Brain Injuries
Conditions
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.
Interventions
DRUGExenatide
50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours
Sponsors
AstraZeneca
Medtronic
University of North Carolina, Chapel Hill
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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 |
| 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 |
| Median Insulin Use | Over 48 hours from infusion initiation | Calculated from number of insulin units administered over 48 hours starting at infusion initiation |
| 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 |
| 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. |
| 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 |
| 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 |
| 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 |
| Median Daily Cerebral Perfusion Pressure | Over 48 hours from infusion initiation | Calculated from hourly measurements starting at infusion initiation over 48 hours |
| 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. |
| 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 |
| 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. |
| Exenatide Elimination Rate Constant After Discontinuation of Infusion | 24 hours | — |
| Exenatide Area Under the Concentration-time Curve After Discontinuation of Infusion | 24 hours | — |
| 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 |
| Median Hospital Length of Stay | From enrollment to 30 days post study drug discontinuation | Defined as the number of days admitted to the hospital |
| Median Daily Intracranial Pressure | Over 48 hours from infusion initiation | Calculated from hourly measurements starting at infusion initiation over 48 hours |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Exenatide Exenatide: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours | 8 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Discharged from Critical Care Unit | 1 |
Baseline characteristics
| Characteristic | Exenatide | — |
|---|---|---|
| Age, Continuous | 64.0 years | — |
| Cerebral Perfusion Pressure | — | — mmHg |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | — |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 7 Participants | — |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | — |
| Glasgow Coma Scale (GCS) | 10.5 units on a scale | — |
| Glucose | 191.0 mg/dL | — |
| Hemoglobin A1c (%) | 6.5 percent | — |
| Hunt and Hess Scale | 2.0 units on a scale | — |
| Intensive Care Unit (ICU) Day of Study Drug Administration Day 1 | 4 Participants | — |
| Intensive Care Unit (ICU) Day of Study Drug Administration Day 2 | 4 Participants | — |
| Intracranial Pressure | — | — mmHg |
| Modified Fisher Grade | 3.0 units on a scale | — |
| Past Medical History Cardiovascular Disease | 5 Participants | — |
| Past Medical History Chronic Kidney Disease | 3 Participants | — |
| Past Medical History Diabetes | 4 Participants | — |
| Past Medical History Heart Failure | 1 Participants | — |
| Past Medical History Hyperlipidemia | 4 Participants | — |
| Past Medical History Hypertension | 6 Participants | — |
| Primary Admitting Diagnosis Acute Ischemic Stroke | 3 Participants | — |
| Primary Admitting Diagnosis Intracerebral Hemorrhage | 3 Participants | — |
| Primary Admitting Diagnosis Subarachnoid Hemorrhage | 1 Participants | — |
| Primary Admitting Diagnosis Subdural Hematoma | 1 Participants | — |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | — |
| Race (NIH/OMB) Asian | 0 Participants | — |
| Race (NIH/OMB) Black or African American | 3 Participants | — |
| Race (NIH/OMB) More than one race | 0 Participants | — |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | — |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | — |
| Race (NIH/OMB) White | 4 Participants | — |
| Region of Enrollment United States | 8 Participants | — |
| Sequential Organ Failure Assessment (SOFA) | 2.0 units on a scale | — |
| Sex: Female, Male Female | 1 Participants | — |
| Sex: Female, Male Male | 7 Participants | — |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 3 / 8 |
| other Total, other adverse events | 0 / 8 |
| serious Total, serious adverse events | 3 / 8 |
Outcome results
Primary
Percentage of Critically Ill Patients With Acute Brain Injury Achieving Pre-specified Feasibility Criteria
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
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Exenatide | Percentage of Critically Ill Patients With Acute Brain Injury Achieving Pre-specified Feasibility Criteria | Percentage Experiencing Severe Hypoglycemia | 0 percentage of patients |
| Exenatide | Percentage of Critically Ill Patients With Acute Brain Injury Achieving Pre-specified Feasibility Criteria | Percentage Achieving Glucose within Goal | 87.5 percentage of patients |
| Exenatide | Percentage of Critically Ill Patients With Acute Brain Injury Achieving Pre-specified Feasibility Criteria | Percentage with Nausea Requiring Discontinuation | 0 percentage of patients |
Secondary
Correlation of Exenatide Concentrations With Creatinine Clearance
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Correlation of Exenatide Concentrations With Creatinine Clearance | -0.2 correlation coefficient |
p-value: 0.2Spearman's Correlation Coefficient
Secondary
Exenatide Area Under the Concentration-time Curve After Discontinuation of Infusion
Time frame: 24 hours
Population: 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.
