Clinical trial NCT02058940
Conditions: Brain Injuries
Sponsor: University of North Carolina, Chapel Hill
Start date: 2015-08-01; Completion date: 2017-08-01
Enrollment: 8 participants; Allocation: NA; Intervention model: SINGLE_GROUP

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.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: Exenatide
Intervention descriptions: intervention 1: 50 ng/min IV for 30 minutes, then start 25 ng/min IV for a maximum duration of 48 hours

Protocol documents:
Prot_SAP_000.pdf: 
 
Intravenous Exenatide Infusion in Critically Ill Patients with Acute 
Brain Injury 
 
 
 
NCT number NCT 02058940 
Document Date 08/18/2015 
Most recent IRB approval Date  
(for this document version) 07/10/2017 
 
 


Project Title: Intravenous Exenatide Infusion in Critically Ill Patients with Acute Brain Injury 
 
SPECIFIC AIMS 
     Hyperglycemia is associated with worsened clinical outcome following neurologic injury.1-10 Early landmark 
clinical trials have demonstrated that maintaining normoglycemia by intensive insulin therapy (IIT), as 
compared with tolerating hyperglycemia as an adaptive response, significantly decreased mortality in critically 
ill surgical patients and those in the coronary care unit.11-13 However, more recent trials have failed to confirm 
this benefit, and in some studies IIT was associated with significantly higher rates of all-cause mortality.14-24 
There is evidence to suggest that insulin-induced hypoglycemia is an independent risk factor for mortality in 
critically ill patients.25-28 IIT following neurologic injury has been shown to increase the risk for hypoglycemic 
episodes with no subsequent reduction in mortality and has been associated with a significant decrease in 
cerebral extracellular glucose levels and an increased incidence of other markers of cerebral cellular distress 
including, elevated glutamate, lactate/pyruvate ratio, and glycerol.29-32 Emerging evidence and data from the 
pooled post-hoc analysis of the two prospective, randomized, interventional Leuven trials also suggest that 
glycemic variability has a strong, independent effect on mortality in critically ill populations.33-41 Nevertheless, 
the benefit of IIT in the Leuven trials was determined to be associated with decreases in mean glucose levels 
and glycemic variability, and avoidance of severe hypoglycemia. We have preliminarily found and reported that 
glycemic variability in neurocritical care patients is associated with higher in-hospital mortality.42 Thus it is 
plausible that optimum benefit on mortality in critically ill patients would result from decreasing mean glucose 
levels while at the same time minimizing both glycemic variability and the occurrence of severe hypoglycemia.  
     A potential role for incretin-based therapy in the management of critically ill patients with hyperglycemia 
exists. Glucagon-like peptide-1 (GLP-1) is the most well characterized naturally occurring incretin hormone. 
On ingestion of meals, GLP-1 is secreted from L-cells of the small intestine and subsequently enhances 
glucose-dependent insulin secretion, suppresses postprandial glucagon secretion from pancreatic alpha-cells, 
slows gastric emptying, and signals satiety.43-46 Because the former effects are glucose dependent, the use of 
GLP-1 does not appear to be associated with hypoglycemic risk. The major limitation of endogenous GLP-1 is 
its relatively short half-life due to degradation by the enzyme dipeptidyl peptidase IV (DPP-IV).47 Exenatide, a 
DPP-IV resistant GLP-1 receptor agonist, has recently been added to the therapeutic armamentarium targeting 
hyperglycemia. The effect of GLP-1-based therapy on hyperglycemia following neurologic injury has recently 
been evaluated in patients with acute ischemic stroke.48  Daly and colleagues administered exenatide 
subcutaneously in eleven patients over a median duration of six-days.  They reported no symptomatic 
hypoglycemia or serious adverse effects and a low rate of hyperglycemia (4.9%; defined as > 155 mg/dL); 
however, glycemic variability was not assessed in this study. Additionally, the incidence of nausea and 
vomiting with subcutaneous administration was high with 55% and 45% of patients experiencing these adverse 
effects, respectively.  Despite these promising results with subcutaneous administration, other studies have 
evaluated exenatide’s therapeutic use as a continuous infusion in critically ill populations and have reported low 
incidence of gastrointestinal side effects.49-52 Therefore, there is a need to evaluate the feasibility of exenatide 
infusion in critically ill patients with acute brain injury and investigate its impact on glycemic variability.  
Our long-term goal is to reduce mortality associated with hyperglycemia in critically ill patients. The 
objective of this proof of concept study is to explore the effects of exenatide infusion for hyperglycemia 
following acute neurologic injury. We are well prepared to undertake the proposed research. Our extensive 
experience in recruiting individuals is demonstrated by the excellent response rates to our previous acute 
neurologic injury studies.6,42 Additionally, we have assembled a research team with extensive experience in 
exenatide-based, neurologic injury and medical intervention studies, and experienced neurointensivist 
collaborator. 
 


