Study to Evaluate the Effect of Naltrexone and Bupropion Extended-Release Combination on Cardiac Repolarization in Healthy Participants

A Randomized, Double-Blind, Placebo- and Moxifloxacin Positive-Controlled (Open-Label), Cross-Over Study to Evaluate the Potential Effect of Naltrexone and Bupropion Extended-Release Combination on Cardiac Repolarization in Healthy Subjects

The purpose of this study is to evaluate the potential effect of naltrexone and bupropion extended-release combination on cardiac repolarization in healthy participants.

Study Overview

• Status: Completed
• Conditions: Heart Repolarization
• Intervention / Treatment: Drug: Naltrexone HCl/bupropion HCl; Other: Placebo; Drug: Moxifloxacin

Detailed Description

The drug being tested in this study is called naltrexone HCl/bupropion HCl (NB). NB is approved by the U.S. Food and Drug Administration (FDA) in addition to a reduced-calorie diet and increased physical activity for chronic weight management in adults who are obese or who are overweight and have at least one additional weight-related condition such as high blood pressure, diabetes or high cholesterol. This study is conducted to determine the potential effect of NB relative to placebo on cardiac repolarization.

The study will enroll approximately 84 participants. Participants will be randomly assigned (by chance, like flipping a coin) to 1 of 6 treatment sequences, which will remain undisclosed to the participant and study doctor during the study (unless there is an urgent medical need):

• Naltrexone/Bupropion + Placebo + Moxifloxacin
• Placebo + Moxifloxacin + Naltrexone/Bupropion
• Moxifloxacin + Naltrexone/Bupropion + Placebo
• Naltrexone/Bupropion + Moxifloxacin + Placebo
• Placebo + Naltrexone/Bupropion + Moxifloxacin
• Moxifloxacin + Placebo + Naltrexone/Bupropion

This study is consisted of 3 periods separated by a washout period (Days 11 through 25). Participants will be admitted to the clinic on Day -2 (Check-in) of each study period and will remain confined to the clinic until the morning of Day 12 of each study period. On Day -1 and Day 11 of each period, participants will undergo 24 hour Holter recordings using an ambulatory electrocardiograph recorder.

This single center trial will be conducted in the United States. The overall time to participate in this study is approximately 96 days.

• Study Type: Interventional
• Enrollment (Actual): 84
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Texas
    • Austin, Texas, United States

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Is a healthy male or female.
2. Is aged 18 to 55 years, inclusive, at signing of informed consent and first dose of study drug.
3. Weighs at least 50 kilogram (kg) and has a body mass index (BMI) of 18.0 to 35.0 kilogram per square meter (kg/m^2), inclusive, at screening.

Exclusion Criteria:

1. Has known hypersensitivity to moxifloxacin or other quinolone antibiotics or any component of the formulation of naltrexone/bupropion.
2. Has a history of seizure of any etiology, or of predisposition to seizures.
3. Has a history of significant cardiac disease.
4. Has a history of bulimia.
5. Has a history of anorexia nervosa.
6. Has a hemoglobin concentration less than (<) 12 gram per deciliter (g/dL) at screening or check-in (day -2) of period 1.
7. Has resting heart rate outside the normal range of 45 to 100 beats per minute at screening or check-in (day -2) of period 1.
8. Has orthostatic blood pressure greater than or equal to (>=) 25 millimeters of mercury (mm Hg) at screening or check-in (day -2) of period 1.
9. Has sustained supine systolic blood pressure >=140 mm Hg or <=90 mm Hg or a diastolic blood pressure >=90 mm Hg or <=50 mm Hg at screening or check-in (day -2) of period 1.
10. Has abnormal screening or check-in (day -2) of period 1 ECG indicating a second- or third-degree atrioventricular block, or 1 or more of the following: PR >220 msec, QRS >120 msec, and QTcF >450 msec, or any rhythm other than sinus rhythm that is interpreted by the investigator to be clinically significant or could interfere with an accurate measurement of the QT interval.
11. Has family history of long QT syndrome.
12. Had extensive exercising in normal life, for example, marathon running, triathlon, physical sports at a contest level.

Study Plan

How is the study designed?

