Study of the Effects of Intravenous Exenatide on Cardiac Repolarization

Study Overview
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Brief Summary
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Two-Part, Randomized, Placebo and Active-Controlled, Double-Blind, Thorough QT Study Evaluating the Effects of Intravenous Exenatide on Cardiac Repolarization in Healthy Male and Female Volunteers

Detailed Description
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This single-center Phase I study will consist of 2 parts, a Pilot Part and a Core Part. The Pilot Part of the study will be an open-label, non-randomized, single-treatment design in 10 healthy male and female subjects to determine if an infusion regimen of a 6-h continuous IV infusion of exenatide will lead to a mean plasma steady state concentration of 500 pg/mL. The Core part of the study will be a double-blind (except for the use of open label active control moxifloxacin), randomized, placebo-controlled,3 period, 6-sequence, cross-over design in 72 healthy male and female subjects to evaluate whether exenatide at therapeutic and supra-therapeutic concentrations has a pharmacological effect on cardiac repolarization (threshold value >10 msec).

Official Title
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Two-Part, Randomized, Placebo and Active-Controlled, Double-Blind, Thorough QT Study Evaluating the Effects of Intravenous Exenatide on Cardiac Repolarization in Healthy Male and Female Volunteers

Conditions
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Healthy Adult Male and Female Volunteers

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


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Body mass index (BMI) between 19 to 35 kg/m2 inclusive. Women of child bearing potential - use of an additional adequate method of contraception during the study and until 1 additional menstrual cycle following the end-of-study (EOS) visit. Adequate methods of contraception for women of child bearing potential (WOCBP) include: mechanical products (ie, intrauterine device [IUD]-copper IUD); or barrier methods (eg, diaphragm, condoms, cervical cap) with spermacide. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (AP), and bilirubin within normal range at Screening. Fasting triglycerides within the normal range at Screening Exclusion Criteria: History of type 1 or type 2 diabetes, or history of hypoglycemia. History or evidence of myocardial infarction, congestive heart failure, syncope not related to heart arrhythmia, coronary revascularization (coronary artery bypass grafting or percutaneous coronary intervention), unstable angina, or cerebrovascular accident or stroke or TIA. History of atrial fibrillation, flutter, or non-sustained or sustained VT. Personal or family history of sudden death or long QT syndrome. History of uncontrolled hypertension. History or evidence of acute or chronic pancreatitis. History of liver disease. Abnormal renal function. History of medullary thyroid cancer or a personal or family history of multiple endocrine neoplasia type 2. Thyroid-stimulating hormone (TSH) outside of normal limits at Screening . Weight loss surgery. History of malignancy (not including basal or squamous cell carcinoma of the skin with past 5 years). (Subjects who have been disease free for greater than 5 years may be included.) History of active alcohol within 1 year prior to Screening. History of drug abuse within 5 years prior to Screening or a positive prestudy drug screen. Weekly consumption of more than 14 alcoholic beverages for females and more than 21 alcoholic beverages for males. Smoke more than 10 cigarettes per day. Excessive in xanthine consumption (more than 5 cups of coffee or equivalent per day). History of hypersensitivity to any of the medications used in this study. Women that are pregnant, lactating, or planning to become pregnant. History of or positive results on screening tests for hepatitis B and/or hepatitis C and/or human immunodeficiency virus (HIV). History or evidence of immunocompromised status. Prior or current treatment with any GLP-1 receptor agonist (eg, Bydureon™, Byetta®, Victoza®, Tanzeum® or exogenous native GLP-1) or prior participation in an ITCA 650 clinical trial. Any gastrointestinal complaints within 7 days prior to first dosing. Use of medications within 14 days of first dose other than hormone replacement therapy and oral contraceptives. Chronic (8 consecutive days or greater) treatment with systemic corticosteroids.

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

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: IV exenatide - pilot study<br>IV Exenatide Infusion 0.1250 mcg/kg/hour for 0.5 hours followed by 0.0625 mcg/kg/hour for 5.5 hours, preceded by IV Palonosetron 0.25 mg for nausea/vomiting prophylaxis. | Drug: Exenatide<br>* 6 hour IV infusion (double infusion of 0.1250 mcg/kg/hour for 30 min followed by infusion rate (1X) of 0.0625 mcg/kg/hour for 5.5 hours).<br>Drug: Palonosetron<br>* 0.25 mg administered IV within 30 minutes prior to initiating the infusion of exenatide<br>|
| Experimental: Treatment Group A - core study<br>IV Exenatide Infusion 0.1250 mcg/kg/hour for 0.5 hours followed by 0.0625 mcg/kg/hour for 5.5 hours, preceded by IV Palonosetron 0.25 mg for nausea/vomiting prophylaxis. | Drug: Exenatide<br>* 6 hour IV infusion (double infusion of 0.1250 mcg/kg/hour for 30 min followed by infusion rate (1X) of 0.0625 mcg/kg/hour for 5.5 hours).<br>Drug: Palonosetron<br>* 0.25 mg administered IV within 30 minutes prior to initiating the infusion of exenatide<br>|
| Experimental: Treatment Group B - core study<br>IV infusion of placebo over 6 hours, preceded by IV Palonosetron 0.25 mg for nausea/vomiting prophylaxis. | Drug: Placebo<br>* 6 hour IV infusion.<br>Drug: Palonosetron<br>* 0.25 mg administered IV within 30 minutes prior to initiating the infusion of exenatide<br>|
| Experimental: Treatment Group C - core study<br>IV infusion of placebo over 6 hours and a single oral dose of 400 mg moxifloxacin within 1 min of start of infusion, preceded by IV Palonosetron 0.25 mg for nausea/vomiting prophylaxis. | Drug: Placebo<br>* 6 hour IV infusion.<br>Drug: Moxifloxacin<br>* 400 mg oral dose moxifloxacin within 1 min of start of infusion of exenatide<br>Drug: Palonosetron<br>* 0.25 mg administered IV within 30 minutes prior to initiating the infusion of exenatide<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pilot Study: Establishment of mean plasma steady state concentration of 500 pg/mL |  | 35 days | 
| Core Study: Changes to QTc interval changes (threshold > 10 msec) measurements |  | 56 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pilot Study: Adverse events as assessed by subjective subject reporting, laboratory testing, ECG, physical examinations, and vital signs |  | 35 days | 
| Core Study: Measurement of exenatide plasma concentrations and relationship to changes in QTc interval measurements | Relationship between plasma concentrations of exenatide and QTc interval. | 56 days | 
| Core Study: Changes in PR, RR, QRS, QT, T- and U- wave morphology |  | 56 days | 
| Core Study: Measurement of QTc interval changes moxifloxacin as active control |  | 56 days | 
| Core Study: Adverse events as assessed by subjective subject reporting, laboratory testing, ECG, physical examinations, and vital signs |  | 56 days | 
| Pilot Study: Maximum concentration (CMax) of exenatide |  | 35 days | 
| Pilot Study: Time to maximum concentration (TMax) of exenatide |  | 35 days | 
| Pilot Study: Area under the curve (AUC) of exenatide |  | 35 days | 
| Pilot Study: Steady state concentration (Css) of exenatide |  | 35 days | 
| Pilot Study: Half life (T1/2) of exenatide |  | 35 days | 
| Core Study: Half life (T1/2) of exenatide |  | 56 days | 
| Core Study: Steady state concentration (Css) of exenatide |  | 56 days | 
| Core Study: Area under the curve (AUC) of exenatide |  | 56 days | 
| Core Study: Maximum concentration (CMax) |  | 56 days | 
| Core Study: Time to maximum concentration (TMax) of exenatide |  | 56 days |