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

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

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.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: HYD; Drug: Placebo for moxifloxacin; Drug: Moxifloxacin; Drug: Placebo for HYD

• Study Type: Interventional
• Enrollment (Actual): 208
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States, 78744
      • PPD Phase I Clinic

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 48 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: HYD	Drug: HYD; 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.; Drug: Placebo for moxifloxacin; Placebo to match moxifloxacin tablets administered orally on the mornings of day 9, day 12, and day 15 only.
Other: Moxifloxacin; Moxifloxacin is the positive control.	Drug: Moxifloxacin; Moxifloxacin 400 mg tablets administered orally on the morning of day 9, day 12, and day 15 only.; Other Names: Avelox®; Drug: Placebo for HYD; Placebo to match HYD tablets administered orally every 24 hours.
Placebo Comparator: Placebo; Placebo for HYD and placebo for moxifloxacin	Drug: Placebo for moxifloxacin; Placebo to match moxifloxacin tablets administered orally on the mornings of day 9, day 12, and day 15 only.; Drug: Placebo for HYD; Placebo to match HYD tablets administered orally every 24 hours.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Purdue Pharma LP

Study record dates

Study Major Dates

• Study Start: November 1, 2012
• Primary Completion (Actual): May 1, 2013
• Study Completion (Actual): May 1, 2013

Study Registration Dates

• First Submitted: September 15, 2014
• First Submitted That Met QC Criteria: September 15, 2014
• First Posted (Estimate): September 17, 2014

Study Record Updates

• Last Update Posted (Estimate): September 17, 2014
• Last Update Submitted That Met QC Criteria: September 15, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Healthy volunteers; Opioid; ECG; QTcI
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Contraceptive Agents, Hormonal; Contraceptive Agents; Reproductive Control Agents; Contraceptives, Oral, Combined; Contraceptives, Oral; Contraceptive Agents, Female; Moxifloxacin; Norgestimate, ethinyl estradiol drug combination
• Other Study ID Numbers: HYD1009