | 44 |
| Total | 132 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 2 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 2 |
Baseline characteristics
| Characteristic | BTDS | Placebo | Moxifloxacin | Total |
|---|---|---|---|---|
| Age Continuous | 30.8 years STANDARD_DEVIATION 9.46 | 34.1 years STANDARD_DEVIATION 10.7 | 28.8 years STANDARD_DEVIATION 9.69 | 31.2 years STANDARD_DEVIATION 10.1 |
| Sex: Female, Male Female | 22 Participants | 23 Participants | 23 Participants | 68 Participants |
| Sex: Female, Male Male | 22 Participants | 21 Participants | 21 Participants | 64 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 43 / 44 | 31 / 44 | 12 / 44 |
| serious Total, serious adverse events | 0 / 44 | 0 / 44 | 1 / 44 |
Outcome results
Primary
The Comparison of BTDS to Placebo Transdermal System (TDS): the Average Difference From Baseline Using QT Corrected From Within-subject Data (QTci) on Day 13
Observed time from start of the QRS complex to end of the T wave (QT), and the time between the 2 R waves (RR) data for each of 4 electrocardiographs (ECGs) over an approximate 10-minute interval at each nominal time point. The average QT and QTc data over the 2 pretreatment days were used as the baseline. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected from within-subject data (QTci) msec.
Time frame: Baseline to Day 13
Population: The full analysis population for ECGs (N = 131) was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose digital QT/QTc evaluation.~For the comparison of BTDS to placebo (N = 88), the subjects randomized to moxifloxacin were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BTDS | The Comparison of BTDS to Placebo Transdermal System (TDS): the Average Difference From Baseline Using QT Corrected From Within-subject Data (QTci) on Day 13 | 4.20 QTci (msec) | Standard Deviation 7.44 |
| Placebo | The Comparison of BTDS to Placebo Transdermal System (TDS): the Average Difference From Baseline Using QT Corrected From Within-subject Data (QTci) on Day 13 | -1.71 QTci (msec) | Standard Deviation 6.92 |
p-value: <0.00190% CI: [3.4, 8.4]ANCOVA
Primary
The Comparison of Moxifloxacin to Placebo Transdermal System (TDS): the Average Difference From Baseline Using QT Interval Corrected From Within-subject Data (QTci) on Day 13
Observed time from start of the QRS complex to end of the T wave (QT), and the time between the 2 R waves (RR) data for each of 4 electrocardiographs (ECGs) over an approximate 10-minute interval at each nominal time point. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected from within-subject data (QTci) msec.
Time frame: Baseline to Day 13
Population: The full analysis population for ECGs (N = 131) was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose digital QT/QTc evaluation.~For the comparison of moxifloxacin to placebo (N=88), the subjects randomized to BTDS were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BTDS | The Comparison of Moxifloxacin to Placebo Transdermal System (TDS): the Average Difference From Baseline Using QT Interval Corrected From Within-subject Data (QTci) on Day 13 | 4.17 QTci (msec) | Standard Deviation 7.22 |
| Placebo | The Comparison of Moxifloxacin to Placebo Transdermal System (TDS): the Average Difference From Baseline Using QT Interval Corrected From Within-subject Data (QTci) on Day 13 | -1.69 QTci (msec) | Standard Deviation 6.92 |
Comparison: Day 13 analysisp-value: <0.00190% CI: [3.3, 8.4]ANCOVA
Secondary
The Average Differences Between BTDS vs Placebo From Baseline by Interval Corrected From Within-subject Data (QTci) on Day 6
QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected from within-subject data (QTci) msec.
Time frame: Baseline to Day 6
Population: The full analysis population for ECGs (N = 131) was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose digital QT/QTc evaluation.~For the comparison of BTDS to placebo (N = 88), the subjects randomized to moxifloxacin were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BTDS | The Average Differences Between BTDS vs Placebo From Baseline by Interval Corrected From Within-subject Data (QTci) on Day 6 | -1.06 QTci (msec) | Standard Deviation 6.17 |
| Placebo | The Average Differences Between BTDS vs Placebo From Baseline by Interval Corrected From Within-subject Data (QTci) on Day 6 | -1.46 QTci (msec) | Standard Deviation 6.69 |
p-value: 0.7790% CI: [-1.8, 2.6]ANCOVA
Secondary
The Average Differences Between Moxifloxacin vs Placebo From Baseline by Interval Corrected From Within-subject Data (QTci) on Day 6
QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected from within-subject data (QTci) msec.
Time frame: Baseline to Day 6
Population: The full analysis population for ECGs (N = 131) was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose digital QT/QTc evaluation~For the comparison of moxifloxacin to placebo (N = 88), the subjects randomized to BTDS were excluded.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| BTDS | The Average Differences Between Moxifloxacin vs Placebo From Baseline by Interval Corrected From Within-subject Data (QTci) on Day 6 | 6.26 QTci (msec) | Standard Deviation 6.11 |
| Placebo | The Average Differences Between Moxifloxacin vs Placebo From Baseline by Interval Corrected From Within-subject Data (QTci) on Day 6 | -1.38 QTci (msec) | Standard Deviation 6.69 |
p-value: <0.00190% CI: [5.4, 9.9]ANCOVA
Secondary
The Average Differences From Baseline Between BTDS and Placebo by Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13
QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc (QT interval corrected for heart rate) data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected by Bazett's method (QTcB) msec.
