Antiseizure Medication for Severe Brain Injury

Overseen By Varina L Boerwinkle, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 4

Waitlist Available

Sponsor: University of North Carolina, Chapel Hill

No Placebo Group

Prior Safety Data

Trial Summary

What is the purpose of this trial?

The goal of this clinical trial is to explore the effect of FDA-approved antiseizure drugs in the brain connectivity patterns of severe and moderate acute brain injury patients with suppression of consciousness. The main questions it aims to answer are: * Does the antiseizure medication reduce the functional connectivity of seizure networks, as identified by resting state functional MRI (rs-fMRI), within this specific target population? * What is the prevalence of seizure networks in patients from the target population, both with EEG suggestive and not suggestive of epileptogenic activity? Participants will have a rs-fMRI and those with seizure networks will receive treatment with two antiseizure medications and a post-treatment rs-fMRI. Researchers will compare the pretreatment and post-treatment rs-fMRIs to see if there are changes in the participant's functional connectivity including seizure networks and typical resting state networks.

Do I need to stop my current medications for this trial?

The trial protocol does not specify if you need to stop your current medications. However, if you have known allergies or contraindications to the trial's antiseizure medications, you may not be eligible to participate.

What data supports the idea that Antiseizure Medication for Severe Brain Injury is an effective drug?

The available research shows that antiseizure medications like sodium valproate and lacosamide are effective in controlling seizures. For instance, in a study with sodium valproate, 15 out of 35 patients achieved complete seizure control, and 12 others benefited from the drug. Lacosamide has been shown to reduce seizure frequency in patients with partial-onset seizures when used alongside other drugs. It was also effective in a case of severe, ongoing seizures where other medications failed. These findings suggest that these drugs can be effective in managing seizures. ^{1 2 3 4 5}

What safety data is available for antiseizure medications used in severe brain injury?

Lacosamide (Vimpat) has been studied extensively as an adjunctive therapy for partial-onset seizures in patients with epilepsy. It has been approved by the European Commission and the FDA, and is available in both oral and intravenous forms. Clinical trials have shown that lacosamide is generally well tolerated and effective in reducing seizure frequency in adults and adolescents. Long-term studies indicate sustained efficacy and safety over several years. The drug is also used as monotherapy in the USA and has shown noninferiority to carbamazepine in terms of seizure freedom. Safety data for children aged 4 years and older is extrapolated from adult data, with preliminary studies supporting its efficacy and safety in this age group. ^{2 3 4 6 7}

Is the drug Lacosamide Injectable Product, Levetiracetam, Phenobarbital Sodium Injection, Phosphenytoin, Valproate Sodium a promising treatment for severe brain injury?

Yes, these drugs show promise for treating severe brain injury. Lacosamide is approved for seizures, Levetiracetam is preferred for brain injury in children, and Valproate Sodium has been effective in reducing seizures. These drugs are considered to have favorable profiles for preventing seizures after brain injury. ^{8 9 10 11 12}

Research Team

Emilio G. Cediel, MD

Principal Investigator

UNC-Chapel Hill

Varina L Boerwinkle, MD

Principal Investigator

UNC-Chapel Hill

Eligibility Criteria

This trial is for ICU patients with severe brain injuries from events like stroke or cardiac arrest, who are stable enough for an MRI but have a Glasgow Coma Scale score under 9. They must be within 3 to 45 days of their injury and not allergic to the study drugs, pregnant, brain dead, have contraindications for MRI scans, epilepsy history, or severe neurological dependence.

Inclusion Criteria

Currently ICU hospitalized

I have been diagnosed with an acute brain injury from a trauma or lack of oxygen.

3 to 45 days from acute brain injury to enrollment time by medical chart review

Exclusion Criteria

My doctor says I can't have 2 of the 5 specific treatments in the study.

My medical records show a history of epilepsy.

You are pregnant based on your medical history or a positive pregnancy test.

Treatment Details

Interventions

• Lacosamide Injectable Product (Antiseizure Medication)
• Levetiracetam (Antiseizure Medication)
• Phenobarbital Sodium Injection (Antiseizure Medication)
• Phosphenytoin (Antiseizure Medication)
• Valproate Sodium (Antiseizure Medication)

Trial Overview The study tests if FDA-approved antiseizure medications can change how seizure networks in the brain connect after serious injury. Patients' brains are scanned before and after treatment using rs-fMRI to see if there's any difference in these connections.

