Intravenous Exenatide in Patients With Acute Brain Injury

• Sponsor: University of North Carolina, Chapel Hill (Other)
• Overall Status: Completed
• CT.gov ID: NCT02058940
• Collaborator: AstraZeneca (Industry), Medtronic (Industry)
• Enrollment: 8
• Location: 1
• Arm: 1
• Duration (Months): 24
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

The purpose of this study is to assess the feasibility of exenatide infusion for the treatment of high blood sugars following acute brain injury.

Condition or Disease	Intervention/Treatment	Phase
Brain Injuries	Drug: Exenatide	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Intravenous Exenatide Infusion in Critically Ill Patients With Acute Brain Injury
• Study Start Date: Aug 1, 2015
• Actual Primary Completion Date: Aug 1, 2017
• Actual Study Completion Date: Aug 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Exenatide	Drug: Exenatide; 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours

Outcome Measures

Primary Outcome Measures

1. Percentage of Critically Ill Patients With Acute Brain Injury Achieving Pre-specified Feasibility Criteria [Over 48 hours from infusion initiation]

   Feasibility is defined as the percentage of patients 1) experiencing severe hypoglycemia (<40 mg/dL); 2) achieving glucose measurements within goal (110-180 mg/dL); and 3) experiencing nausea requiring discontinuation of exenatide therapy. The pre-specified criteria for determining feasibility includes the following: 1) at least 75% of patients achieving glucose measurements within goal (110-180 mg/dL) and 2) no more than 25% of patients experiencing severe hypoglycemia (<40 mg/dL) or nausea requiring exenatide discontinuation.

Secondary Outcome Measures

1. Median Glucose Concentration During Exenatide Infusion [Over 48 hours from infusion initiation]

   Calculated from hourly blood glucose samples starting at infusion initiation over 48 hours

2. Percentage of Glucose Measurements Within Goal Range [Over 48 hours from infusion initiation]

   Percentage of glucose measurements within goal range is calculated as the number of glucose measurements within goal range (110-180 mg/dL) for all patients/total number of glucose measurements collected for all patients.

3. Median Time to Reach Glucose Measurements Within Goal Range (110-180 mg/dL) [Over 48 hours from infusion initiation]

   Calculated from hourly blood glucose samples starting at infusion initiation over 48 hours

4. Glycemic Variability [Over 48 hours from infusion initiation]

   Glycemic variability is defined as the standard deviation of glucose calculated from hourly glucose measurements starting at infusion initiation over 48 hours

5. Median Insulin Use [Over 48 hours from infusion initiation]

   Calculated from number of insulin units administered over 48 hours starting at infusion initiation

6. Percentage of Patients Requiring Rescue Insulin Infusion Protocol [Over 48 hours from infusion initiation]

   Defined as the percentage of patients requiring an insulin infusion to control glucose concentrations during exenatide treatment

7. Percentage of Hypoglycemic Episodes (<80 mg/dL) [Over 48 hours from infusion initiation]

   Percentage of hypoglycemic episodes is calculated as the total number of glucose measurements <80 mg/dL for all patients/total number of glucose measurements collected for all patients.

8. Percentage of Patients With >1 Episode of Hypoglycemia (<80 mg/dL) [Over 48 hours from infusion initiation]

   Calculated from hourly blood glucose samples starting at infusion initiation over 48 hours

9. Percentage of Patients Experiencing Metabolic Crisis [Over 48 hours from infusion initiation]

   Metabolic crisis is defined as cerebral microdialysate glucose concentration <0.7 mmol/L in combination with lactate pyruvate ratio >40. Calculated from hourly microdialysis samples starting at infusion initiation over 48 hours

10. Median Daily Intracranial Pressure [Over 48 hours from infusion initiation]

    Calculated from hourly measurements starting at infusion initiation over 48 hours

11. Median Daily Cerebral Perfusion Pressure [Over 48 hours from infusion initiation]

    Calculated from hourly measurements starting at infusion initiation over 48 hours

12. Percentage of Hypotensive Episodes (SBP<100 mmHg) [Over 48 hours from infusion initiation]

    Defined as the number of hypotensive episodes (SBP<100 mmHg)for all patients/total number of blood pressure measurements collected for all patients.

