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

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

Official Title
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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

Conditions
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Healthy Subjects

Intervention / Treatment
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* Drug: Exenatide
* Drug: Moxifloxacin
* Drug: Placebo comparator


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: Crossover Assignment
Masking: Triple


Arms and Interventions

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

What is the study measuring?
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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 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, exenatide, Amylin, Lilly, QT interval