We plan to accomplish the grant objectives by pursuing the following specific aims: 
1. To demonstrate the feasibility of exenatide infusion in critically ill patients with acute brain injury 
utilizing continuous glucose monitoring.   
Background and Rationale: 
Hyperglycemia, hypoglycemia, and glycemic variability are all associated with poor outcomes in critically 
ill patients. Elevated glucose during the acute period of hospitalization has been linked to mortality in 
patients with traumatic brain injury and intracerebral hemorrhage.6,49 Hypoglycemia is associated with 
increased mortality in critically ill patients achieving goal glucose levels of 80 – 120 mg/dL and has been 
associated with cerebral distress.25,27,32,50  Glycemic variability has also been found to be an independent risk 
factor for mortality in critically ill patients.33,51-54 In a study comparing the impact of glycemic variability in 
patients with and without diabetes, high glycemic variability was associated with increased mortality in 
patients without diabetes.36 Recent studies have also begun to demonstrate the impact of glycemic 
variability on clinical outcomes in patients with acute brain injury.  Matsushima and colleagues 
demonstrated that glucose variability was significantly associated with poorer long-term functional 
outcomes in patients with traumatic brain injury.55 Kurtz and colleagues reported that glucose variability 
was associated with cerebral metabolic distress and increased mortality at hospital discharge in patients with 
severe brain injury.56 Blayau and colleagues found that glycemic variability is an independent predictor of 
mortality in ICU patients with traumatic brain injury.57 Investigators in our group reported that large glucose 
variability during the acute phase of spontaneous intracerebral hemorrhage is associated with higher in-
hospital mortality.58 Therefore, it might be reasonable to hypothesize that optimal benefit might occur in 
patients with acute brain injury from control of overall glycemic levels (mean glucose levels) in 
conjunction with minimizing glycemic variability, while strictly avoiding the occurrence of hypoglycemia. 
 
A potential role for incretin-based therapy in the management of critically ill patients with hyperglycemia 
exists. The effect of GLP-1-based therapy via continuous infusion on hyperglycemia following acute brain 
injury has not been previously evaluated, however, few studies have evaluated its therapeutic use in other 
critically ill populations. Following major surgery, GLP-1 infusion (1.2 pmol/kg/min) administered to eight 
patients with type 2 diabetes resulted in normalization of hyperglycemia (126 mg/dL) within 150 minutes of 
initiation.59 Following coronary artery bypass graft surgery, GLP-1 infusion had been demonstrated to 
normalize blood glucose compared to both placebo and IIT with doses of 1.5 and 3.6 pmol/kg/min, 
respectively.59,60 Other published data support that GLP-1 infusion attenuates glycemic response in severely 
ill patients hyperglycemic during total parenteral nutrition, enteral or intragastric feeding.61,62  Intravenous 
GLP-1 infusion has been well-tolerated in all critically ill populations evaluated with minimal adverse 
events reported. Hypoglycemic events were not recorded in the majority of studies.58,59,61,62 One episode of 
asymptomatic hypoglycemia (43 mg/dL) occurred with GLP-1 treatment, but resolved following temporary 
cessation of the infusion. 
 
The main expected outcome of this work is to demonstrate the feasibility of exenatide infusion in the 
management of hyperglycemia following acute brain injury. We are proposing to evaluate this aim by 
utilizing continuous glucose monitoring (CGM). CGM has the potential to provide real-time measurement 
of systemic glucose concentrations.  This allows for more intensive monitoring of glycemic variability as 
well as hyper- and hypoglycemic events.  Schuster and colleagues reported CGM is reasonable and accurate 
in surgical ICU patients, many of whom had recent abdominal surgery and required use of pressors and 
large-volume resuscitation.63 Holzinger and colleagues found that CGM reduced hypoglycemic events in 
critically ill patients64 and also reported that the accuracy and reliability of CGM in critically ill patients was 


not impacted by circulatory shock requiring norepinephrine therapy.65 CGM will provide a direct 
representation of the overall glycemic status in order to evaluate the potential of exenatide as a treatment of 
hyperglycemia following acute brain injury.    
 
2. To evaluate the pharmacokinetic parameters of exenatide in critically ill patients with acute brain injury. 
Background and Rationale: 
Critically ill patients and patients with acute brain injury have been shown to experience a hyperdynamic 
state resulting in an elevation of creatinine clearance, termed augmented renal clearance (ARC).66-68 Patients 
with ARC have the potential to eliminate exenatide more quickly than we currently anticipate, as renal 
clearance is the predominant route of elimination of this drug.  This will directly impact the ability to 
achieve therapeutic drug concentrations with the current recommended dosing regimen.  
 
A recent study by Udy and colleagues evaluated the incidence of ARC in generally critically ill patients 
throughout their ICU stay.66 They found that 65.1% of patients manifested ARC on at least one occasion 
during the first seven days in the ICU.  More specifically, a limited amount of information exists evaluating 
ARC in patients with acute brain injury.  In patients with traumatic brain injury, Udy and colleagues 
demonstrated an incidence of ARC in 85% of patients with the mean maximum creatinine clearance being 
179 mL/min/1.73 m2.67 In addition, an abstract recently presented at the 2013 Neurocritical Care Annual 
Meeting utilized vancomycin serum concentrations and determined that patients with aneurysmal 
subarachnoid hemorrhage also appear to have an increase in renal clearance, with an estimated creatinine 
clearance of > 140 mL/min.68 
 
Our research team has experience in this area as we have also utilized vancomycin serum concentrations to 
describe drug pharmacokinetics in patients with acute brain injury who underwent thermoregulation.69  In 
patients who underwent controlled normothermia and received vancomycin, we found that the median 
measured trough concentration and median calculated half-life were significantly lower than predicted 
values, suggesting that the elevated renal elimination of vancomycin due to ARC outweighs a potential 
reduction in drug elimination caused by controlled normothermia. This resulted in subtherapeutic 
vancomycin serum concentrations, which may lead to serious complications.69   
 
Therefore, determining the incidence of ARC in this patient population and its impact on exenatide 
pharmacokinetic parameters is a critical area for further study as ARC may result in subtherapeutic 
concentrations of exenatide.  We are proposing to evaluate this aim by measuring serum concentrations of 
exenatide and directly measuring urinary creatinine clearances concurrently.  This will provide a direct 
representation of the overall renal function along with the incidence of ARC and allow for comparison of 
the patient’s renal function with exenatide serum concentrations.      
 
