A Safety Study to Assess the Effects of Therapeutic and Supratherapeutic Exenatide Concentrations on QT Interval in Healthy Subjects

A Randomized, Phase 1, Three-Period, Placebo- and Positive-Controlled, Double-Blind, Crossover Study to Assess the Electrophysiological Effects of Exenatide at Therapeutic and Supratherapeutic Concentrations on the 12-Lead Electrocardiogram QT Interval in Healthy Subjects

Compare the effect of exenatide (therapeutic and supratherapeutic concentrations), moxifloxacin and placebo on the QT interval.

Study Overview

• Status: Completed
• Conditions: Healthy Subjects
• Intervention / Treatment: Drug: Exenatide; Drug: Placebo comparator; Drug: Moxifloxacin

• Study Type: Interventional
• Enrollment (Actual): 94
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Florida
    • Daytona Beach, Florida, United States
      • Research Site
  • Indiana
    • Evansville, Indiana, United States
      • Research Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Is overtly healthy, as determined by medical history and physical examination
• Has body mass index (BMI) between 25 and 35 kg/m2
• Has fasting serum glucose <110 mg/dL
• Has no clinically significant blood pressure or heart rate readings as judged by the investigator at study start
• Has electrocardiogram (ECG) results judged as not clinically significant by the investigator at study start

Exclusion Criteria:

• Has a clinically significant medical condition that could potentially affect study participation and/or personal well-being
• Has an abnormality in the 12-lead ECG that, in the opinion of the investigator, increases the risk of participating in the study, such as a Bazett's corrected QT (QTcB) interval >450 ms.
• Family history of sudden death
• Personal history of unexplained syncope within last year, or family history of Long QT Syndrome, or significant active cardiac disease, or symptoms of angina pectoris or transient ischemic attacks within the previous 6 months

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo	Drug: Placebo comparator; IV Placebo (matching volume of placebo)
Experimental: Exenatide	Drug: Exenatide; IV Exenatide (therapeutic and supratherapeutic concentrations)
Active Comparator: Moxifloxacin	Drug: Moxifloxacin; Oral Moxifloxacin (400 mg)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Comparison of Least Squares (LS) Mean Changes From Baseline in Population-based Corrected QT Intervals (QTcP) Between Exenatide and Placebo on Day 1 Averaged Over 1300h, 1400h, 1500h (Target Steady State Exenatide Concentration of 200 pg/mL)	Factors in QT correction formulas were first estimated using pre-therapy data. The most appropriate correction method (QTcP) minimized the mean squared individual QTc/RR regression slope with on-exenatide data. Adequacy of correction was validated with on-placebo data. Change from baseline in QTcP was analyzed by a mixed-effects model for repeated measures (MMRM) between exenatide and placebo.	Baseline, Day 1
Comparison of LS Mean Changes From Baseline in QTcP Intervals Between Exenatide and Placebo on Day 2 Averaged Over 1300h, 1400h, 1500h (Target Steady State Exenatide Concentration of 300 pg/mL)	Factors in QT correction formulas were first estimated using pre-therapy data. The most appropriate correction method (QTcP) minimized the mean squared individual QTc/RR regression slope with on-exenatide data. Adequacy of correction was validated with on-placebo data. Change from baseline in QTcP was analyzed by a MMRM between exenatide and placebo.	Baseline, Day 2
Comparison of LS Mean Changes From Baseline in QTcP Intervals Between Exenatide and Placebo on Day 3 Averaged Over 1300h, 1400h, 1500h (Target Steady State Exenatide Concentration of 500 pg/mL)	Factors in QT correction formulas were first estimated using pre-therapy data. The most appropriate correction method (QTcP) minimized the mean squared individual QTc/RR regression slope with on-exenatide data. Adequacy of correction was validated with on-placebo data. Change from baseline in QTcP was analyzed by a MMRM between exenatide and placebo.	Baseline, Day 3

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assay Sensitivity of Moxifloxacin at 1000h (1 Hour Post-administration of Moxifloxacin) on Day 2	Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo.	Baseline, Day 2
Assay Sensitivity of Moxifloxacin at 1100h (2 Hour Post-administration of Moxifloxacin) on Day 2	Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo.	Baseline, Day 2
Assay Sensitivity of Moxifloxacin at 1200h (3 Hour Post-administration of Moxifloxacin) on Day 2	Change from baseline in QTcP was analyzed by a MMRM between moxifloxacin and placebo.	Baseline, Day 2
Number of Subjects With QTcP Interval >450msec at Any Timepoint on Any Day in Exenatide and Placebo	Number of subjects with QTcP > 450 msec at any timepoint on any day was summarized by frequency for exenatide and placebo.	Day 1, 2, or 3
Number of Subjects With Increase of QTcP Interval From Baseline >30msec at Any Timepoint on Any Day in Exenatide and Placebo	Number of subjects with increase of QTcP interval from baseline >30 msec at any timepoint on any day was summarized by frequency for exenatide and placebo.	Baseline, Day 1, 2, or 3
Plasma Exenatide Concentrations at Steady State on Day 1, 2 and 3	The plasma exenatide concentration at steady state was descriptively summarized by geometric mean, standard error, and its effect on placebo-adjusted change from baseline in QTcP was assessed.	Baseline, Day 1, 2, and 3

Collaborators and Investigators

• Sponsor: AstraZeneca
• Collaborators: Eli Lilly and Company
• Investigators: Study Director: Vice President Research and Development, MD, Amylin Pharmaceuticals, LLC.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): April 1, 2011
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: February 9, 2011
• First Submitted That Met QC Criteria: February 14, 2011
• First Posted (Estimate): February 16, 2011

Study Record Updates

• Last Update Posted (Estimate): April 14, 2015
• Last Update Submitted That Met QC Criteria: March 24, 2015
• Last Verified: March 1, 2015

More Information

Terms related to this study

• Keywords: Diabetes; exenatide; Lilly; Amylin; QT interval
• Additional Relevant MeSH Terms: Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Anti-Obesity Agents; Incretins; Moxifloxacin; Exenatide
• Other Study ID Numbers: BCB112