Feasibility Study of Exenatide by Continuous Subcutaneous Infusion

Study Overview
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Brief Summary
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This is an open-label study to investigate the feasibility of administering exenatide by continuous subcutaneous infusion to healthy subjects. Study will consist of two parts i.e. Part A and B. In Part A 2 healthy subjects will receive exenatide infusion over 24 hours followed by a follow-up visit 10 to 14 days after discharge from clinic. In Part B approximately 6 healthy subjects will receive subcutaneous infusions of exenatide for maximum of 7 days followed by a follow-up visit 10 to 14 days after discharge from clinic.

Official Title
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An Open-Label Exploratory Study to Investigate the Feasibility of Administering Exenatide by Continuous Subcutaneous Infusion to Healthy Subjects

Conditions
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Obesity

Intervention / Treatment
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* Drug: Exenatide


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria Male/females aged between 18 and 60 years of age inclusive, at the time of signing the informed consent. Healthy as determined by a responsible and experienced physician, based on a medical evaluation including medical history, physical examination, laboratory tests and 12-lead ECG. A subject with a clinical abnormality or laboratory parameter(s) which is/are not specifically listed in the inclusion or exclusion criteria, outside the reference range for the population being studied may be included only if the Investigator agrees and documents that the finding is unlikely to introduce additional risk factors and will not interfere with the study procedures and objectives. Body Mass Index within the range 18 to 35 kilograms/meter squared (kg/m^2) inclusive. A female subject is eligible to participate if she is of non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone > 40 milli international unit/mililiter (mL) and estradiol <40 picogram/mL (<147 picomoles/Liter) is confirmatory. Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. Child-bearing potential females must agree to use one of the contraception methods. This criterion must be followed from the time of the first dose of study medication until follow up visit. Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form. Based on QT interval corrected for heart rate (QTc) of single electrocardiogram (ECG): QTc by Fridericia's formula <450 millisecond (msec). Aspartate aminotransferase and Alanine aminotransferase <2x upper limit of normal (ULN); alkaline phosphatase and bilirubin <= 1.5xULN (isolated bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin <35%). Exclusion Criteria Subjects with a personal or family history of thyroid carcinoma or Type 2 Familial Endocrine Neoplasia. History of uncorrected thyroid dysfunction or an abnormal thyroid functions as assessed by thyroid stimulating hormones. Subjects with a history of severe gastrointestinal disease, or abnormal renal function. Subjects with previous exposure to a Glucagon-like peptide-1 mimetic. History of chronic or acute pancreatitis. Note: Subjects with a lipase value above 1.5X ULN at screening are excluded. Current or chronic history of liver disease, or hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones). History of regular alcohol consumption within 6 months of the study defined as: An average weekly intake of >14 drinks for males or >7 drinks for females. One drink is equivalent to 12 grams of alcohol: 12 ounces (360 mL) of beer, 5 ounces (150 mL) of wine or 1.5 ounces (45 mL) of 80 proof distilled spirits. History of sensitivity to heparin or heparin-induced thrombocytopenia. History of sensitivity to any of the study medications, or components thereof or a history of drug or other allergy. Criteria Based Upon Diagnostic Assessments A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody result within 3 months of screening. A positive pre-study drug/alcohol screen. A subject with a positive urine cotinine test result will be excluded from the study unless in the judgment of the Investigator the subject will be able to abstain from using tobacco for the duration of the in-house period of the study. A positive test for human immuno virus antibody. Other Criteria Where participation in the study would result in donation of blood or blood products in excess of 500 mL within a 56 day period. The subject has participated in a clinical trial and has received an investigational product within the following time period prior to the first dosing day in the current study: 30 days, 5 half-lives or twice the duration of the biological effect of the investigational product (whichever is longer). Exposure to more than four new chemical entities within 12 months prior to the first dosing day.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exenatide infusion in Part A<br>Subjects in Part A will receive exenatide as a subcutaneous infusion at a constant rate for 24 hours. | Drug: Exenatide<br>* Prefilled pen containing 2.4 mL of drug will be transferred into MiniMed Paradigm Real-Time Revel device for subcutaneous infusion.<br>|
| Experimental: Exenatide infusion in Part B<br>Subjects in Part B will receive exenatide with daily increases in the infusion rate. | Drug: Exenatide<br>* Prefilled pen containing 2.4 mL of drug will be transferred into MiniMed Paradigm Real-Time Revel device for subcutaneous infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Characterization of interruptions or deviations from prescribed exenatide infusion in Part A | To investigate the feasibility of administering exenatide via continuous subcutaneous infusion | 2 days | 
| Characterization of interruptions or deviations from prescribed exenatide infusion in Part B | To investigate the feasibility of administering exenatide via continuous subcutaneous infusion | 8 days | 
| Infusion rate adjustments when nausea/vomiting occurs in Part B | To investigate the feasibility of administering exenatide via continuous subcutaneous infusion. Infusion rate adjustment will be done to achieve tolerable infusion rate when nausea/vomiting occurs | 8 days | 
| Number of participants with adverse events (AEs) in Part A | AEs will be collected from the Day -1 and until the follow-up contact. AE data will be collected to evaluate the ability to monitor and maintain acceptable safety | 17 days | 
| Number of participants with AEs in Part B | AEs will be collected from the Day -1 and until the follow-up contact. AE data will be collected to evaluate the ability to monitor and maintain acceptable safety | 23 days | 
| Laboratory parameter assessment in Part A | Laboratory parameters include: hematology, clinical chemistry, and urinalysis | 17 days | 
| Laboratory parameter assessment in Part B | Laboratory parameters include: hematology, clinical chemistry, and urinalysis | 23 days | 
| Vital sign assessment in Part A | Vital signs measurement include: systolic and diastolic blood pressure, and pulse rate | 17 days | 
| Vital sign assessment in Part B | Vital signs measurement include: systolic and diastolic blood pressure, and pulse rate | 23 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK) profile of exenatide in Part A | PK parameters include: area under concentration time curve from time 0 to 24 hours (AUC0 to24), maximum observed concentration from time 0 to 24 hours (Cmax0 to 24), and average concentration from time 0 to 24 hours (Cavg0 to 24) versus time | PK samples will be collected at pre-dose, and at 0.5, 1, 2, 4, 6, 10, 14, 24, and 26 hours post dose. | 
| Pharmacokinetic (PK) profile of exenatide in Part B | PK parameters include: AUC0-24, Cmax0 to 24, and Cavg0 to 24 versus time for each of 7 days and AUC0 to 168, Cmax0 to 168, and Cavg0 to 168 versus time over entire infusion period. | 8 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Nausea, subcutaneous infusion, exenatide