3. To determine the impact of exenatide infusion on cerebral extracellular glucose levels and other markers 
of cellular distress utilizing cerebral microdialysis in eligible critically ill patients with acute brain injury. 
Background and Rationale:  
Recently both experimental and clinical studies have shown that even mild hypoglycemia may result in 
cerebral metabolic distress.70-72 Overall these studies show that the brain can be acidotic even with “normal” 
serum glucose concentrations and this cerebral glycopenia is related to poor functional outcome.72 There is 
convincing evidence to suggest that measures to avoid both hyperglycemia and hypoglycemia in 
neurocritical care patients are essential.   
 


Studies conducted that have evaluated IIT in neurocritical care patients have not shown differences in 
mortality or functional outcome when tight glucose control is used.29-32,73-75 Some of these studies have 
shown lower infection rates in neurocritical care patients but increased risk of hypoglycemic episodes 
(serum glucose < 50-80 mg/dL).29-31 This increased risk of hypoglycemia is of significant concern as 
evidenced by an observational study of 172 patients following subarachnoid hemorrhage who were treated 
with an IIT protocol targeting blood glucose between 80 and 110 mg/dL and the adverse effect this 
complication had on functional outcome.76 In this study a blood glucose nadir of < 80 mg/dL was 
independently associated with higher rates of cerebral infarction, symptomatic cerebral vasospasm, and poor 
functional outcome. 
 
Cerebral microdialysis is a well-established laboratory tool that is increasingly used as a bedside monitor of 
brain tissue biochemistry in the neurocritical care unit.  Metabolic crisis, measured in the interstitial space 
by cerebral microdialysis, is defined as a high lactate pyruvate ratio (LPR >40) in combination with a low 
extracellular cerebral glucose level (<0.7 mmol/l).77-79 Serum glucose levels directly affect the availability of 
extracellular brain glucose and therefore brain metabolism. Under optimal conditions, energy supply to the 
brain is adjusted to meet the individual demand, which is higher after severe brain injury.80-81 A reduction in 
energy supply can be caused by reduced cerebral blood flow, which decreases oxygen and glucose supply, 
resulting in a shift to anaerobic metabolism with increased brain lactate.82 Alternatively, low glucose 
availability can lead to a decrease in brain pyruvate without an increase in lactate.32,72 This metabolic crisis 
has been linked to poor outcome in comatose patients.83,84  
 
Recently, tight glycemic control with IIT has been associated with metabolic crisis in patients with acute 
brain injury.32,49,71 In these studies, tight glucose control (goal 80-120 mg/dL) was associated with a 
significant increase in the incidence of dialysate glucose levels <0.7 mmol/L, LPR >30, and increased in 
glutamate.  Marcoux et al. reported that the percentage of time LPR was above 30 was significantly 
correlated with the extent of frontal lobe atrophy 6 months following injury even in patients with a normal 
frontal lobe on initial CT scan.50 It is becoming apparent that IIT is not only associated with hypoglycemic 
episodes but also with direct extracellular evidence of cellular distress and brain metabolic crisis. 
 
Therefore, in neurocritical care patients, interventions that maintain cerebral extracellular glucose levels 
without causing an increase in markers of cellular distress are anticipated to be particularly effective in the 
management of acute hyperglycemia. We propose to determine the impact of exenatide infusion on cerebral 
extracellular glucose levels in eligible critically ill patients with acute brain injury.  
 
APPROACH 
 
Study Design: Single-center, prospective, non-randomized, open-label feasibility demonstration trial of 
exenatide infusion following acute brain injury. 
 
Randomized Design (if applicable): NA 
 
Study Population: Critically ill patients with acute brain injury.  
 
 
 
 


Major Inclusion Criteria for Initiation of Study Drug: 
1. Adults ≥18 years  
2. Acute brain injury resulting in admission to the NSICU for an anticipated length of stay >48 hours 
3. Two blood glucose concentrations  > 150 mg/dL and ≤ 300 mg/dL  
4. Informed consent obtained via patient’s designated proxy 
 
Major Exclusion Criteria for Initiation of Study Drug: 
1. Pregnant (verified by urine or serum pregnancy test within 24 hours of initiation of infusion) or lactating 
females 
2. Type 1 diabetes mellitus 
3. History of pancreatitis or risk factors for acute pancreatitis (i.e ethanol abuse, gall stones) 
4. Renal insufficiency defined as CrCL < 45 mL/min  
5. Known history of gastroparesis 
6. History of surgery on stomach, esophageous or duodeneum 
7. Diabetic Ketoacidosis or Hyperosmolar Hyperglycemic Nonketotic Syndrome 
8. Concurrent steroid use or planned post-operative steroid use 
9. History of organ transplantation 
10. Brain death or suspected imminent brain death within the next 72 hours  
11. Refractory intracranial hypertension defined as ICP > 25 mmHg for greater than 15 minutes and refractory 
to medical intervention 
12. Currently enrolled in another investigational drug or device protocol 
13. 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 
14. Known allergy to exenatide 
 
