Intravenous Exenatide (Byetta) During Surgery

• Sponsor: Thomas Jefferson University (Other)
• Overall Status: Completed
• CT.gov ID: NCT00882050
• Collaborator: Amylin Pharmaceuticals, LLC. (Industry), Eli Lilly and Company (Industry)
• Enrollment: 104
• Location: 1
• Arms: 3
• Duration (Months): 85
• Patients Per Site Per Month: 1.2

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Euglycemia; Hypoglycemia; Hyperglycemia	Drug: Exenatide 0.27 ng/kg/min; Drug: Exenatide 0.41 ng/kg/min; Drug: Placebo	Phase 1/Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 104 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Intravenous Exenatide (Byetta) for the Treatment of Perioperative Hyperglycemia: Rollover Phase I/II Trial
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Apr 1, 2016
• Actual Study Completion Date: Apr 1, 2016

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Exentatide 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).	Drug: Exenatide 0.27 ng/kg/min; Exenatide to be infused intravenously at 0.27 ng/kg/min (0.066 pmol/kg/min) for a duration of 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).; Other Names: Byetta
Experimental: Exentatide 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).	Drug: Exenatide 0.41 ng/kg/min; Exenatide to be infused intravenously 0.41 ng/kg/min (0.099 pmol/kg/min) for a duration of 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).; Other Names: Byetta
Placebo Comparator: Placebo IV NSS 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).	Drug: Placebo; Intravenous Placebo of NSS infused at same rate as drug 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).; Other Names: Normal Saline Solution

Outcome Measures

Primary Outcome Measures

1. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104

Sponsors and Collaborators

• Thomas Jefferson University
• Amylin Pharmaceuticals, LLC.
• Eli Lilly and Company

Investigators

• Study Director: Benjamin A. Kohl, MD, University of Pennsylvania

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Thomas Jefferson University
• ClinicalTrials.gov Identifier: NCT00882050
• Other Study ID Numbers: 808104
• First Posted: Apr 16, 2009
• Last Update Posted: Jan 21, 2022
• Last Verified: Dec 1, 2021

• Additional relevant MeSH terms: Hypoglycemia; Hyperglycemia; Exenatide

Study Results

Participant Flow

Recruitment Details	Screening started in the appropriate surgical clinic on 3/29/2009 and continued until 5/14/2012 when Dr. Ben Kohl was recruited away from Penn. Recruitment resumed with Dr. Prakash Patel on 9/22/14 and ended 3/20/2015. During active enrollment 104 subjects were enrolled and an additional 96 potential subjects failed screening or declined.

Arm/Group Title	Exentatide 0.27 ng/kg/Min	Exentatide 0.41 ng/kg/Min	Placebo IV NSS
Arm/Group Description	Exenatide IV 0.27 ng/kg/min (0.066 pmol/kg/min) over 3-6 hours. Induction of anesthesia will be equal to intubation time and drug will start (+ or-3 min). Blood will be collected prior to intubation and then 10 and 30 min after drug initiation and every 30 min (+or-2 min) until the IV is stopped and/or at extubation. Sample collection every 30 min post extubation for 2 hours, and once at 24 hours after extubation. Analysis of GLP-1, Glucose, Potassium, Insulin, Glucagon, Epinephrine, Norepinephrine, Cortisol, and free fatty acids (FFA) will be conducted.	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 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).
Period Title: Overall Study
STARTED	32	33	39
COMPLETED	31	33	39
NOT COMPLETED	1	0	0

Baseline Characteristics

Arm/Group Title	Exentatide 0.27 ng/kg/Min	Exentatide 0.41 ng/kg/Min	Placebo of IV NSS	Total
Arm/Group Description	Demographics Exen 0.27 ng/kg/min Sex: Female 9 Male 23 Age , mean (SD) 64.1 (13.41) Race: African American: 2 Caucasian: 30 Ethnicity: Non-Hispanic 32	Table 1: Demographics Exen 0.41 ng/kg/min Sex: Female 13 Male 20 Age , mean (SD) 67.4 (11.98) Race: African American: 2 Caucasian: 31 Ethnicity: Non-Hispanic 33	Table 1: Demographics placebo Sex: Female 11 Male 28 Age, mean (SD) 66.2 (13.56) Race: African American: 5 Caucasian: 34 Ethnicity: Non-Hispanic 39	Total of all reporting groups
Overall Participants	32	33	39	104
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	14 43.8%	12 36.4%	18 46.2%	44 42.3%
>=65 years	18 56.3%	21 63.6%	21 53.8%	60 57.7%
Age (years) [Mean (Full Range) ]
Mean (Full Range) [years]	64.1	67.4	66.2	65.9
Sex: Female, Male (Count of Participants)
Female	9 28.1%	13 39.4%	11 28.2%	33 31.7%
Male	23 71.9%	20 60.6%	28 71.8%	71 68.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	2 6.3%	2 6.1%	5 12.8%	9 8.7%
White	30 93.8%	31 93.9%	34 87.2%	95 91.3%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	32 100%	33 100%	39 100%	104 100%

Outcome Measures

1. Primary Outcome

Title	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,
Description	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.
Time Frame	Baseline and 90 minutes after starting infusion;

Outcome Measure Data

Analysis Population Description

104 subjects were enrolled. 39 subjects randomized to placebo, 32 in 0.27 ng/kg/min, and 33 to 41 ng/kg/minute. One subject was removed from the study at the request of the surgeon. No intraoperative blinded infusions (study drug) were discontinued in any other case.