13. Percentage of Patients With >1 Episode of Hypotensive Episode (SBP<100 mmHg) [Over 48 hours from infusion initiation]

    Calculated from blood pressure measurements starting at infusion initiation over 48 hours

14. Correlation of Exenatide Concentrations With Creatinine Clearance [Over 48 hours from infusion initiation]

    Spearman's correlation coefficient calculated from exenatide concentrations and urine creatinine measurements collected for all patients during the study period. A correlation coefficient is a numerical measure of some type of correlation, meaning a statistical relationship between two variables. Spearman's correlation coefficient assumes values in the range from -1 to +1, where +1 indicates the strongest possible agreement and -1 the strongest possible disagreement.

15. Exenatide Elimination Rate Constant After Discontinuation of Infusion [24 hours]

16. Exenatide Area Under the Concentration-time Curve After Discontinuation of Infusion [24 hours]

17. Median Intensive Care Unit Length of Stay [From enrollment to 30 days post study drug discontinuation]

    Defined as the number of days admitted to the Intensive Care Unit

18. Median Hospital Length of Stay [From enrollment to 30 days post study drug discontinuation]

    Defined as the number of days admitted to the hospital

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Adults ≥18 years

• Acute brain injury resulting in admission to the Neurosciences Intensive Care Unit for an anticipated length of stay >48 hours

• Two Blood glucose concentrations > 150 mg/dL and ≤300 mg/dL

• Informed consent obtained via proxy

Exclusion Criteria:

• Pregnant (verified by urine or serum pregnancy test within 24 hours of initiation of infusion) or lactating females

• Type 1 diabetes mellitus

• History of pancreatitis or risk factors for acute pancreatitis (i.e ethanol abuse, gall stones)

• Renal insufficiency defined as creatinine clearance (CrCL) < 45 mL/min

• Known history of gastroparesis

• History of surgery on stomach, esophagus or duodenum

• Diabetic Ketoacidosis or Hyperosmolar Hyperglycemic Nonketotic Syndrome

• Concurrent steroid use or planned post-operative steroid use

• History of organ transplantation

• Brain death or suspected imminent brain death within the next 72 hours

• Refractory intracranial hypertension defined as intracranial pressure (ICP) > 25 mmHg for greater than 15 minutes and refractory to medical intervention

• Currently enrolled in another investigational drug or device protocol

• Insulin infusion within 3 hours of study drug administration or confirmed long acting insulin or sulfonylurea use prior to admission within 24 hours of study drug administration

• Known allergy to exenatide

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of North Carolina; UNC Medical Center	Chapel Hill	North Carolina	United States	27599

Sponsors and Collaborators

• University of North Carolina, Chapel Hill
• AstraZeneca
• Medtronic

Investigators

• Principal Investigator: Nicole R. Pinelli, PharmD, University of North Carolina, Chapel Hill

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 18, 2015

More Information

Publications

None provided.

• Responsible Party: University of North Carolina, Chapel Hill
• ClinicalTrials.gov Identifier: NCT02058940
• Other Study ID Numbers: 13-1391; Astra Zeneca Pharmaceuticals; Medtronic MiniMed, Inc
• First Posted: Feb 10, 2014
• Last Update Posted: Jul 12, 2018
• Last Verified: Sep 1, 2017