Methodology: 
1. Subjects: Adult patients (≥18 years) with two consecutive blood glucose readings of  >150 mg/dL and ≤300 
mg/dL will be eligible for inclusion in this study. The study population will be limited to those with acute brain 
injury resulting in admission to the NSICU for an anticipated length of stay >48 hours and who will not have 
planned steroid use post-operatively.  Patients with imminent brain death or refractory intracranial hypertension 
will not be enrolled. Pregnant (verified by urine or serum pregnancy test within 24 hours of initiation of 
exenatide infusion) or lacting females, and those with a history of type 1 diabetes mellitus, pancreatitis or risk 
factors for acute pancreatitis (i.e. ethanol abuse, gall stones), renal insufficiency (CrCL < 45 mL/min), 
gastroparesis, surgery on stomach, esophageous, or duodeneum or those with organ transplantation will be 
excluded. Additionally, those presenting with diabetic ketoacidosis or hyperosmolar hyperglycemic nonketotic 
syndrome will be excluded. Individuals receiving steroids or planned post-operative administration, insulin 
infusion within 3 hours of study drug administration, long acting insulin or sulfonylureas within 24 hours of 
study drug administration, another investigational drug or device, or those with known allergy to any of the 
study protocol drugs will be excluded. Recruitment will continue until 24 subjects receive study drug and 
complete the study protocol.  
2. Glycemic Control Protocol: All study related protocols will be conducted in the Neuroscience Intensive Care 
Unit (NSICU). All patients admitted to the NSICU and that meet the eligibility criteria will be approached for 
consent to the study. Study drug will only be administered to those subjects providing consent via legally 
authorized representative and meeting glycemic thresholds. The study nurse will initiate the exenatide infusion 


for the second consecutive blood glucose value >150 mg/dL but ≤300 mg/dL and continue per protocol for a 
maximum duration of 48 hours. Exenatide will be administered by intravenous infusion (50 ng/min for 30 
minutes, then start exenatide infusion 25 ng/min) for the second consecutive blood glucose value >150 mg/dL 
but ≤300 mg/dL and continue per protocol for a maximum duration of 48 hours (dose, route, titration schedule, 
and duration). Exenatide will be prepared by the Investigational Drug Service. The exenatide infusion initiation 
and maintenance protocols are outlined in Tables 1&2 of the attached study protocol.The exenatide infusion 
blood glucose goal will be 110-180 mg/dL. During the exenatide infusion, glucose measurements will be 
obtained hourly. The exenatide infusion will be temporarily discontinued for blood glucose <110 mg/dL. The 
exenatide infusion will be restarted once the blood glucose level is at least 110 mg/dL. Episodes of 
hypoglycemia will be treated according to the following guidelines: 1) glucose <70 mg/dL will be provided 25 
mL of dextrose 50% (1/2 amp) 2) blood glucose will be re-checked in 5 minutes; if mental status changes 
caused by hypoglycemia are not reversed or blood glucose remains <70 mg/dL, the above dextrose 
administration will be repeated, 3) serum glucose will be checked hourly after dextrose administration and the 
episode has resolved. Exenatide infusion will be restarted beginning with the second hourly glucose check that 
is ≥110 mg/dL. Insulin sensitive sliding scale using formulary rapid acting insulin will be used for blood 
glucose 181-300 mg/dL starting at the 2nd hourly glucose check (≥2 hours since exenatide initiation). The 
physician will be notified for any blood glucose >300 mg/dL for initiation of a rescue insulin infusion protocol. 
All glucose values will be documented in the ICU Electronic Documentation System.  
Table 1: Exenatide Infusion Initiation Protocol 
Glucose 
(mg/dL) 
Action 
151-300 
Give exenatide 50 ng/min for 30 minutes, then start exenatide infusion 25 ng/min 
Give prokinetic agent per NSICU protocol (reglan, erythomycin, etc) 
Check glucose hourly 
Monitor blood pressure continuously during exenatide infusion. If SBP <100 mmHg, contact 
physician. Decision to discontinue exenatide infusion will be made at the discretion of the treating 
physician.   
 
Table 2: Exenatide Infusion Maintenance Protocol 
Glucose 
(mg/dL) 
Action 
<70 
Discontinue exenatide infusion.  
Give 25 mL of dextrose 50% (1/2 amp) IVP – Recheck glucose in 5 minutes and notify physician.  
Check glucose hourly after hypoglycemia is resolved. 
When 2 in a row hourly glucose checks are greater than 109 restart exenatide infusion at 25 ng/min 
Notify physician when glucose greater than 80 mg/dL 
Monitor blood pressure continuously during infusion (if SBP<100 mmHg, contact physician)  
80-109  
Temporarily discontinue exenatide infusion 
Check glucose hourly  
When glucose greater than 109 restart exenatide infusion at 25 ng/min 
Note: If 3 in a row hourly checks are less than 110 restart protocol from beginning. Change glucose 
check to q4h and exenatide protocol for second glucose greater than 180 mg/dL 
Monitor blood pressure continuously during infusion (if SBP<100 mmHg, contact physician) 


