Preventing Epilepsy After Traumatic Brain Injury With Topiramate (PEPTO)

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 Overview

• Status: Terminated
• Conditions: Epilepsy; Traumatic Brain Injury
• Intervention / Treatment: Drug: topiramate; Drug: topiramate; Drug: phenytoin

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 6
• Phase: Early Phase 1

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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 -

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 1; Phenytoin 20mg/kg load, then Topiramate, 100 mg twice daily, starting at 24 hours post-TBI for 6 days.	Drug: topiramate; 100 mg twice per day for 3 months; Other Names: Topamax; Drug: topiramate; 100 twice per day for 6 days after loading dose of phenytoin; Other Names: Topamax
Experimental: 2; topiramate for 3 months after loading dose of phenytoin	Drug: topiramate; 100 mg twice per day for 3 months; Other Names: Topamax; Drug: topiramate; 100 twice per day for 6 days after loading dose of phenytoin; Other Names: Topamax
Placebo Comparator: 3; Phenytoin 20 mg/kg as loading dose than 300 mg/day for total of 7 days	Drug: phenytoin; loading dose of 20 mg/kg and then 300 mg/day for total of 7 days; Other Names: Dilantin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Adverse events	2 years
Early and late seizures after traumatic brain injury	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Functional recovery after traumatic brain injury	2 years

Collaborators and Investigators

• Sponsor: University of Pennsylvania
• Investigators: Principal Investigator: Marc A Dichter, MD, PhD, University of Pennsylvania

Study record dates

Study Major Dates

• Study Start: November 1, 2004
• Primary Completion (Actual): February 1, 2009
• Study Completion (Actual): February 1, 2009

Study Registration Dates

• First Submitted: January 11, 2008
• First Submitted That Met QC Criteria: January 22, 2008
• First Posted (Estimate): January 23, 2008

Study Record Updates

• Last Update Posted (Actual): June 27, 2017
• Last Update Submitted That Met QC Criteria: June 26, 2017
• Last Verified: June 1, 2017

More Information

Terms related to this study

• Keywords: epilepsy; traumatic brain injury; tbi
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Epilepsy; Brain Injuries; Wounds and Injuries; Brain Injuries, Traumatic; Hypoglycemic Agents; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Topiramate; Phenytoin
• Other Study ID Numbers: PR043514