Participant Groups

Group I: Seizure network Positive subjects Experimental Treatment 5 Interventions

Participants in this group include all SzNET-Positive subjects, whether EEG-Positive or EEG-Negative. Within six days of their initial rs-fMRI study, they will receive both loading and maintenance doses of two intervention drug regimens from the study's list. For participants with a GCS of 9 to 12, the research team will choose one of the two selected ASMs, and will omit its loading dose. Maintenance doses should be administered every 12 hours, starting 12 hours after the loading dose, with a maximum of 19 doses allowed. A second rs-fMRI and EEG will occur after participants have received at least five maintenance doses. Following these assessments, the use of the intervention drugs as part of the research intervention will cease. However, if medically necessary, these drugs can continue as part of regular therapy. Note that repeat EEG and rs-fMRI assessments Must occur no longer than 72 hours after the last dose of the intervention drug regimen.

Group II: Seizure network Negative subjects Active Control 1 Intervention

Participants in this group encompass all SzNET-Negative subjects, including those who are EEG-Positive and EEG-Negative. These participants will not receive interventions after the initial study indicated rs-fMRI. They will neither receive repeat rs-fMRI or repeat EEG.

Lacosamide Injectable Product is already approved in Canada, Japan for the following indications:

Approved in Canada as Vimpat for:

• Partial-onset seizures
• Primary generalized tonic-clonic seizures

Approved in Japan as Vimpat for:

• Partial-onset seizures
• Primary generalized tonic-clonic seizures

Who Is Running the Clinical Trial?

University of North Carolina, Chapel Hill

Lead Sponsor

Trials

1,588

Recruited

4,364,000+

Findings from Research

In a study of 35 patients with various types of epilepsy treated with sodium valproate, 15 achieved complete seizure control, indicating its efficacy, especially in those with petit mal epilepsy.

Most patients tolerated sodium valproate well, with few experiencing side effects, and many reported feeling better compared to previous treatments, suggesting it is a safe option for managing epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Sodium valproate (Epilim) in epilepsy: a trial. Briant, RH., Foote, SE., Wallis, WE.[2013]

Lacosamide (Vimpat) was approved in August 2008 by the European Commission and in October 2008 by the FDA as an adjunctive therapy for partial-onset seizures in epilepsy patients.

The approval indicates that lacosamide is considered a safe and effective option to help manage seizures when used alongside other treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lacosamide. Perucca, E., Yasothan, U., Clincke, G., et al.[2018]

Lacosamide (Vimpat) is an antiepileptic drug that works through a dual mechanism: it enhances the slow inactivation of voltage-gated sodium channels and modulates the CRMP-2 protein, which is involved in neuroprotection.

Clinical studies have shown that lacosamide effectively reduces seizure frequency in patients with partial-onset seizures when used alongside other antiepileptic medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lacosamide. A new antiepileptic drug as adjunctive therapy in patients with partial-onset seizures]. Saussele, T.[2018]

Lacosamide is effective as both monotherapy (in the USA) and adjunctive therapy for focal seizures in adults and adolescents, showing significant reductions in seizure rates compared to placebo in clinical trials.

Patients can safely switch from oral to intravenous lacosamide therapy at the same dosage, making it a flexible treatment option, especially when oral administration is not feasible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lacosamide: A Review in Focal Seizures in Patients with Epilepsy. Scott, LJ.[2018]

Lacosamide was successfully used to control refractory convulsive status epilepticus (CSE) in a 38-year-old male patient after multiple other treatments failed, demonstrating its potential efficacy in severe cases.

The treatment with lacosamide (300 mg) led to complete remission of epileptic activity within 30 minutes and was well tolerated, marking it as a promising option for managing refractory CSE.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Successful treatment for refractory convulsive status epilepticus by non-parenteral lacosamide. Tilz, C., Resch, R., Hofer, T., et al.[2018]

Lacosamide is an effective add-on treatment for patients over 16 with drug-resistant focal seizures, showing good safety and tolerability in randomized clinical trials.