Arm/Group Title	Exentatide 0.27 ng/kg/Min	Exenatide 0.41ng/kg/Min	Placebo IV NSS
Arm/Group Description	Experimental: IV Exenatide to be infused by intravenous method at 0.27 ng/kg/min (0.099 pmol/kg/min) over 3 to 6 hours. Minimum time of infusion 90 minutes.	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. Minimum time of infusion 90 minutes.	Placebo: IV NSS to be infused by intravenous method at rate for experimental drug over 3 to 6 hours. Minimum 90 minutes.
Measure Participants	32	33	39
Pre glucose levels	112.3 (24.1)	108.1 (27.8)	110.4 (17.3)
at 90 minutes post infusion glucose levels	120.3 (36.3)	125.0 (22.9)	120.8 (29.7)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exentatide 0.27 ng/kg/Min, Exenatide 0.41ng/kg/Min, Placebo IV NSS
	Comments	logistic regression
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Regression, Logistic
	Comments
Other Statistical Analysis		Because we tested interventions against the placebo arm, we increased our subjects to overcome loss of power. 23 per group will provide 80% power assuming a reduced alpha of 0.01 to accommodate the multiple testing issues.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Exentatide 0.27 ng/kg/Min, Exenatide 0.41ng/kg/Min, Placebo IV NSS
	Comments	Primary t tests of glucose between the 3 groups at 90 minutes post. Secondary MANOVA to determine the effect over time. Change in mean glucose of 20 mg/dl between all groups detectable by 18 subjects per group assuming a SD of 20mg/dl., an 82% power with an alpha of 0.05. Because we tested interventions against the placebo arm, we increased our subjects to overcome loss of power. 23 per group will provide 80% power assuming a reduced alpha of 0.01 to accommodate the multiple testing issues.
	Type of Statistical Test	Superiority
	Comments	Demographic data analyzed with nominal data tested by chi-square, ordinal data by Mann-Whitney, and normal data by t-test. Further, a linear regression analysis to determine the effect of intervention dose on glucose level and typical confounders such as age, weight, and type of surgery was completed. Adverse and SAEs were analyzed by chi-square for occurrence.
Statistical Test of Hypothesis	p-Value	0.05
	Comments	Due to have 3 trial groups our p value was adjusted for multiple comparisons as a a priori threshold (if a single comparison) was 0.05.
	Method	Regression, Logistic
	Comments	The regression (see above) is a secondary analysis. Groups had been stratified on diabetic (y/n) to balance this potential confounder

Adverse Events

Time Frame	AEs were collected on each subject from time of signed consent until 24 hours post surgery. This time frame was approximately one month.
Adverse Event Reporting Description	Any untoward or unfavorable medical occurrence in a participant, including any abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally associated with the participant's participation in the research, whether or not considered related to the participant's participation in the research.
Arm/Group Title	Exentatide 0.27 ng/kg/Min		Exenatide 0.41ng/kg/Min		Placebo IV NSS
Arm/Group Description	Exenatide to be infused by intravenous method at 0.27 ng/kg/min (0.066 pmol/kg/min) over 3-6 hours. Minimum 90 minutes post infusion.		Exenatide to be infused by intravenous method at 0.41 ng/kg/min (0.066 pmol/kg/min) over 3-6 hours. Minimum 90 minutes post infusion.		Placebo IV NSS to be at the rate of the experimental groups over 3-6 hours. Minimum 90 minutes post infusion.
All Cause Mortality
	Exentatide 0.27 ng/kg/Min		Exenatide 0.41ng/kg/Min		Placebo IV NSS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/33 (0%)		0/39 (0%)
Serious Adverse Events
	Exentatide 0.27 ng/kg/Min		Exenatide 0.41ng/kg/Min		Placebo IV NSS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/32 (0%)		0/33 (0%)		0/39 (0%)
Other (Not Including Serious) Adverse Events
	Exentatide 0.27 ng/kg/Min		Exenatide 0.41ng/kg/Min		Placebo IV NSS
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/32 (6.3%)		0/33 (0%)		0/39 (0%)
Cardiac disorders
Ischemia	1/32 (3.1%)	1	0/33 (0%)	0	0/39 (0%)	0
Vascular disorders
Left sided weakness	1/32 (3.1%)	1	0/33 (0%)	0	0/39 (0%)	0

Limitations/Caveats

Change in PI during the trial led to intermittent study activitity and a delay in enrollment which prolonged the study and final data entry.

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.