Design Details

• Allocation: RANDOMIZED
• Interventional Model: CROSSOVER
• Masking: QUADRUPLE

Number of Arms

6

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Nalterxone/Bupropion + Placebo + Moxifloxacin; Naltrexone hydrochloride (HCl) 8 milligram (mg)/bupropion HCl 90 mg (NB) placebo-matching 2 tablets, orally, once in the morning on Day -1, NB, 1 extended-release tablet, orally, twice daily and NB placebo-matching 1 tablet, orally, twice daily from Days 1 to 3, NB, 2 extended-release tablets, orally, twice daily from Days 4 to 10 and once in the morning on Day 11 in treatment period 1, followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10, and once in the morning on Day 11 in treatment period 2, followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10, moxifloxacin 400 mg, tablet, orally, once in the morning on Day 11 in treatment period 3.	Drug: Naltrexone HCl/bupropion HCl; Naltrexone HCl/bupropion HCl extended-release tablet.; Other: Placebo; Naltrexone/bupropion placebo-matching tablets.; Drug: Moxifloxacin; Moxifloxacin tablet.
EXPERIMENTAL: Placebo + Moxifloxacin + Naltrexone/Bupropion; NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10 and once in the morning on Day 11 in treatment period 1, followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10, moxifloxacin 400 mg, tablet, orally, once in the morning on Day 11 in treatment period 2, followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, NB, 1 extended-release tablet, orally, twice daily and NB placebo-matching 1 tablet, orally, twice daily from Days 1 to 3, NB, 2 extended-release tablets, orally, twice daily from Days 4 to 10 and once in the morning on Day 11 in treatment period 3.	Drug: Naltrexone HCl/bupropion HCl; Naltrexone HCl/bupropion HCl extended-release tablet.; Other: Placebo; Naltrexone/bupropion placebo-matching tablets.; Drug: Moxifloxacin; Moxifloxacin tablet.
EXPERIMENTAL: Moxifloxacin + Naltrexone/Bupropion + Placebo; NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10, moxifloxacin 400 mg, tablet, orally, once in the morning on Day 11 in treatment period 1, followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, NB, 1 extended-release tablet, orally, twice daily and NB placebo-matching 1 tablet, orally, twice daily from Days 1 to 3, NB, 2 extended-release tablets, orally, twice daily from Day 4 to 10, and once in the morning on Day 11 in treatment period 2, followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10 and once in the morning on Day 11 in the treatment period 3.	Drug: Naltrexone HCl/bupropion HCl; Naltrexone HCl/bupropion HCl extended-release tablet.; Other: Placebo; Naltrexone/bupropion placebo-matching tablets.; Drug: Moxifloxacin; Moxifloxacin tablet.
EXPERIMENTAL: Naltrexone/Bupropion + Moxifloxacin + Placebo; NB placebo-matching 2 tablets, orally, once in the morning on Day -1, NB, 1 extended-release tablet, orally, twice daily and NB placebo-matching 1 tablet, orally, twice daily from Days 1 to 3, NB, 2 extended-release tablets, orally, twice daily from Days 4 to 10 and once in the morning on Day 11 in treatment period 1, followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10, moxifloxacin 400 mg, tablet, orally, once in the morning on Day 11 in treatment period 2 followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10 and once in the morning on Day 11 in treatment period 3.	Drug: Naltrexone HCl/bupropion HCl; Naltrexone HCl/bupropion HCl extended-release tablet.; Other: Placebo; Naltrexone/bupropion placebo-matching tablets.; Drug: Moxifloxacin; Moxifloxacin tablet.
EXPERIMENTAL: Placebo + Naltrexone/Bupropion + Moxifloxacin; NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10 and once in the morning on Day 11 in treatment period 1, followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, NB, 1 extended-release tablet, orally, twice daily and NB placebo-matching 1 tablet, orally, twice daily from Days 1 to 3, NB, 2 extended-release tablets, orally, twice daily from Days 4 to 10 and once in the morning on Day 11 in treatment period 2 followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10, moxifloxacin 400 mg, tablet, orally, once in the morning on Day 11 in treatment period 3.	Drug: Naltrexone HCl/bupropion HCl; Naltrexone HCl/bupropion HCl extended-release tablet.; Other: Placebo; Naltrexone/bupropion placebo-matching tablets.; Drug: Moxifloxacin; Moxifloxacin tablet.
