Traumatic Neuroprotection and Epilepsy Prevention of Valproate Acid (VPA)

Clinical Study on the Neuroprotection and Epilepsy Prevention of Valproate Acid Administered After Severe Traumatic Brain Injury

1. Background:

   Preliminary studies have suggested that valproate acid (VPA) may promote neuron survival, inhibit apoptosis, decrease the neuron function deficit in cerebral ischemia, and promote the brain functional recovery after traumatic brain injury (TBI). Besides, in the guide of prevention and treatment of epilepsy in 2007, VPA was one of the antiepileptic drugs which were suggested to prevent early epilepsy after TBI (less than 7 days).

2. Objectives:

   Our main objective was to evaluate whether VPA could protect brain and improve recovery of brain function after severe TBI. The secondary objective was to explore whether VPA could prevent late epilepsy after severe TBI (more than 7 days).

3. Methods:

We would enroll 160 patients who were in a vegetative or minimally conscious state 4 to 16 weeks after TBI and who were receiving inpatient rehabilitation. Patients were randomly assigned to receive VPA or placebo for 4 weeks and were followed for 2 weeks after the treatment was discontinued. The rate of functional recovery on the Disability Rating Scale (DRS; range, 0 to 29, with higher scores indicating greater disability) was compared over the 4 weeks of treatment (primary outcome) and during the 2-week washout period with the use of mixed-effects regression models.

Study Overview

• Status: Unknown
• Conditions: Traumatic Brain Injury
• Intervention / Treatment: Drug: valproate acid

• Study Type: Interventional
• Enrollment (Anticipated): 160
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Hu S Jie, M.D., Ph.D.; Phone Number: 086-29-84773307; Email: hushijie@fmmu.edu.cn
• Study Contact Backup: Name: Hu S Jie, M.D., Ph.D.; Phone Number: 086 13992888996; Email: hushijie1979@126.com

Study Locations

• China
  • Shaanxi
    • Xi'an City, Shaanxi, China, 710032
      • Recruiting
      • Institute of Neurosurgery, Xijing Hospital, Fourth Military Medical University
      • Contact: Hu S Jie, M.D., Ph.D.; Phone Number: 086 029 84773307; Email: hushijie@fmmu.edu.cn
      • Contact: Fei Zhou, M.D., Ph.D.; Phone Number: 086 029 13992888996; Email: feizhou@fmmu.edu.cn
      • Principal Investigator: Hu S Jie, M.D., Ph.D.

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 65 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Eligible patients were 16 to 65 years of age with all genders.
• The patients had sustained a nonpenetrating traumatic brain injury 4 to 16 weeks before enrollment, with the confirmation of CT or MRI.
• Additional eligibility criteria were a vegetative state or a minimally conscious state, as indicated by a Disability Rating Scale (DRS) score greater than 11.
• There was an inability both to follow commands consistently and to engage in functional communication, as assessed by the score on the Coma Recovery Scale-Revised (CRS-R)
• All the patients had provided written informed consent.
• The patients were receiving usual inpatient rehabilitation and treatment at each site.

Exclusion Criteria:

• unstable health state,including:Be allergic to VPA, or with serious allergic diseases or allergic constitutions;With serious cardiovascular diseases, hepatic, renal, or psychiatric diseases;With serious respiratory, endocrine, or blood system diseases;With serious infections or malignant tumors; With weakened immunologic status;Addison's diseases;With alcohol or drug abuse.
• Any disability related to the central nervous system that predated the traumatic brain injury.
• Pregnancy or breastfeeding females.
• More than one seizure in the previous month.
• Prior treatment with VPA
• In the case of patients who were undergoing evaluation for ventricular shunt placement or receiving a psychoactive medication, enrollment was deferred until shunt placement had been completed or psychoactive medications discontinued.
• The patients had enrolled the other studies in the past three months or are engaging the other studies.
• The patients were assessed as unqualified for the study according to the comprehensive evaluation opinion brought forward by the research team.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: placebo
Experimental: valproate acid; The patients began receiving treatment at a dose of 400 mg VPA twice daily on the day after randomization by intravenous drip, with this dose continued for 14 days.The dose was increased to 500 mg twice daily at week 3 and to 400 mg three times daily at week 4 if the DRS score had not improved by at least 2 points from baseline. After the week 4 assessment, the study drug was tapered over a period of 2 to 3 days, with assessment of the patients continued through week 6. Additional procedural details are provided in the study protocol.	Drug: valproate acid; valproate acid is a common drug which is applied for epilepsy prevention and treatment.; Other Names: Sodium valproate

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
DRS scores	The DRS score includes measures of eye opening, verbalization, and motor response (derived from the Glasgow Coma Scale); cognitive understanding of feeding, dressing, and grooming; degree of assistance and supervision required; and employability. Scores range from 0 to 29, with higher values indicating greater disability.	On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
the time of break out and state of epilepsy	When the patient were admitted into the study, the breakout and the severity of epilepsy would be monitored and treated until the end of the trial.	from 0 to 42 days when the epilepsy break out
brain MRI scan	Brain MRI scan is applied to monitor the degree and progress of the brain damage.	6 weeks after treatment
the blood concentration of VPA	the blood was collected to detect the concentration about 2 hours after the medication of VPA	On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CRS-R score	The CRS-R score is a standardized neurobehavioral assessment tool comprising six hierarchically organized subscales (i.e., auditory, visual, motor, oromotor-verbal, communication, and arousal); scores range from 0 to 23, with higher scores indicating a higher level of neurobehavioral function.	On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study
function of kidney	There are three main indicators: blood creatinine, urea nitrogen, and uric acid. These indicator are used as a monitor of the kidney safety.	On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study
function of liver	There are several main indicators including ALT, AST, Tbil, D-bil, I-bil, ALB,GLB, and ALP, and so on. These indicators could monitor the change of liver function in case of liver damage.	On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study
Physiological and pathological reflex check		On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study
muscular strength and tension test	There are 6 grades in muscular strength test. And muscular tension test was referred to Modified Ashworth scale.	On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study

Collaborators and Investigators

• Sponsor: Xijing Hospital
• Investigators: Study Director: Fei Zhou, M.D., Ph.D., Institute of Neurosurgery, Xijing Hospital, Fourth Military Medical University

Study record dates

Study Major Dates

• Study Start: October 1, 2013
• Primary Completion (Anticipated): December 1, 2016
• Study Completion (Anticipated): December 1, 2016

Study Registration Dates

• First Submitted: October 28, 2013
• First Submitted That Met QC Criteria: January 2, 2014
• First Posted (Estimate): January 6, 2014

Study Record Updates

• Last Update Posted (Estimate): January 6, 2014
• Last Update Submitted That Met QC Criteria: January 2, 2014
• Last Verified: November 1, 2013

More Information

Terms related to this study

• Keywords: epilepsy; traumatic brain injury; brain protection; valproate acid
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Wounds and Injuries; Craniocerebral Trauma; Trauma, Nervous System; Epilepsy; Brain Injuries; Brain Injuries, Traumatic; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Tranquilizing Agents; Psychotropic Drugs; GABA Agents; Anticonvulsants; Antimanic Agents; Valproic Acid
• Other Study ID Numbers: 20130814-7