Official Title: “Preventing Epilepsy After Traumatic Brain Injury: A Pilot, Single-Center Randomized Trial of Topiramate to Prevent Seizures After Moderate to Severe TBI”

Our hypothesis is that topiramate will reduce acute seizures after traumatic brain injury and will help prevent the development of epilepsy after traumatic brain injury.

Study Type: Interventional

Study Design: Prevention, Randomized, Open Label, Active Control, Parallel Assignment

Study Primary Completion Date: February 2009

Traumatic brain injury (TBI) causes epilepsy in up to 30% of civilian and 50% of military head injuries, exacerbating chronic neurological disability. There is currently no method for preventing epilepsy after TBI. We hypothesize that the new antiepileptic drug, topiramate (TPM), will (1) reduce acute seizures and prevent the development of epilepsy following TBI and (2) improve neurological recovery. We propose to perform a pilot clinical trial to develop the necessary infrastructure for larger scale randomized clinical trials to test TPM, and, possibly, other new antiepileptic drugs with neuroprotective properties, for their ability to prevent epilepsy after TBI. Subjects with TBI will be randomized within 24 hours to one of three groups: 1) TPM for one week, 2) TPM for three months, or 3) phenytoin for one week. Subjects will be followed for two years for the development of seizures and for neurological outcome. Serial EEGs and MRIs will be performed to explore potential mechanisms for the development of epilepsy after TBI. These new tools for the clinical study of epilepsy prevention, and neuroprotection in general, will be developed that can be applied to a wide variety of studies and which will facilitate future research in this critical area.

Intervention(s) in this Clinical Trial

• Drug: topiramate
  • 100 mg twice per day for 3 months
• Drug: topiramate
  • 100 twice per day for 6 days after loading dose of phenytoin
• Drug: phenytoin
  • loading dose of 20 mg/kg and then 300 mg/day for total of 7 days

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
  • Phenytoin 20mg/kg load, then Topiramate, 100 mg twice daily, starting at 24 hours post-TBI for 6 days.
• Experimental: 2
  • topiramate for 3 months after loading dose of phenytoin
• Placebo Comparator: 3
  • Phenytoin 20 mg/kg as loading dose than 300 mg/day for total of 7 days

Primary Measures

• Early and late seizures after traumatic brain injury
  • Time Frame: 2 years
    Safety Issue?: Yes
• Adverse events
  • Time Frame: 2 years
    Safety Issue?: Yes

Secondary Measures

• Functional recovery after traumatic brain injury
  • Time Frame: 2 years
    Safety Issue?: No

Inclusion Criteria:

• 1. Moderate to severe traumatic brain injury, defined as one or more of the following: penetrating head wound seizure within the first hour after injury intracerebral hematoma or cortical contusion subdural or epidural hematoma Glasgow Coma Score <= 12 or motor score 1-5 (if intubated). Patients who have been pharmacologically paralyzed will be evaluated after the paralytic has worn off or been pharmacologically reversed depressed skull fracture requirement for emergent neurosurgical procedure
• 2. Time since TBI less than 24 hours
• 3. Age greater than or equal to 18 years
• 4. Subject capable of giving informed consent or have an acceptable surrogate capable of giving consent on the subject's behalf. -

Exclusion Criteria:

• 1. Known prior history of epilepsy or unprovoked seizures. Patients with a history of acute symptomatic seizures (e.g. febrile seizure, alcohol withdrawal seizure) will not be excluded
• 2. Administration of an antiepileptic drug before enrollment
• 3. History of allergy to topiramate or phenytoin
• 4. Pregnancy or breast-feeding. Women of childbearing potential must have a negative pregnancy test (urine pregnancy test or serum beta-HCG) before randomization
• 5. Compromised renal function with serum creatinine > 2
• 6. Severe concurrent illness with life expectancy <6 months
• 7. Treatment with another investigational agent for TBI
• 8. Unable to take medications orally and contraindication to placement of nasogastric tube.
• 9. Irreversibly fatal TBI
• 1. All four findings: Glasgow Coma Score = 3, no pupillary reaction, age > 45 years, and severe coagulopathy OR
• 2. Severe brainstem lesion on neuroimaging studies
• 10. Patients with a history of kidney stones or glaucoma.
• 11. Inability to maintain adequate fluid intake while taking topiramate.
• 12. Patients whose TBI is a result of self inflicted injury
• 13. Patient's who are currently using illicit drugs -

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: N/A

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: University of Pennsylvania

Overall Clinical Trial Officials and Contacts

Marc A Dichter, MD, PhD Principal Investigator University of Pennsylvania  

Overall Contact: Kelly S Maxwell 215 614 0520 kelly.maxwell@uphs.upenn.edu

Information obtained from ClinicalTrials.gov on September 05, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00598923

Study ID Number: PR043514

ClinicalTrials.gov Identifier: NCT00598923

Health Authority: United States: Food and Drug Administration