110-180  
Continue exenatide infusion per protocol 
Check glucose hourly 
Monitor blood pressure continuously during infusion (if SBP<100 mmHg, contact physician) 
181-216  
1st hourly glucose check (=1 hour since exenatide initiation): continue exenatide infusion protocol 
≥2nd hourly glucose check (≥2 hours since exenatide initiation): Give 2 units of formulary available 
rapid acting insulin subcutaneously and continue exenatide infusion protocol 
Check glucose hourly 
Monitor blood pressure continuously during infusion (if SBP <100 mmHg, contact physician) 
217-252  
1st hourly glucose check (=1 hour since exenatide initiation): continue exenatide infusion protocol 
≥2nd hourly glucose check (≥2 hours since exenatide initiation): Give 4 units of formulary available 
rapid acting insulin subcutaneously and continue exenatide infusion protocol 
Check glucose hourly 
Monitor blood pressure continuously during infusion (if SBP <100 mmHg, contact physician) 
253-300  
1st hourly glucose check (=1 hour since exenatide initiation): continue exenatide infusion protocol 
≥2nd hourly glucose check (≥2 hours since exenatide initiation): Give 6 units of formulary available 
rapid acting insulin subcutaneously and continue exenatide infusion protocol 
Check glucose hourly 
Monitor blood pressure continuously during infusion (if SBP <100 mmHg, contact physician) 
>300  
Recheck blood glucose within 5 minutes 
If confirmed, contact physician to discontinue exenatide and initiate rescue insulin infusion 
protocol (NSICU insulin infusion protocol) 
3. Glycemic Variability Protocol:  The Guardian REAL-Time Continuous Glucose Monitoring System (CGMS, 
Medtronic MiniMed, Northridge, CA) will be used to assess glycemic variability. The CGMS device carries an 
FDA-approved indication to supplement but not replace routine standard monitoring in patients. As such, 
the nursing staff will be blinded to the CGMS readings. All therapeutic decisions will be based upon standard of 
care glucose monitoring as outlined in the glycemic control protocol.  
The CGMS is composed of a subcutaneous sensor that uses the glucose oxidase reaction for generation of an 
electrical current. A wireless transmitter connects to the sensor, and the signal is analyzed and converted to a 
measurement of the subcutaneous glucose level by a pager-sized device. Glucose levels are measured and 
recorded every 5 minutes. The subcutaneous glucose sensor will be deployed using the insertion kit available by 
the manufacturer. The sensors will be preferentially placed in the anterior abdomen. In the event the anterior 
abdomen is not available, the sensor will be placed in the upper thigh. Routine blood glucose measurements will 
be obtained hourly while the patient is receiving exenatide for purposes of calibration of the CGMS. After the 
initial calibration, the CGMS will be calibrated every 12 hours at a minimum.  Sensors will be monitored daily 
by an investigator and 1 day after removal. The CGMS will be performed for 72 hours (48 hours during study 
drug infusion and an additional 24 hours during follow-up after study drug is discontinued). 
4. Pharmacokinetic Protocol: 
All patients admitted to the NSICU that meet the eligibility criteria will be approached for consent of blood 
samples obtained for pharmacokinetic analysis. Blood samples will be collected at 0, 12, 24, 36, and 48 hours 
after the start of the infusion.  Approximately 30 mL of blood will be collected over 48 hours for 
pharmacokinetic sampling.  The exenatide concentrations will be processed by Tandem Labs. An 8-hour urine 
collection for measuring creatinine clearance will be performed as the primary method of measuring renal 


