Euglycemia, Hyperglycemia, Hypoglycemia
Conditions
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.
Interventions
DRUGExenatide 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).
DRUGExenatide 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).
DRUGPlacebo
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).
Sponsors
Amylin Pharmaceuticals, LLC.
Eli Lilly and Company
Thomas Jefferson University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
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.
Participants by arm
| Arm | Count |
|---|---|
| Exentatide 0.27 ng/kg/Min 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 | 32 |
| Exentatide 0.41 ng/kg/Min 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 | 33 |
| Placebo of IV NSS 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 | 39 |
| Total | 104 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Physician Decision | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Exentatide 0.41 ng/kg/Min | Placebo of IV NSS | Total | Exentatide 0.27 ng/kg/Min |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 21 Participants | 21 Participants | 60 Participants | 18 Participants |
| Age, Categorical Between 18 and 65 years | 12 Participants | 18 Participants | 44 Participants | 14 Participants |
| Age, Continuous | 67.4 years | 66.2 years | 65.9 years | 64.1 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 9 Participants | 2 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 31 Participants | 34 Participants | 95 Participants | 30 Participants |
| Region of Enrollment United States | 33 Participants | 39 Participants | 104 Participants | 32 Participants |
| Sex: Female, Male Female | 13 Participants | 11 Participants | 33 Participants | 9 Participants |
| Sex: Female, Male Male | 20 Participants | 28 Participants | 71 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 32 | 0 / 33 | 0 / 39 |
| other Total, other adverse events | 2 / 32 | 0 / 33 | 0 / 39 |
| serious Total, serious adverse events | 0 / 32 | 0 / 33 | 0 / 39 |
Outcome results
Primary
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,
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;
Population: 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 | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Exentatide 0.27 ng/kg/Min | 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, | Pre glucose levels | 112.3 mlg/dL | Standard Deviation 24.1 |
| Exentatide 0.27 ng/kg/Min | 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, | at 90 minutes post infusion glucose levels | 120.3 mlg/dL | Standard Deviation 36.3 |
| Exenatide 0.41ng/kg/Min | 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, | Pre glucose levels | 108.1 mlg/dL | Standard Deviation 27.8 |
| Exenatide 0.41ng/kg/Min | 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, | at 90 minutes post infusion glucose levels | 125.0 mlg/dL | Standard Deviation 22.9 |
| Placebo IV NSS | 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, | Pre glucose levels | 110.4 mlg/dL | Standard Deviation 17.3 |
| Placebo IV NSS | 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, | at 90 minutes post infusion glucose levels | 120.8 mlg/dL | Standard Deviation 29.7 |
Comparison: logistic regressionp-value: 0.05Regression, Logistic
Comparison: 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.p-value: 0.05Regression, Logistic