Secondary
Exenatide Elimination Rate Constant After Discontinuation of Infusion
Time frame: 24 hours
Population: 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.
Secondary
Glycemic Variability
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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exenatide | Glycemic Variability | 22.2 mg/dL |
Secondary
Median Daily Cerebral Perfusion Pressure
Calculated from hourly measurements starting at infusion initiation over 48 hours
Time frame: Over 48 hours from infusion initiation
Population: 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.
Secondary
Median Daily Intracranial Pressure
Calculated from hourly measurements starting at infusion initiation over 48 hours
Time frame: Over 48 hours from infusion initiation
Population: 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.
Secondary
Median Glucose Concentration During Exenatide Infusion
Calculated from hourly blood glucose samples starting at infusion initiation over 48 hours
Time frame: Over 48 hours from infusion initiation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exenatide | Median Glucose Concentration During Exenatide Infusion | 137.0 mg/dL |
Secondary
Median Hospital Length of Stay
Defined as the number of days admitted to the hospital
Time frame: From enrollment to 30 days post study drug discontinuation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exenatide | Median Hospital Length of Stay | 12.5 days |
Secondary
Median Insulin Use
Calculated from number of insulin units administered over 48 hours starting at infusion initiation
Time frame: Over 48 hours from infusion initiation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exenatide | Median Insulin Use | 0.03 units/kg |
Secondary
Median Intensive Care Unit Length of Stay
Defined as the number of days admitted to the Intensive Care Unit
Time frame: From enrollment to 30 days post study drug discontinuation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exenatide | Median Intensive Care Unit Length of Stay | 9.0 days |
Secondary
Median Time to Reach Glucose Measurements Within Goal Range (110-180 mg/dL)
Calculated from hourly blood glucose samples starting at infusion initiation over 48 hours
Time frame: Over 48 hours from infusion initiation
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Exenatide | Median Time to Reach Glucose Measurements Within Goal Range (110-180 mg/dL) | 200.0 minutes |
Secondary
Percentage of Glucose Measurements Within Goal Range
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Percentage of Glucose Measurements Within Goal Range | 69.6 percentage of measurements |
Secondary
Percentage of Hypoglycemic Episodes (<80 mg/dL)
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Percentage of Hypoglycemic Episodes (<80 mg/dL) | 1.2 percentage of measurements |
Secondary
Percentage of Hypotensive Episodes (SBP<100 mmHg)
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Percentage of Hypotensive Episodes (SBP<100 mmHg) | 1.2 percentage of measurements |
Secondary
Percentage of Patients Experiencing Metabolic Crisis
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
Population: No patients received invasive intracranial multimodal monitoring as a part of their standard of care, as such, these endpoints were not collected.
Secondary
Percentage of Patients Requiring Rescue Insulin Infusion Protocol
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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Percentage of Patients Requiring Rescue Insulin Infusion Protocol | 0 percentage of patients |
Secondary
Percentage of Patients With >1 Episode of Hypoglycemia (<80 mg/dL)
Calculated from hourly blood glucose samples starting at infusion initiation over 48 hours
Time frame: Over 48 hours from infusion initiation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Percentage of Patients With >1 Episode of Hypoglycemia (<80 mg/dL) | 12.5 percentage of patients |
Secondary
Percentage of Patients With >1 Episode of Hypotensive Episode (SBP<100 mmHg)
Calculated from blood pressure measurements starting at infusion initiation over 48 hours
Time frame: Over 48 hours from infusion initiation
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Exenatide | Percentage of Patients With >1 Episode of Hypotensive Episode (SBP<100 mmHg) | 12.5 percentage of patients |