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Traumatic Neuroprotection and Epilepsy Prevention of Valproate Acid (VPA)

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ClinicalTrials.gov Identifier: NCT02027987
Recruitment Status : Unknown
Verified November 2013 by Xijing Hospital.
Recruitment status was:  Recruiting
First Posted : January 6, 2014
Last Update Posted : January 6, 2014
Sponsor:
Information provided by (Responsible Party):
Xijing Hospital

Brief Summary:
  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.


Condition or disease Intervention/treatment Phase
Traumatic Brain Injury Drug: valproate acid Phase 1

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 160 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Official Title: Clinical Study on the Neuroprotection and Epilepsy Prevention of Valproate Acid Administered After Severe Traumatic Brain Injury
Study Start Date : October 2013
Estimated Primary Completion Date : December 2016
Estimated Study Completion Date : December 2016


Arm Intervention/treatment
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 Name: Sodium valproate

Placebo Comparator: placebo



Primary Outcome Measures :
  1. DRS scores [ Time Frame: On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study ]
    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.


Secondary Outcome Measures :
  1. the time of break out and state of epilepsy [ Time Frame: from 0 to 42 days when the epilepsy break out ]
    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.

  2. brain MRI scan [ Time Frame: 6 weeks after treatment ]
    Brain MRI scan is applied to monitor the degree and progress of the brain damage.

  3. the blood concentration of VPA [ Time Frame: On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study ]
    the blood was collected to detect the concentration about 2 hours after the medication of VPA


Other Outcome Measures:
  1. CRS-R score [ Time Frame: On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study ]
    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.

  2. function of kidney [ Time Frame: On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study ]
    There are three main indicators: blood creatinine, urea nitrogen, and uric acid. These indicator are used as a monitor of the kidney safety.

  3. function of liver [ Time Frame: On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study ]
    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.

  4. Physiological and pathological reflex check [ Time Frame: On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study ]
  5. muscular strength and tension test [ Time Frame: On the 0,7th,14th,21st,28th,35th,42nd days since admitted into the study ]
    There are 6 grades in muscular strength test. And muscular tension test was referred to Modified Ashworth scale.



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Ages Eligible for Study:   16 Years to 65 Years   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02027987


Contacts
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Contact: Hu S Jie, M.D., Ph.D. 086-29-84773307 hushijie@fmmu.edu.cn
Contact: Hu S Jie, M.D., Ph.D. 086 13992888996 hushijie1979@126.com

Locations
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China, Shaanxi
Institute of Neurosurgery, Xijing Hospital, Fourth Military Medical University Recruiting
Xi'an City, Shaanxi, China, 710032
Contact: Hu S Jie, M.D., Ph.D.    086 029 84773307    hushijie@fmmu.edu.cn   
Contact: Fei Zhou, M.D., Ph.D.    086 029 13992888996    feizhou@fmmu.edu.cn   
Principal Investigator: Hu S Jie, M.D., Ph.D.         
Sponsors and Collaborators
Xijing Hospital
Investigators
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Study Director: Fei Zhou, M.D., Ph.D. Institute of Neurosurgery, Xijing Hospital, Fourth Military Medical University

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Responsible Party: Xijing Hospital
ClinicalTrials.gov Identifier: NCT02027987     History of Changes
Other Study ID Numbers: 20130814-7
First Posted: January 6, 2014    Key Record Dates
Last Update Posted: January 6, 2014
Last Verified: November 2013
Keywords provided by Xijing Hospital:
valproate acid
traumatic brain injury
brain protection
epilepsy
Additional relevant MeSH terms:
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Brain Injuries
Epilepsy
Brain Injuries, Traumatic
Wounds and Injuries
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Craniocerebral Trauma
Trauma, Nervous System
Valproic Acid
Anticonvulsants
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
GABA Agents
Neurotransmitter Agents
Physiological Effects of Drugs
Antimanic Agents
Tranquilizing Agents
Central Nervous System Depressants
Psychotropic Drugs