Traumatic Neuroprotection and Epilepsy Prevention of Valproate Acid

NCT02027987 — Phase 1, Unknown, 160 participants, Xijing Hospital

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

Registry	NCT02027987, acronym VPA
Status	Unknown
Phase	Phase 1
Study type	Interventional; randomized, parallel, masking: quadruple, prevention
Enrollment	160 (Estimated)
Sponsor	Xijing Hospital (Other)
Conditions	Traumatic Brain Injury
Interventions	valproate acid (Drug)
Dates	start 2013-10-01, primary completion 2016-12-01 (estimated), completion 2016-12-01 (estimated), first posted 2014-01-06, last updated 2014-01-06
Locations	1 site in China

-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.

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+Arms and interventions

Arm	Type	Interventions	Description
valproate acid	Experimental	Drug: 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.
placebo	Placebo comparator

valproate acid (Drug), also known as Sodium valproate: valproate acid is a common drug which is applied for epilepsy prevention and treatment.

+Outcome measures

Primary outcomes

DRS scores [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 outcomes

the time of break out and state of epilepsy [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.
brain MRI scan [6 weeks after treatment]: Brain MRI scan is applied to monitor the degree and progress of the brain damage.
the blood concentration of VPA [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 outcomes

CRS-R score [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.
function of kidney [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.
function of liver [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.
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 [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.

+Eligibility

Sex: All, ages: 16 Years to 65 Years

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.

+Locations (1)

Facility	City	Country	Status
Institute of Neurosurgery, Xijing Hospital, Fourth Military Medical University	Xi'an, Shaanxi	China	Recruiting

+Investigators

Fei Zhou, M.D., Ph.D., Study director, Institute of Neurosurgery, Xijing Hospital, Fourth Military Medical University

My Notes

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