The Effect of Hydrocodone Bitartrate (HYD) Extended-Release Tablets on QT /QTc Intervals in Healthy Adult Subjects

Study Overview
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Brief Summary
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Evaluate the effect of multiple doses (once daily for 3 days each of HYD 80, 120, and 160 mg tablets) on the QT/QTc interval.

Official Title
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A Randomized, Double-blind, Placebo- and Positive-Controlled, Parallel Group, Dose Escalating Study of the Effect of Hydrocodone Bitartrate (HYD) Extended-Release Tablets at Doses up to 160 mg on QT/QTc in Healthy Adult Subjects

Conditions
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Healthy

Intervention / Treatment
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* Drug: HYD
* Drug: Moxifloxacin
* Drug: Placebo for HYD
* Drug: Placebo for moxifloxacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent; Body weight ranging from 50 to 100 kilograms (kg) [110 to 220 pounds] and body mass index (BMI) of 18 to 30 (kg/m2); Males and females aged 18 to 50 years; Willing to eat the food supplied during the study; Willing to refrain from strenuous exercise through the end-of-study visit. Subjects did not begin a new exercise program nor participate in any unusually strenuous physical exertion; Healthy and free of significant abnormal findings as determined by medical history, physical examination, clinical laboratory values, vital signs, and safety 12-lead ECG; Females of childbearing potential must use 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 be postmenopausal for ≥ 1 year and have elevated serum follicle stimulating hormone (FSH). 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 may interfere with drug absorption, 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 hydrocodone, opioids, psychotropic or hypnotic drugs, 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 of study drug 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 of study drug; Any significant illness during the 30 days preceding the initial dose of study drug in this study; 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: QT data corrected for heart rate using the Fridericia formula (QTcF) interval >450 milliseconds (msec) PR interval >240 msec or QRS >110 msec Evidence of second- or third-degree atrioventricular block Pathological Q-waves (defined as Q-wave >40 msec or depth >0.5 millivolts [mV]) Evidence of ventricular pre-excitation, complete left bundle branch block (LBBB), right bundle branch block (RBBB), or incomplete RBBB With a resting heart rate (HR) outside the range of 40 to 90 beats per minute (bpm); Abnormalities on physical examination, vital signs, safety 12-lead ECG, or clinical laboratory values, unless those abnormalities are judged clinically insignificant by the investigator; Oxygen saturation <94% as measured by pulse oximetry (SpO2); Refusal to abstain completely from caffeine or xanthine during confinement; Refusal to abstain from consumption of alcoholic beverages 48 hours prior to initial study drug administration through the end-of-study visit; Blood or blood products donated within 30 days prior to initial study drug administration or any time through the end-of-study visit, except as required by the study protocol; History of smoking or use of nicotine products within 45 days of initial study drug administration or a positive urine cotinine test; Positive results of urine drug screen or alcohol screen; Positive results of hepatitis B surface antigen (HBsAg), hepatitis C antibody (anti-HCV); 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.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 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

Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: HYD<br> | Drug: HYD<br>* Hydrocodone bitartrate 80 mg (day 9), 120 mg (day 12), 160 mg [(1) 40 mg tablet + (1) 120 mg tablet] (day 15) extended-release tablets administered orally every 24 hours.<br>Drug: Placebo for moxifloxacin<br>* Placebo to match moxifloxacin tablets administered orally on the mornings of day 9, day 12, and day 15 only.<br>|
| Other: Moxifloxacin<br>Moxifloxacin is the positive control. | Drug: Moxifloxacin<br>* Moxifloxacin 400 mg tablets administered orally on the morning of day 9, day 12, and day 15 only.<br>* Other names: Avelox®;Drug: Placebo for HYD<br>* Placebo to match HYD tablets administered orally every 24 hours.<br>|
| Placebo Comparator: Placebo<br>Placebo for HYD and placebo for moxifloxacin | Drug: Placebo for HYD<br>* Placebo to match HYD tablets administered orally every 24 hours.<br>Drug: Placebo for moxifloxacin<br>* Placebo to match moxifloxacin tablets administered orally on the mornings of day 9, day 12, and day 15 only.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time-matched analysis on QT data (change from baseline, placebo-subtracted) corrected for heart rate (QTc), based on an individual correction (QTcI) method | The electrocardiogram (ECG) effects of HYD 80 mg (day 9) on the QT/QTc interval | Baseline and Day 9 | 
| The time-matched analysis on QT data (change from baseline, placebo-subtracted) corrected for heart rate (QTc), based on an individual correction (QTcI) method | The ECG effects of HYD 120 mg (day 12) on the QT/QTc interval | Baseline and Day 12 | 
| The time-matched analysis on QT data (change from baseline, placebo-subtracted) corrected for heart rate (QTc), based on an individual correction (QTcI) method | The ECG effects of HYD 160 mg (day 15) on the QT/QTc interval | Baseline and Day 15 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The time-matched analysis on QT data (change from baseline, placebo-subtracted) corrected for heart rate (QTc), based on an individual correction (QTcI) method | The ECG effects of moxifloxacin (day 9) on the QT/QTc interval | Baseline and Day 9 | 
| The time-matched analysis on QT data (change from baseline, placebo-subtracted) corrected for heart rate (QTc), based on an individual correction (QTcI) method | The ECG effects of moxifloxacin (day 12) on the QT/QTc interval | Baseline and Day 12 | 
| The time-matched analysis on QT data (change from baseline, placebo-subtracted) corrected for heart rate (QTc), based on an individual correction (QTcI) method | The ECG effects of moxifloxacin (day 15) on the QT/QTc interval | Baseline and Day 15 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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ECG, Healthy volunteers, Opioid, QTcI