function. Eight-hour urine collections will be obtained on a daily basis for 72 hours (48 hours during study drug 
infusion and an additional 24 hours during follow-up after study drug is discontinued). 
5. Bedside Cerebral Microdialysis Protocol: Patients admitted to the NSICU that meet the eligibility criteria and 
who also receive invasive intracranial multimodal monitoring as part of their standard of care will be invited to 
participate in the bedside cerebral microdialysis protocol. The bedside cerebral microdialysis protocol is in 
addition to the glycemic control, glycemic variability, and pharmacokinetic protocols. These patients will have 
the option of declining cerebral microdialysis but still remaining part of the other components of the study.   
The addition of the FDA approved Cerebral Microdialysis probe (please see attached appendix) will be placed 
through the pre-existing invasive multimodal monitoring used as standard of care in these patients. No 
additional invasive procedures will be initiatied in these study participants. The microdialysis  probes (CMA70, 
10-mm membrane length, CMA Microdialysis, Stockholm, Sweden) will be placed in a standard fashion via a 
triple lumen skull bolt used as standard of care. The catheter location will be assessed in patients who have a 
follow-up CT scan. Catheters will be perfused by a battery driven microdialysis pump (CMA106, CMA 
Microdialysis) with artificial cerebrospinal fluid perfusion fluid (CMA Microdialysis, Stockholm, Sweden: 
NaCl 147 mmol/L, KCL 2.7 mmol/l, CaCl2 1.2 mmol/l, MgCl2 0.85 mmol/l) at a flow rate of 0.3 ml/min, which 
yields a recovery rate between 65-72%.92 The dialysate will be collected in microvials designed for low 
evaporation and minute volumes. The samples will be analyzed immediately with the bedside mobile 
photometric, enzyme-kinetic analyzer (CMA600 Microdialysis analyzer; CMA Microdialysis, Stockholm, 
Sweden) every hour using a method previously described.93 The initial 60 minute sample will not be used to 
allow for stabilization of the probe.  The biochemical analysis includes parameters of energy metabolism 
(glucose, pyruvate, lactate, lactate:pyruvate ratio), glutamate (marker of cerebral ischemia), and glycerol 
(marker of cell membrane degradation).  Microdialysis will be performed for 72 hours (48 hours during study 
drug infusion and an additional 24 hours during follow-up after study drug is discontinued) and daily medians 
of the microdialystate concentrations will be calculated for each patient.  The microdialysis samples collected 
will be stored at -80 °C in a freezer for a period of three years. The samples will be stored in the event that the 
samples need to be re-run during the study period.  The freezer is connected to an alarm system and these stored 
samples will not be shared. 
6. General Management Protocol: All patients will be managed using standard NSICU protocols.  ICP will be 
kept < 25 mmHg using a stepwise management strategy (management strategies will be recorded).  Patients 
fluid will be maintained with crystalloids without glucose and enteral nutrition will be started as soon as 
possible.  No patients will receive intravenous or oral steroids for their brain injury.  Seizure prophylaxis will be 
provided per protocol for 7 days and sedation/analgesia will be provided as needed and titrated to standard 
monitoring scales or ICP. A prokinetic agent will be initiated for study subjects per NSICU protocol. Blood 
pressure will be monitored continuously throughout the study period for all subjects. All medications received 
during study drug infusion will be recorded. 
7. Safety Data: 
 
1 ADVERSE EVENTS 
An Adverse Event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing 
medical condition in a patient or clinical investigation subject administered an investigational (medicinal) 
product and that does not necessarily have a causal relationship with this treatment. An AE can therefore be any 


unfavorable and unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the use of investigational product, whether or not considered related to the 
investigational product. 
Adverse events can be spontaneously reported or elicited during open-ended questioning, examination, or 
evaluation of a subject. (In order to prevent reporting bias, subjects should not be questioned regarding the 
specific occurrence of one or more AEs.) 
1.1 
Serious Adverse Events 
A serious AE (SAE) is any untoward medical occurrence that at any dose:  
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of death at the time of the event; it 
does not refer to an event which hypothetically might have caused death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing hospitalization (see NOTE below) 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect  
• is an important medical event (defined as a medical event(s) that may not be immediately life-threatening or 
result in death or hospitalization but, based upon appropriate medical and scientific judgment, may 
jeopardize the subject or may require intervention [eg, medical, surgical] to prevent one of the other serious 
outcomes listed in the definition above.) Examples of such events include, but are not limited to, intensive 
treatment in an emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization.)   
Suspected transmission of an infectious agent (eg, any organism, virus or infectious particle, pathogenic or non-
pathogenic) via the study drug is an SAE. 
Although pregnancy, overdose, and cancer are not always serious by regulatory definition, these events must be 
handled as SAEs.  (See Section 6.1.1 for reporting pregnancies.) 
NOTE:  
The following hospitalizations are not considered SAEs in clinical studies:  
− a visit to the emergency room or other hospital department < 24 hours, that does not result in admission 
(unless considered "important medical event" or event life threatening) 
− elective surgery, planned prior to signing consent 
− admissions as per protocol for a planned medical/surgical procedure 
− routine health assessment requiring admission for baseline/trending of health status (eg, routine 
colonoscopy) 
− medical/surgical admission for purpose other than remedying ill health state and was planned prior to 
entry into the study. Appropriate documentation is required in these cases 
− admission encountered for another life circumstance that carries no bearing on health status and requires 
no medical/surgical intervention (eg, lack of housing, economic inadequacy, care-giver respite, family 
circumstances, administrative). 


1.1.1 
Serious Adverse Event Collection and Reporting 
Following the subject’s written consent to participate in the study, all SAEs, whether related or not related to 
study drug, must be collected, including those thought to be associated with protocol-specified procedures. All 
SAEs must be collected that occur during the screening period and within 30 days of discontinuation of dosing.  
If applicable, SAEs must be collected that relate to any later protocol-specified procedure (eg, a follow-up skin 
biopsy).  
The investigator should report any SAE occurring after these time periods that is believed to be related to study 
drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding its status of seriousness.  
If the investigator believes that an SAE is not related to the study drug, but is potentially related to the 
conditions of the study (such as withdrawal of previous therapy, or a complication of a study procedure), the 
relationship should be specified in the narrative section of the SAE Report Form. 
SAEs, whether related or not related to study drug, and pregnancies must be reported within 24 hours. SAEs 
must be recorded on the SAE Report Form; pregnancies on a Pregnancy Surveillance Form (electronic or paper 
forms).   
For studies capturing SAEs/pregnancies through electronic data capture (EDC), electronic submission is the 
required method for reporting. The paper forms should be used and submitted immediately, only in the event 
the electronic system is unavailable for transmission. When paper forms are used, the original paper forms are 
to remain on site. 
If only limited information is initially available, follow-up reports are required. (Note: Follow-up SAE reports 
should include the same investigator term(s) initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new information becomes 
available, a follow-up SAE report should be sent within 24 hours using the same procedure used for 
transmitting the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
1.2 
Nonserious Adverse Events 
A nonserious adverse event is an AE not classified as serious. 
1.2.1 
Nonserious Adverse Event Collection and Reporting 
The collection of nonserious AE information should begin at initiation of study drug. Nonserious AE 
information should also be collected from the start of a placebo lead-in period or other observational period 
intended to establish a baseline status for the subjects. 
Nonserious AEs should be followed to resolution or stabilization, or reported as SAEs if they become serious 
(see Section 6.1.1). Follow-up is also required for nonserious AEs that cause interruption or discontinuation of 
study drug, or those that are present at the end of study treatment as appropriate. All identified nonserious AEs 
must be recorded and described on the nonserious AE page of the CRF (paper or electronic).  
Completion of supplemental CRFs may be requested for AEs and/or laboratory abnormalities that are 
reported/identified during the course of the study. 


