A Study to Evaluate the Safety and Tolerability of Valproic Acid in Trauma Patients(Part 2)

THIS IS THE SECOND PART OF A 2-PART STUDY. Part 1 of the study will be a single center study
intended to assess the safety and tolerability of valproic acid dosages at 15 mg/kg, 30
mg/kg, 60 mg/kg, 90 mg/kg, 120 mg/kg, 150 mg/kg 180 mg/kg, 210 mg/kg and 250 mg/kg. Up to 72
healthy subjects (9 dose groups of 8 subjects) will receive single doses of valproic acid or
placebo via a 60-min IV infusion in a ratio of 3:1 active drug: placebo. ID: VPA-C-002

Part 2 of the study will be a multi-center, double blind, placebo-controlled study in trauma
patients with hemorrhagic shock. The patients will be able to consent themselves, or if
unable due to injuries, a Legally Authorized Representative will consent for them. Up to 12
patients (2 dose groups of 6 patients) will receive single doses of valproic acid or placebo
via a 60-min IV infusion in a ratio of 2:1 active drug : placebo. The dose levels in Part 2
will be the two highest doses that are demonstrated to have acceptable safety profile based
on the review of safety data from Part 1 (130mg/kg and 140mg/kg).

Inclusion Criteria:

1. Male and non-pregnant female trauma patients between the ages of 18-70 years,
inclusive.

2. Blunt or penetrating trauma resulting in two or more systolic blood pressure readings
of ≤ 110 mmHg at any point during transport to the hospital or within the first hour
after arrival in the emergency department. Systolic blood pressure readings of ≤ 110
mmHg need not be consecutive (Eastridge et al., 2007).

3. Patient's admission to the emergency department results in trauma team activation (per
institutional criteria, see Appendix 7).

4. Patient's injuries are considered potentially survivable by the attending trauma
surgeon on initial evaluation.

5. Able to provide informed consent or consent can be obtained from a representative
(spouse or other legally authorized representative) in the event that the subject is
unconscious or otherwise impaired.

6. Female subjects must be postmenopausal, surgically sterilized, or have a negative
urinary pregnancy test on arrival. Criteria for menopause include age > 45 with
absence of menses for > 12 months. Criteria for surgical sterilization include
hysterectomy and/or oophorectomy. Tubal ligation with menses within the past 12 months
is not considered to be surgical sterilization.

7. Body mass index (BMI) between 18 kg/m2 and 35 kg/m2

Exclusion Criteria:

1. Subjects with known history of adverse reaction to Valproic acid.

2. Subjects with known history of hepatitis B or C or clinical history of hepatic
dysfunction, pancreatitis, or renal insufficiency.

3. Subjects with -amylase >400 U/L or lipase >300 U/L or creatinine >ULN

4. Subjects with AST or ALT >3X Upper limit of normal (ULN) or total bilirubin >1.5X
Upper limit of normal (ULN)

5. Subjects with 2nd or 3rd degree burns of any size and location.

6. Female subjects who are pregnant or lactating.

7. Subjects who are currently incarcerated.

8. Subjects with severe traumatic brain injury (with Glasgow Coma Scale score <8 on
arrival to the emergency department).

9. Non-hemorrhagic causes of shock, including septic, cardiogenic, or neurogenic shock or
mechanical reasons such as tension pneumothorax or cardiac temponade.

10. Subjects with inadequate venous access.

11. Subject with a hemoglobin level of less than 8g/dL.