Intravenous Exenatide (Byetta) During Surgery

Phase 1

Completed

Conditions: Hypoglycemia
Euglycemia
Hyperglycemia

Interventions: Drug: Exenatide 0.27 ng/kg/min
Drug: Exenatide 0.41 ng/kg/min
Drug: Placebo

Registration Number: NCT00882050

Lead Sponsor: Thomas Jefferson University

Brief Summary: The purpose of this project is to study if intravenous Exenatide is effective at maintaining normal blood glucose levels and preventing low blood glucose levels during surgery.

Detailed Description: This is a single-center, block randomized, double-blind, placebo-controlled, dose-ranging study. Subjects will be randomized in equal proportions to one of three treatment arms: placebo of normal saline solution, 0.27 ng/kg/min (0.066 pmol/kg/min) IV Exenatide, and 0.41 ng/kg/min (0.099 pmol/kg/min) IV Exenatide. We will use a block number of 30 (please see power analysis) so that balance between each of the three groups will be maintained over the enrollment period. We will stratify the randomization scheme to ensure balance of diabetics and non-diabetics within the groups.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 104

Inclusion Criteria

Age (>18 years)
Weight of > 50 kg and < 150 kg
Ability to provide informed consent
Elective surgery including:
Cardiac surgery to include elective CABG with or without single or multivalve repair or replacement and/or single or multivalve repair/replacement requiring CPB and sternotomy (to include subjects who are undergoing first time or redo cardiac surgery)
Abdominal aortic aneurysm repair
Carotid endarterectomy
Esophagectomy
Cystectomy
Nephrectomy
If female, subject must be non-lactating, and, if of childbearing potential, must have a negative urine pregnancy test within 24 hours prior to receiving study drug

Exclusion Criteria

Age (<18 years)
Inability to provide informed consent
History or risk of pancreatitis (e.g. ethanol abuse, gall stones)
Receipt of an investigational drug or device with 30 days prior to surgery
Use of any concomitant medication listed above on the day of surgery
Known allergy to Exenatide, fentanyl, midazolam, isoflurane, propofol, heparin or neuromuscular blockers
Known substance abuse
Surgical procedure other than:

Cardiac surgery to include elective CABG with or without single or multivalve repair or replacement and/or single or multivalve repair/ replacement requiring CPB and sternotomy (to include subjects who are undergoing first time or redo cardiac surgery)

Abdominal aortic aneurysm repair
Carotid endarterectomy
Esophagectomy
Cystectomy
Nephrectomy
- Insulin dependent diabetes mellitis
- Anticipated administration of intraoperative steroids
- Major end organ dysfunction, defined as:
Current intravenous inotropic agents
Preoperative use of intra-aortic balloon pump (IABP), left ventricular assist device (LVAD), or extracorporeal membrane oxygenation (ECMO)
Renal
Preoperative serum Creatinine > 2.0 mg/dL
Hepatic
History of abnormal hepatic function in the past
Hematologic
Preoperative hematocrit (HCT) < 30%
Platelet count < 100,000/mm3
History of bleeding or clotting disorder

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Exentatide 0.27 ng/kg/min	Exenatide 0.27 ng/kg/min	Exenatide to be infused by intravenous method at 0.27 ng/kg/min (0.066 pmol/kg/min) over 3-6 hours. * Induction of anesthesia will be equal to Intubation time. Infusion will begin at this time point (+ or - 3 minutes). * Blood samples will be obtained prior to intubation and then 10 and 30 minutes after drug initiation and every 30 minutes (+ or - 2 minutes) thereafter until the infusion is stopped. The drug infusion will be stopped at extubation. Blood will then be sampled every 30 minutes (+ or - 2 minutes) post extubation for 2 hours, and once 24 hours after extubation. * Blood plasma levels will be collected (8-10 mls) for analysis of GLP-1, Glucose, Potassium, Insulin, Glucagon, Epinephrine, Norepinephrine, Cortisol, and free fatty acids (FFA).
Exentatide 0.41 ng/kg/min	Exenatide 0.41 ng/kg/min	Experimental: IV Exenatide to be infused by intravenous method at 0.41 ng/kg/min (0.099 pmol/kg/min) over 3 to 6 hours. * Induction of anesthesia will be equal to Intubation time. Infusion will begin at this time point (+ or - 3 minutes). * Blood samples will be obtained prior to intubation and then 10 and 30 minutes after drug initiation and every 30 minutes (+ or - 2 minutes) thereafter until the infusion is stopped. The drug infusion will be stopped at extubation. Blood will then be sampled every 30 minutes (+ or - 2 minutes) post extubation for 2 hours, and once 24 hours after extubation. * Blood plasma levels will be collected (8-10 mls) for analysis of GLP-1, Glucose, Potassium, Insulin,Glucagon, Epinephrine, Norepinephrine, Cortisol, and free fatty acids (FFA).
Placebo IV NSS	Placebo	Placebo of IV normal saline solution as comparator. * Induction of anesthesia will be equal to Intubation time. Infusion will begin at this time point (+ or - 3 minutes). * Blood samples will be obtained prior to intubation and then 10 and 30 minutes after drug initiation and every 30 minutes (+ or - 2 minutes) thereafter until the infusion is stopped. The drug infusion will be stopped at extubation. Blood will then be sampled every 30 minutes (+ or - 2 minutes) post extubation for 2 hours, and once 24 hours after extubation. * Blood plasma levels will be collected (8-10 mls) for analysis of GLP-1, Glucose, Potassium, Insulin, Glucagon, Epinephrine, Norepinephrine, Cortisol, and free fatty acids (FFA).

Primary Outcome Measures

Name	Time	Method
The Primary Objective is to Determine the Ability of Intravenous Exenatide to: Maintain Intraoperative Euglycemia in Subjects With Initial Blood Glucose < 126 mg/dL in Surgical Subjects as Compared to Placebo,	Baseline and 90 minutes after starting infusion;	Logistic regression analysis will be utizlized to determine maintenance of euglycemia (yes v no) for our primary analysis. A standard area under the curve (AUC) analysis will be performed for each time point to map out drug deposition. Assuming a standard 2 compartment model, 10 subjects per group is sufficient to accurately predict mean AUC. Our primary analysis should provide ample statistical power.

Secondary Outcome Measures