Time frame: Baseline to Day 6 and Day 13
Population: The full analysis population for ECGs (N = 131) was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose digital QT/QTc evaluation.~For the comparison of BTDS to placebo (N = 88), the subjects randomized to moxifloxacin were excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BTDS | The Average Differences From Baseline Between BTDS and Placebo by Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13 | QTcB Day 6 | -0.37 QTcB (msec) | Standard Deviation 7.18 |
| BTDS | The Average Differences From Baseline Between BTDS and Placebo by Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13 | QTcB Day 13 | 6.31 QTcB (msec) | Standard Deviation 8.73 |
| Placebo | The Average Differences From Baseline Between BTDS and Placebo by Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13 | QTcB Day 6 | -0.24 QTcB (msec) | Standard Deviation 8.15 |
| Placebo | The Average Differences From Baseline Between BTDS and Placebo by Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13 | QTcB Day 13 | -0.86 QTcB (msec) | Standard Deviation 8.49 |
Comparison: Day 6 analysisp-value: 0.93690% CI: [-2.9, 2.6]ANCOVA
Comparison: Day 13 analysisp-value: <0.00190% CI: [4.2, 10.1]ANCOVA
Secondary
The Average Differences From Baseline Between BTDS and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13
QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc (interval corrected for heart rate) data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected by Fridericia's method (QTcF) msec.
Time frame: Baseline to Day 6 and Day 13
Population: The full analysis population for ECGs (N = 131) was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose digital QT/QTc evaluation.~For the comparison of BTDS to placebo (N = 88), the subjects randomized to moxifloxacin were excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BTDS | The Average Differences From Baseline Between BTDS and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13 | QTcF Day 6 | -1.04 QTcF (msec) | Standard Deviation 7.32 |
| BTDS | The Average Differences From Baseline Between BTDS and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13 | QTcF Day 13 | 4.13 QTcF (msec) | Standard Deviation 8.3 |
| Placebo | The Average Differences From Baseline Between BTDS and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13 | QTcF Day 6 | -2.33 QTcF (msec) | Standard Deviation 8.07 |
| Placebo | The Average Differences From Baseline Between BTDS and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13 | QTcF Day 13 | -1.88 QTcF (msec) | Standard Deviation 7.67 |
Comparison: Day 6 analysisp-value: 0.42790% CI: [-1.4, 4]ANCOVA
Comparison: Day 13 analysisp-value: 0.00190% CI: [3.2, 8.8]ANCOVA
Secondary
The Average Differences From Baseline Between Moxifloxacin and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13
QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc (interval corrected for heart rate) data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected by Fridericia's method (QTcF) msec.
Time frame: Baseline to Day 6 and Day 13
Population: The full analysis population for ECGs (N = 131) was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose digital QT/QTc evaluation.~For the comparison of moxifloxacin to placebo (N = 88), the subjects randomized to BTDS were excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BTDS | The Average Differences From Baseline Between Moxifloxacin and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13 | QTcF Day 6 | 4.74 QTcF (msec) | Standard Deviation 7.21 |
| BTDS | The Average Differences From Baseline Between Moxifloxacin and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13 | QTcF Day 13 | 2.83 QTcF (msec) | Standard Deviation 7.81 |
| Placebo | The Average Differences From Baseline Between Moxifloxacin and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13 | QTcF Day 6 | -2.12 QTcF (msec) | Standard Deviation 8.07 |
| Placebo | The Average Differences From Baseline Between Moxifloxacin and Placebo by Fridericia's Corrected Interval (QTcF) on Day 6 and Day 13 | QTcF Day 13 | -1.85 QTcF (msec) | Standard Deviation 7.67 |
Comparison: Day 6 analysisp-value: <0.00190% CI: [4.2, 9.6]ANCOVA
Comparison: Day 13 analysisp-value: 0.00690% CI: [1.9, 7.4]ANCOVA
Secondary
The Average Differences From Baseline Between Moxifloxacin and Placebo of Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13
QT and RR data were determined for each of 4 ECGs over an approximate 10-minute interval at each nominal time point. The average QT and QTc data from the replicate ECGs at each nominal time point were calculated. The average QT and QTc data over the 2 pretreatment days were used as the baseline QT and QTc values. Observed time from start of the QRS complex to end of the T wave (QT); interval corrected for heart rate (QTc) msec; interval corrected by Bazett's method (QTcB) msec.
Time frame: Baseline to Day 6 and Day 13
Population: The full analysis population for ECGs (N = 131) was defined as all subjects who received at least 1 dose of study drug and had at least 1 postdose digital QT/QTc evaluation.~For the comparison of moxifloxacin to placebo (N=88), the subjects randomized to BTDS were excluded.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|---|
| BTDS | The Average Differences From Baseline Between Moxifloxacin and Placebo of Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13 | QTcB Day 6 | 8.13 QTcB (msec) | Standard Deviation 6.92 |
| BTDS | The Average Differences From Baseline Between Moxifloxacin and Placebo of Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13 | QTcB Day 13 | 6.55 QTcB (msec) | Standard Deviation 8.59 |
| Placebo | The Average Differences From Baseline Between Moxifloxacin and Placebo of Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13 | QTcB Day 6 | -0.09 QTcB (msec) | Standard Deviation 8.15 |
| Placebo | The Average Differences From Baseline Between Moxifloxacin and Placebo of Bazett Corrected QT Interval (QTcB) on Day 6 and Day 13 | QTcB Day 13 | -0.84 QTcB (msec) | Standard Deviation 8.49 |
Comparison: Day 6 analysisp-value: <0.00190% CI: [5.5, 10.9]ANCOVA
Comparison: Day 13 analysisp-value: <0.00190% CI: [4.3, 10.5]ANCOVA