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

Primary Purpose

Shock,Hemorrhagic, Trauma

Status

Terminated

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Valproic Acid

Isotonic saline solution

About this trial

This is an interventional treatment trial for Shock,Hemorrhagic

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.
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Sites / Locations

Massachusetts General Hospital
The University of Michigan

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Valproic acid (Depacon)

Isotonic saline solution

Arm Description

Valproic acid by IV infusion over one hour

The placebo administered by IV infusion over 1 hour

Outcomes

Primary Outcome Measures

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).

Secondary Outcome Measures

Full Information

NCT ID

NCT02872428

First Posted

May 23, 2016

Last Updated

October 31, 2017

Sponsor

Dr. Hasan Alam

1. Study Identification

Unique Protocol Identification Number

NCT02872428

Brief Title

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

Official Title

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)

Study Type

Interventional

2. Study Status

Record Verification Date

October 2017

Overall Recruitment Status

Terminated

Why Stopped

at request of funding group because of failure to enroll more than one patient

Study Start Date

November 2016 (Actual)

Primary Completion Date

September 29, 2017 (Actual)

Study Completion Date

September 29, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor-Investigator

Name of the Sponsor

Dr. Hasan Alam

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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

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).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Shock,Hemorrhagic, Trauma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

1 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Valproic acid (Depacon)

Arm Type

Experimental

Arm Description

Valproic acid by IV infusion over one hour

Arm Title

Isotonic saline solution

Arm Type

Placebo Comparator

Arm Description

The placebo administered by IV infusion over 1 hour

Intervention Type

Drug

Intervention Name(s)

Valproic Acid

Other Intervention Name(s)

Depacon

Intervention Description

By infusion over 1 hour

Intervention Type

Drug

Intervention Name(s)

Isotonic saline solution

Intervention Description

By infusion over 1 hour

Primary Outcome Measure Information:

Title

Dose limiting toxicity (DLT)

Description

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).

Time Frame

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.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

70 Years

Accepts Healthy Volunteers

Eligibility Criteria

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. -

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Hasan Alam, MD

Organizational Affiliation

University of Michigan

Official's Role

Principal Investigator

Facility Information:

Facility Name

Massachusetts General Hospital

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02114

Country

United States

Facility Name

The University of Michigan

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48109

Country

United States

12. IPD Sharing Statement

Learn more about this trial

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

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