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

Study Overview
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Brief Summary
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THIS IS THE SECOND PART OF A 2-PART STUDY. The purpose of the first part of this study was to determine the safety and tolerability of ascending doses of valproic acid (also known as Depacon) administered as intravenous infusion (IV) in doses ranging from 15 mg/kg to 250 mg/kg in healthy subjects. ID: VPA-C-002 The second part of the study will also be to determine the safety and tolerability of single ascending doses of valproic acid administered as IV in trauma subjects with hemorrhagic shock.

Detailed Description
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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).

Official Title
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A Phase 1, Single Ascending Dose, Double Blind, Placebo Controlled Study to Evaluate the Safety and Tolerability of Valproic Acid in Healthy Volunteers (Part 1) or Trauma Patients(Part 2)

Conditions
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Shock,Hemorrhagic, Trauma

Intervention / Treatment
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* Drug: Valproic Acid
* Drug: Isotonic saline solution


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and non-pregnant female trauma patients between the ages of 18-70 years, inclusive. 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). Patient's admission to the emergency department results in trauma team activation (per institutional criteria, see Appendix 7). Patient's injuries are considered potentially survivable by the attending trauma surgeon on initial evaluation. 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. 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. Body mass index (BMI) between 18 kg/m2 and 35 kg/m2 Exclusion Criteria: Subjects with known history of adverse reaction to Valproic acid. Subjects with known history of hepatitis B or C or clinical history of hepatic dysfunction, pancreatitis, or renal insufficiency. Subjects with -amylase >400 U/L or lipase >300 U/L or creatinine >ULN Subjects with AST or ALT >3X Upper limit of normal (ULN) or total bilirubin >1.5X Upper limit of normal (ULN) Subjects with 2nd or 3rd degree burns of any size and location. Female subjects who are pregnant or lactating. Subjects who are currently incarcerated. Subjects with severe traumatic brain injury (with Glasgow Coma Scale score <8 on arrival to the emergency department). Non-hemorrhagic causes of shock, including septic, cardiogenic, or neurogenic shock or mechanical reasons such as tension pneumothorax or cardiac temponade. Subjects with inadequate venous access. Subject with a hemoglobin level of less than 8g/dL. -

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Valproic acid (Depacon)<br>Valproic acid by IV infusion over one hour | Drug: Valproic Acid<br>* By infusion over 1 hour<br>* Other names: Depacon;|
| Placebo Comparator: Isotonic saline solution<br>The placebo administered by IV infusion over 1 hour | Drug: Isotonic saline solution<br>* By infusion over 1 hour<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Dose limiting toxicity (DLT) | Dose limiting toxicity (DLT) will be measured by drug-related grade 2 (moderate) or higher toxicity indicators (excluding fever, chills, nausea or other possible infusion-related effects). | As this is a safety study, subjects will be monitored for side-effects beginning immediately after the one hour infusion until the follow-up visit (between 2-6 weeks post infusion) is completed. |