1.3 
Laboratory Test Abnormalities 
The following laboratory abnormalities should be captured on the nonserious AE CRF Page or SAE Report 
Form (paper or electronic) as appropriate: 
• Any laboratory test result that is clinically significant or meets the definition of an SAE  
• Any laboratory abnormality that required the subject to have the study drug discontinued or interrupted 
• Any laboratory abnormality that required the subject to receive specific corrective therapy. 
It is expected that wherever possible, the clinical, rather than the laboratory term would be used by the reporting 
investigator (eg, anemia versus low hemoglobin value). 
1.4 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of investigational product exposure, including during at least 6 
half lives after product administration, the investigational product will be permanently discontinued in an 
appropriate manner (eg, dose tapering if necessary for subject safety). Protocol-required procedures for study 
discontinuation and follow-up must be performed on the subject unless contraindicated by pregnancy (eg, x-ray 
studies). Other appropriate pregnancy follow-up procedures should be considered if indicated. 
The investigator must immediately notify the Medical Monitor of this event and complete and forward a 
Pregnancy Surveillance Form to within 24 hours and in accordance with SAE reporting procedures described in 
Section 6.1.1.  
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, 
where applicable, offspring information must be reported on the Pregnancy Surveillance Form. 
If, following initiation of the investigational product, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of investigational product exposure, including during at least 6 
half lives after product administration, the investigational product will be permanently discontinued in an 
appropriate manner (eg, dose tapering if necessary for subject safety). Protocol-required procedures for study 
discontinuation and follow-up must be performed on the subject unless contraindicated by pregnancy (eg, x-ray 
studies). Other appropriate pregnancy follow-up procedures should be considered if indicated. 
The investigator must immediately notify the Medical Monitor of this event and complete and forward a 
Pregnancy Surveillance Form within 24 hours and in accordance with SAE reporting procedures described in 
Section  6.1.1.  
Follow-up information regarding the course of the pregnancy, including perinatal and neonatal outcome and, 
where applicable, offspring information must be reported on the Pregnancy Surveillance Form. 
Not applicable. 
Not applicable. 
Any pregnancy that occurs in a female partner of a male study participant should be reported to the sponsor. 
Information on this pregnancy will be collected on the Pregnancy Surveillance Form. 
 
 


1.5 
Overdose 
All occurrences of overdose must be reported as SAEs (see Section 6.1.1 for reporting details). 
An overdose is defined as the accidental or intentional administration of any dose of a product that is considered 
both excessive and medically important. All occurrences of overdose must be reported as an SAE (see Section 
6.1.1 for reporting details.). 
1.6 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, electrocardiograms, x-rays, and 
any other potential safety assessments, whether or not these procedures are required by the protocol, should also 
be recorded as a nonserious or serious AE, as appropriate, and reported accordingly.  
2 
DATA MONITORING COMMITTEE AND OTHER EXTERNAL COMMITTEES 
Not applicable 
8. Measurements: Blood glucose from the arterial line will be measured at baseline (prior to exenatide), hourly 
during the 48 hour exenatide infusion per protocol (table 2) and continue for an additional 24 hours following 
exenatide discontinuation. The continuous glucose monitor will measure the interstitial glucose level every 5 
minutes beginning at baseline (prior to exenatide) until 24 hours following exenatide discontinuation. Blood 
samples for pharmacokinetic analysis will be collected in serum separator tubes at 0, 12, 24, 36 and 48 hours 
after the start of the infusion. Eight-hour urine collections will be obtained on a daily basis for 72 hours (48 
hours during study drug infusion and an additional 24 hours during follow-up after study drug is discontinued). 
Microdialystate concentrations will be collected at baseline (prior to exenatide), and hourly during the 48-hour 
exenatide infusion for parameters of energy metabolism (glucose, pyruvate, lactate, lactate:pyruvate ratio), 
glutamate (marker of cerebral ischemia), and glycerol (marker of cell membrane degradation) and for an 
additional 24 hours following study drug discontinuation. Blood pressure will be measured continuously 
throughout the study period. Intracranial pressure (ICP) will be measured continuously during the exenatide 
infusion.  Intracranial pressure values will be recorded at baseline (prior to exenatide) and daily mean ICP and 
cerebral perfusion pressure values will be reported. Baseline demographic information (e.g. gender, age, 
ethnicity) and disease severity information [e.g. Glasgow coma score, SOFA score (Sequential Organ Failure 
Assessment), Hunt Hess classification, Fisher grade, primary diagnosis, past medical history (including 
measurement of hemoglobin A1c), neurologic exam/computed tomography scan abnormalities] will be 
collected.  The ICU day of study drug administration will be recorded and the total hospital and ICU lengths of 
stay will be recorded. 
 
