A Randomized Controlled Trial of Glutamine Dipeptide in Severe Trauma

Design: Double-blind, randomized controlled trial of glutamine dipeptide given IV within the
first 24 hours following severe trauma versus placebo for 7 days.

Primary Aim: To assess IR, patients will undergo EHC on study day 2 and 7 or day of
discharge from ICU.

Secondary Aims: Near continuous data capture of glycemic control via CPOE system will be
assessed for surrogate measures of IR. Other laboratory endpoints that may serve as
biomarkers of the stress response will be collected daily to day 7. Patients will be
followed for mortality and infectious morbidity for 28 days or until hospital discharge.

Inclusion and Exclusion Criteria:

To ensure that the injured patient cohort identified for entry is at sufficient risk for the
development of organ dysfunction, infectious complications, and death, while surviving in
the ICU for 5 days or longer, the investigators analyzed patient visits to VUMC to identify
entry criteria that provided roughly 20% mortality with appropriate length of stay.
Enrollment criteria include:

- Severe trauma (ISS > 16)

- Mechanical ventilation

- Either blood transfusion or inotropic support prior to enrollment.

- No prior history of diabetes Enrollment Goals: A total of 24 subjects in this trial at
Vanderbilt University Medical Center.

Subject identification: All mechanically ventilated, adult patients admitted directly to the
Trauma ICU will be screened for appropriate ISS, transfusion need, and inotropic support
within the first 24 hrs of admission.

Informed consent and subject enrollment: If the patient meets inclusion and exclusion
criteria, the subject's legally authorized representative (LAR) will be approached for
consent for trial participation.

Randomization of study subjects: Patients will be randomized in blocks to receive either
placebo or IV glutamine dipeptide (1:1) using a computerized randomization algorithm.
Solutions will be prepared by an unblinded pharmacist and placed in identical infusion bags;
study and placebo solutions will have identical appearance and smell.

Study Measurements: Surrogate measures of IR will include: mean serum glucose, insulin
requirement on standard glycemic control protocol, serum insulin, C-peptide, adiponectin,
glutamine and isoprostane levels each standardized to individual patient nutritional
provision throughout the ICU stay. Biomarkers of the physiologic stress response and their
recovery include TNF, IL-6, IL-8 and estradiol.

Clinical Data from Medical Record: Clinical data will be obtained during the course of
standard care. All data is maintained in an electronic medical record and electronic data
repository. Discrete data points will be validated at the point of entry and captured
prospectively.

Clinical Endpoints: Patients will be followed for 28 days or until hospital discharge to
assess for patient survival and for infectious complications. Infections will be defined
using CDC definitions. For ventilated patients, quantitative bronchoscopic alveolar lavage
will be performed except where contraindicated. Patients will be assessed daily until
discharge and at day 28 for infections and survival. Daily SOFA scores will be captured from
admission until day 7 or discharge from the ICU.

Safety: This study has been approved by the Institutional Review Board and will adhere to
the regulations for the protection of human subjects. GlnD has been approved in Europe for
intravenous use and has been extensively studied in critically ill populations. All other
measurements, other than the EHC are obtained through processes that are standard of care.
Blood samples obtained daily will be less than 10 mL and will not pose more than minimal
risk. Glycemic management is provided as a standard of care and has been documented to be
safe and effective at the investigators institution with blood glucoses obtained every 2
hours. During the euglycemic, hyperinsulinemic clamp, blood glucose is controlled by
altering glucose provision rather than insulin rate. This allows more rapid and precise
adjustments. Measurements are obtained much more frequently than during standard processes.
These methods have previously been validated for safety in the literature and patients are
intensively monitored during the test.

Inclusion Criteria:

1. Severe trauma (ISS > 16) no more than 24 hours prior to initiation of study drug

2. Mechanical Ventilation

3. Blood transfusion OR inotropic support prior to enrollment

4. Estimated BMI <40.0 kg/m2

Exclusion Criteria:

1. Moribund patients, unlikely to survive 24 hours

2. Anticipated ICU stay < 48 hours

3. Pre-existing diabetes mellitus

4. Known allergy to the drug or any components

5. Known pregnancy

6. Corticosteroid administration prior to enrollment

7. Severe traumatic brain injury or uncontrolled intracranial hypertension

8. Current malignancy

9. History of seizures, chronic liver disease, chronic renal failure requiring dialysis
or solid organ transplantation

10. Known HIV/AIDS

11. Known treatment with another investigational product within 30 days