• Additional relevant MeSH terms: Brain Injuries; Wounds and Injuries; Exenatide

Study Results

Participant Flow

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Period Title: Overall Study
STARTED	8
COMPLETED	7
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Overall Participants	8
Age (years) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [years]	64.0
Sex: Female, Male (Count of Participants)
Female	1 12.5%
Male	7 87.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	7 87.5%
Unknown or Not Reported	1 12.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	3 37.5%
White	4 50%
More than one race	0 0%
Unknown or Not Reported	1 12.5%
Region of Enrollment (Count of Participants)
United States	8 100%
Primary Admitting Diagnosis (Count of Participants)
Intracerebral Hemorrhage	3 37.5%
Acute Ischemic Stroke	3 37.5%
Subarachnoid Hemorrhage	1 12.5%
Subdural Hematoma	1 12.5%
Glasgow Coma Scale (GCS) (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	10.5
Sequential Organ Failure Assessment (SOFA) (units on a scale) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [units on a scale]	2.0
Hunt and Hess Scale (units on a scale) [Number]
Number [units on a scale]	2.0
Modified Fisher Grade (units on a scale) [Number]
Number [units on a scale]	3.0
Intracranial Pressure (mmHg) [Median (Inter-Quartile Range) ]
Cerebral Perfusion Pressure (mmHg) [Median (Inter-Quartile Range) ]
Past Medical History (Count of Participants)
Diabetes	4 50%
Hypertension	6 75%
Hyperlipidemia	4 50%
Cardiovascular Disease	5 62.5%
Chronic Kidney Disease	3 37.5%
Heart Failure	1 12.5%
Hemoglobin A1c (%) (percent) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [percent]	6.5
Glucose (mg/dL) [Median (Inter-Quartile Range) ]
Median (Inter-Quartile Range) [mg/dL]	191.0
Intensive Care Unit (ICU) Day of Study Drug Administration (Count of Participants)
Day 1	4 50%
Day 2	4 50%

Outcome Measures

1. Primary Outcome

Title	Percentage of Critically Ill Patients With Acute Brain Injury Achieving Pre-specified Feasibility Criteria
Description	Feasibility is defined as the percentage of patients 1) experiencing severe hypoglycemia (<40 mg/dL); 2) achieving glucose measurements within goal (110-180 mg/dL); and 3) experiencing nausea requiring discontinuation of exenatide therapy. The pre-specified criteria for determining feasibility includes the following: 1) at least 75% of patients achieving glucose measurements within goal (110-180 mg/dL) and 2) no more than 25% of patients experiencing severe hypoglycemia (<40 mg/dL) or nausea requiring exenatide discontinuation.
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Percentage Experiencing Severe Hypoglycemia	0
Percentage Achieving Glucose within Goal	87.5
Percentage with Nausea Requiring Discontinuation	0

2. Secondary Outcome

Title	Median Glucose Concentration During Exenatide Infusion
Description	Calculated from hourly blood glucose samples starting at infusion initiation over 48 hours
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Median (Inter-Quartile Range) [mg/dL]	137.0

3. Secondary Outcome

Title	Percentage of Glucose Measurements Within Goal Range
Description	Percentage of glucose measurements within goal range is calculated as the number of glucose measurements within goal range (110-180 mg/dL) for all patients/total number of glucose measurements collected for all patients.
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Number [percentage of measurements]	69.6

4. Secondary Outcome

Title	Median Time to Reach Glucose Measurements Within Goal Range (110-180 mg/dL)
Description	Calculated from hourly blood glucose samples starting at infusion initiation over 48 hours
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Median (Inter-Quartile Range) [minutes]	200.0

5. Secondary Outcome

Title	Glycemic Variability
Description	Glycemic variability is defined as the standard deviation of glucose calculated from hourly glucose measurements starting at infusion initiation over 48 hours
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Median (Inter-Quartile Range) [mg/dL]	22.2

6. Secondary Outcome

Title	Median Insulin Use
Description	Calculated from number of insulin units administered over 48 hours starting at infusion initiation
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Median (Inter-Quartile Range) [units/kg]	0.03

7. Secondary Outcome

Title	Percentage of Patients Requiring Rescue Insulin Infusion Protocol
Description	Defined as the percentage of patients requiring an insulin infusion to control glucose concentrations during exenatide treatment
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Number [percentage of patients]	0

8. Secondary Outcome

Title	Percentage of Hypoglycemic Episodes (<80 mg/dL)
Description	Percentage of hypoglycemic episodes is calculated as the total number of glucose measurements <80 mg/dL for all patients/total number of glucose measurements collected for all patients.
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Number [percentage of measurements]	1.2

9. Secondary Outcome

Title	Percentage of Patients With >1 Episode of Hypoglycemia (<80 mg/dL)
Description	Calculated from hourly blood glucose samples starting at infusion initiation over 48 hours
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Number [percentage of patients]	12.5

10. Secondary Outcome

Title	Percentage of Patients Experiencing Metabolic Crisis
Description	Metabolic crisis is defined as cerebral microdialysate glucose concentration <0.7 mmol/L in combination with lactate pyruvate ratio >40. Calculated from hourly microdialysis samples starting at infusion initiation over 48 hours
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

No patients received invasive intracranial multimodal monitoring as a part of their standard of care, as such, these endpoints were not collected.