9. Data Management: Each participant will be assigned a unique identification number. No personal 
identification will be used. All study files will be stored in locked cabinets in the Principal Investigator’s office 
in the Pharmacy Administration Department. Data will be entered into the study database using double entry 
(entry and verification) and will be checked for missing or ineligible responses.  
 
 
 
 
 
 
 


10. Outcomes 
 
10.1 The following feasibility endpoints are based upon prior literature (Nice-Sugar and Exenatide Study 
in the Cardiac ICU): 
Proportion of patients experiencing severe hypoglycemia (<40 mg/dL), Proportion of patients achieving plasma 
glucose goal (110-180 mg/dL), Proportion of patients experiencing nausea requiring discontinuation of 
exenatide therapy 
10.2 The following descriptive endpoints are included for describing experience with exenatide use in the 
NSICU population: 
Average blood glucose value during exenatide infusion (48 hours), percent time in glucose range (48 hours), 
mean time to reach plasma glucose goal (110-180 mg/dL), variability outcome (SD)-MADGE, mean insulin use 
required (units/kg body weight), proportion of subjects requiring rescue insulin infusion protocol, number of 
hypoglycemic episodes (<80 mg/dL)/total number of glucose measurements (48 hours), number of subjects with 
>1 hypoglycemic episode (<80 mg/dL)/total number of subjects (48 hours), correlation of exenatide 
concentrations with creatinine clearance during infusion, elimination rate constant and area under the 
concentration-time curve utilizing concentrations after discontinuation of infusion, side effects and adverse 
events (AEs and SAEs), average daily ICP and CPP during study drug infusion, number of hypotensive 
episodes (SBP<100 mmHg) (48 hours), number of subjects with >1 hypotensive episode/total number of 
subjects (48 hours). Other adverse effects will be collected specifically assessing any alterations in gastric 
motility. 
In patients receiving invasive intracranial multimodal monitoring as part of their standard of care, the 
following endpoints associated with exenatide use will be described: 
Percent time outside of range for energy metabolism (glucose <0.7 mmol/L and lactate:pyruvate ratio > 40), 
glutamate (marker of cerebral ischemia), and glycerol (marker of cell membrane degradation) parameters (48 
hours). 
 
Based upon prior literature, the prespecified criteria for determing feasibility include the following: 1) no more 
than 6 patients (25%) experiencing severe hypoglycemia (<40 mg/dL); 2)  at least 18 patients (75%) achieving 
the plasma glucose goal (110-180 mg/dL); 3) no more than 6 patients (25%) experiencing nausea leading to 
exenatide discontinuation. These criteria will be utilized to determine whether a future efficacy trial will be 
pursued.  
 
11. Sample size and justification: A sample size was determined using prior exenatide in critically ill patients 
studies and patient screening information at our site.  Based upon this data, we determined to enroll 24 patients 
who complete 48 hours of exenatide infusion and continuous glucose monitoring. In eligible patients, cerebral 
microdialysis monitoring will also be performed.  It is estimated based on proposed eligibility criteria that 24% 
(n = 200) patients admitted to the NSICU will be eligible for enrollment annually.  With an approximate rate of 
enrollment at 15 – 20%, we are confident we could enroll 30 – 40 subjects annually. 
 
12. Data analysis plan: Prior to analysis, data will be examined for errors, outliers, and asymmetry. When 
appropriate, transformations will be used to reduce asymmetry. An intent-to-treat analysis (defined as all 
individuals consented in the study) will be utilized. Descriptive statistics will be performed. Data will be 
expressed as means ± standard error (SE) or success rates and corresponding 95%CI for continuous and 


dichotomous outcomes, respectively. Analyses will be completed using the statistical software package SAS, 
version 9.2 (SAS institute, Cary, North Carolina).  
 
13. Ethical consideration: The consent procedures will be reviewed and approved by the Institutional Review 
Board. All subjects will provide written informed consent via proxy. The informed consent process will allow 
the proxy to gain an in-depth knowledge of the study purposes and procedures and allow them to make 
informed decisions about willingness to proceed. Participation is voluntary. The proxy will be encouraged to 
ask questions and will be assessed for adequate understanding.  
 
Exenatide required: yes 
 
Placebo required: no 
 
Clinical study duration of treatment: Subjects will be exposed to exenatide treatment for 48 hours. 
 
Clinical study dosing schedule and frequency: exenatide 50 ng/min for 30 minutes, start exenatide infusion 
25 ng/min x 48 hours 
 
Clinical study number of sites: one 
 
Clinical study expected number of subjects screened:  It is estimated based on proposed eligibility criteria 
that 24% (n = 200) patients admitted to the NSICU will be eligible for enrollment annually with an approximate 
rate of enrollment at 15-20%.  
 
Clinical study expected number of subjects enrolled: 24 
 
Clinical study expected number of subjects to complete study: 24 
 
Planned Study Start Date: January 1, 2015 
 
Planned Study End Date: June 30, 2016 
 
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