Phase III Double Blind Trial of Valproate Sodium for Prophylaxis of Post Traumatic Seizures

PROTOCOL OUTLINE: This is a randomized, double blind trial involving 3 treatment groups.

On day 1, controls receive phenytoin IV over 1 hour. On days 2 through 7, controls receive 2 doses each of phenytoin and placebo daily, intravenously. From day 8 through 6 months, controls receive placebo IV 4 times daily, then placebo tablets are administered.

On day 1, the experimental group receives a loading dose of valproate sodium intravenously over 1 hour within 24 hours of injury. Then, patients are divided into 2 subgroups.

From day 2 through 1 month, one group of patients receives valproate IV 4 times daily over 1 hour until tablets are tolerated. Patients receive placebo tablets by mouth 4 times daily from month 2 through month 6.

On day 2, the other group of patients receives valproate IV 4 times daily and continues for 6 months until tablets (same dose) are tolerated.

If patients remain seizure free between day 8 and 6 months, the number of valproate or placebo tablets are tapered over 1 week.

Each patient receives a full neuropsychological and psychosocial examination at 1, 6, and 12 months after injury.

Untreated observation of patients continues until 2 years after injury.

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

Any patient developing the following conditions within 24 hour postinjury:

• Cortical contusion
• Depressed skull fracture
• Subdural hematoma
• Epidural hematoma
• Intracerebral hematoma
• Penetrating head wound
• Seizures occurring subsequent to head injury

--Prior/Concurrent Therapy--

• No antiseizure medication prior to injury or between the injury and study drug loading
• Surgery: No prior neurosurgical operation for which the skull and dura mater were opened

--Patient Characteristics--

• Age: 14 and over
• Hematopoietic: No abnormal coagulation profile
• Hepatic: No history of chronic or alcoholic liver disease Adequate liver function as indicated by ALT less than 1.5 times the upper limit of normal
• Other: Not pregnant No injuries greater than 24 hours old No history of seizures prior to injury No prior history of significant head injury or neurological condition requiring medical attention