EXPERIMENTAL: Moxifloxacin + Placebo + Naltrexone/Bupropion; NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10, moxifloxacin 400 mg, tablet, orally, once in the morning on Day 11 in treatment period 1 followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, twice daily from Days 1 to 10 and once in the morning on Day 11 in treatment period 2 followed by 14 days washout period, followed by NB placebo-matching 2 tablets, orally, once in the morning on Day -1, NB, 1 extended-release tablet, orally, twice daily and NB placebo-matching 1 tablet, orally, twice daily from Days 1 to 3, NB, 2 extended-release tablets, orally, twice daily from Days 4 to 10 and once in the morning on Day 11 in treatment period 3.	Drug: Naltrexone HCl/bupropion HCl; Naltrexone HCl/bupropion HCl extended-release tablet.; Other: Placebo; Naltrexone/bupropion placebo-matching tablets.; Drug: Moxifloxacin; Moxifloxacin tablet.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The time-matched change from Baseline in QT interval with Fridericia correction method (QTcF)	QT and RR intervals will be recorded using ECG machines. Fridericia correction method is calculated by dividing QT interval by the cube root of the RR interval: QTcF = QT/RR^1/3.	Time matched Baseline and Day 11 within 30 minutes predose and up to 23.5 hours postdose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time-Matched Change From Baseline in QT Interval With Bazett Correction Method (QTcB) at Day 11	QT and RR intervals will be recorded using ECG machines. QTcB will be calculated by dividing QT interval by the square root of the RR interval: QTcB = QT/RR^1/2.	Time matched baseline and at multiple time-points (up to 23.5 hours) postdose on Day 11
Time-Matched Change From Baseline in QT Interval With Individual Correction Method (QTcI) at Day 11	QT and RR intervals will be recorded using ECG machines. QTcI will be calculated as QT/RR^beta, where the value of beta will be calculated using linear regression modeling for each subject on all baseline QT - RR interval pairs.	Time matched baseline and at multiple time-points (up to 23.5 hours) postdose on Day 11
Time-Matched Change From Baseline in Uncorrected QT at Day 11		Time matched baseline and at multiple time-points (up to 23.5 hours) postdose on Day 11
Time-Matched Increases From Baseline in QTcF, QTcB, QTcI, and QT > 30 msec and > 60 msec at Day 11	QTcF will be calculated by dividing QT interval by the cube root of the RR interval: QTcF= QT/RR^1/3. QTcB will be calculated by dividing QT interval by the square root of the RR interval: QTcB = QT/RR^1/2. QTcI will be calculated as as QT/RR^beta, where the value of beta will be calculated using linear regression modeling for each subject on all baseline QT - RR interval pairs	Baseline and Day 11
QTcF, QTcB, QTcI, and QT intervals >450 msec, >480 msec or >500 msec at Day 11	QTcF will be calculated by dividing QT interval by the cube root of the RR interval: QTcF= QT/RR^1/3. QTcB will be calculated by dividing QT interval by the square root of the RR interval: QTcB = QT/RR^1/2. QTcI will be calculated as QT/RR^beta., where the value of beta will be calculated using linear regression modeling for each subject on all baseline QT - RR interval pairs.	Day 11
T-U wave complex morphology on Day 11		Day 11
Cmax- Maximum Observed Plasma Concentration for Naltrexone, Bupropion, and their Metabolites		Day 11: predose and at multiple time points (up to 23.5 hours) postdose
Tmax- Time to Reach the Maximum Plasma Concentration (Cmax) for Naltrexone, Bupropion, and their Metabolites		Day 11: predose and at multiple time points (up to 23.5 hours) postdose
9. Percentage of Participants Reporting at least one Treatment-Emergent Adverse Event (TEAE)		Baseline up to 30 days after the last dose of study drug

Collaborators and Investigators

• Sponsor: Orexigen Therapeutics, Inc

Study record dates

Study Major Dates

• Study Start: April 1, 2016
• Primary Completion (ACTUAL): July 1, 2016
• Study Completion (ACTUAL): October 1, 2016

Study Registration Dates

• First Submitted: April 5, 2016
• First Submitted That Met QC Criteria: April 7, 2016
• First Posted (ESTIMATE): April 12, 2016

Study Record Updates

• Last Update Posted (ESTIMATE): November 1, 2016
• Last Update Submitted That Met QC Criteria: October 31, 2016
• Last Verified: October 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Sensory System Agents; Antineoplastic Agents; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Psychotropic Drugs; Neurotransmitter Uptake Inhibitors; Membrane Transport Modulators; Antidepressive Agents; Dopamine Agents; Narcotic Antagonists; Cytochrome P-450 Enzyme Inhibitors; Antidepressive Agents, Second-Generation; Cytochrome P-450 CYP2D6 Inhibitors; Alcohol Deterrents; Dopamine Uptake Inhibitors; Moxifloxacin; Naltrexone; Bupropion
• Other Study ID Numbers: NaltrexBuprop-1001; U1111-1171-3290 (REGISTRY: WHO)