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	0

11. Secondary Outcome

Title	Median Daily Intracranial Pressure
Description	Calculated from hourly measurements starting at infusion initiation over 48 hours
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

No patients with an admitting diagnosis of Subarachnoid Hemorrhage received ICP or CPP monitoring as part of standard of care and therefore data is not reported.

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	0

12. Secondary Outcome

Title	Median Daily Cerebral Perfusion Pressure
Description	Calculated from hourly measurements starting at infusion initiation over 48 hours
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

No patients with an admitting diagnosis of Subarachnoid Hemorrhage received ICP or CPP monitoring as part of standard of care and therefore data is not reported.

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	0

13. Secondary Outcome

Title	Percentage of Hypotensive Episodes (SBP<100 mmHg)
Description	Defined as the number of hypotensive episodes (SBP<100 mmHg)for all patients/total number of blood pressure measurements collected for all patients.
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Number [percentage of measurements]	1.2

14. Secondary Outcome

Title	Percentage of Patients With >1 Episode of Hypotensive Episode (SBP<100 mmHg)
Description	Calculated from blood pressure measurements starting at infusion initiation over 48 hours
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Number [percentage of patients]	12.5

15. Secondary Outcome

Title	Correlation of Exenatide Concentrations With Creatinine Clearance
Description	Spearman's correlation coefficient calculated from exenatide concentrations and urine creatinine measurements collected for all patients during the study period. A correlation coefficient is a numerical measure of some type of correlation, meaning a statistical relationship between two variables. Spearman's correlation coefficient assumes values in the range from -1 to +1, where +1 indicates the strongest possible agreement and -1 the strongest possible disagreement.
Time Frame	Over 48 hours from infusion initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	7
Number [correlation coefficient]	-0.2

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Exenatide
	Comments
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2
	Comments
	Method	Spearman's Correlation Coefficient
	Comments

16. Secondary Outcome

Title	Exenatide Elimination Rate Constant After Discontinuation of Infusion
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

The institutional review board requested the study team limit exenatide concentration sampling to during the infusion. Samples were not collected after discontinuation of study drug. As such, this pharmacokinetic parameter is not reported.

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	0

17. Secondary Outcome

Title	Exenatide Area Under the Concentration-time Curve After Discontinuation of Infusion
Time Frame	24 hours

Outcome Measure Data

Analysis Population Description

The institutional review board requested the study team limit exenatide concentration sampling to during the infusion. Samples were not collected after discontinuation of study drug. As such, this pharmacokinetic parameter is not reported.

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	0

18. Secondary Outcome

Title	Median Intensive Care Unit Length of Stay
Description	Defined as the number of days admitted to the Intensive Care Unit
Time Frame	From enrollment to 30 days post study drug discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Median (Inter-Quartile Range) [days]	9.0

19. Secondary Outcome

Title	Median Hospital Length of Stay
Description	Defined as the number of days admitted to the hospital
Time Frame	From enrollment to 30 days post study drug discontinuation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Measure Participants	8
Median (Inter-Quartile Range) [days]	12.5

Adverse Events

Time Frame	From study enrollment to 30 days post discontinuation of Exenatide, up to 1 month
Arm/Group Title	Exenatide
Arm/Group Description	Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
All Cause Mortality
	Exenatide
	Affected / at Risk (%)	# Events
Total	3/8 (37.5%)
Serious Adverse Events
	Exenatide
	Affected / at Risk (%)	# Events
Total	3/8 (37.5%)
Nervous system disorders
Death	3/8 (37.5%)
Other (Not Including Serious) Adverse Events
	Exenatide
	Affected / at Risk (%)	# Events
Total	0/8 (0%)

Limitations/Caveats

Trial ended early and did not achieve targeted recruitment goals.

More Information

Certain Agreements

All Principal Investigators ARE 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.