The availability of both oral and intravenous forms of lacosamide allows for flexible treatment options, especially beneficial when oral medication is not feasible.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Lacosamide in the treatment of epilepsy]. Petrukhin, AS., Voronkova, KV., Pylaeva, OA.[2018]

Lacosamide is effective in reducing seizure frequency in adults and adolescents with focal-onset seizures, showing sustained efficacy over short-term (up to 18 weeks) and long-term (up to 8 years) treatment periods.

It is also a viable option for children aged 4 years and older, with preliminary data supporting its efficacy and good tolerability as both adjunctive therapy and monotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lacosamide: A Review in Focal-Onset Seizures in Patients with Epilepsy. Hoy, SM.[2019]

Clobazam and rufinamide are effective adjunctive therapies for Lennox-Gastaut syndrome (LGS), with clobazam approved for patients aged 2 years and older and rufinamide for those aged 4 years and older.

Lacosamide and vigabatrin target different seizure types, with lacosamide enhancing sodium channel inactivation for partial onset seizures in patients 17 and older, and vigabatrin used for infantile spasms in very young children and complex partial seizures in adults.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

An overview of third-generation antiseizure drugs: Clobazam, lacosamide, rufinamide, and vigabatrin. Spanaki, MV., Barkley, GL.[2020]

In a study of 167 children with traumatic brain injury (TBI), only 26% received prophylactic antiseizure medications (ASMs), with levetiracetam being the sole medication prescribed, particularly for younger patients and those with severe injuries or abnormal neuroimaging.

Despite being the only ASM used, levetiracetam was associated with a higher rate of early posttraumatic seizures (EPTSs) in children with severe TBI (GCS ≤12), indicating a need for further research on the efficacy and safety of ASMs in pediatric TBI management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Levetiracetam Prophylaxis for Children Admitted With Traumatic Brain Injury. Surtees, TL., Kumar, I., Garton, HJL., et al.[2022]

In a study of 610 patients with traumatic brain injury (TBI), levetiracetam was the most commonly prescribed antiepileptic drug (AED), with over 90% of those receiving AEDs being prescribed this medication.

The study found no significant difference in the rate of early post-traumatic seizures (PTS) between patients who received prophylactic AEDs (2.9%) and those who did not (3.5%), suggesting that the routine use of prophylactic AEDs may need to be reconsidered.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use of antiepileptic medication in early post traumatic seizure prophylaxis at a single institution. Candy, N., Tsimiklis, C., Poonnoose, S., et al.[2020]

In a study involving 132 patients with traumatic brain injury, both valproate and phenytoin were found to have similar low rates of early seizures, indicating that neither drug is superior for this purpose.

Valproate did not show any advantage over short-term phenytoin for preventing late seizures and was associated with a trend toward higher mortality, suggesting it should not be routinely used for posttraumatic seizure prevention.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Valproate therapy for prevention of posttraumatic seizures: a randomized trial. Temkin, NR., Dikmen, SS., Anderson, GD., et al.[2022]

In a double-blind crossover trial involving 20 patients with chronic uncontrolled epilepsy, adding sodium valproate at a dose of 1200 mg/day significantly reduced the frequency of both tonic-clonic and minor seizures.

The treatment was generally safe, with only mild and transient side effects like drowsiness and nausea, suggesting that sodium valproate can be an effective addition to existing anticonvulsant therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Controlled trial of sodium valproate in severe epilepsy. Richens, A., Ahmad, S.[2019]

References

1. New Zealand pubmed.ncbi.nlm.nih.gov

Sodium valproate (Epilim) in epilepsy: a trial. [2013]

2. England pubmed.ncbi.nlm.nih.gov

Lacosamide. [2018]

3. Germany pubmed.ncbi.nlm.nih.gov

[Lacosamide. A new antiepileptic drug as adjunctive therapy in patients with partial-onset seizures]. [2018]

4. New Zealand pubmed.ncbi.nlm.nih.gov

Lacosamide: A Review in Focal Seizures in Patients with Epilepsy. [2018]

5. United States pubmed.ncbi.nlm.nih.gov

Successful treatment for refractory convulsive status epilepticus by non-parenteral lacosamide. [2018]

6. Russia (Federation) pubmed.ncbi.nlm.nih.gov

[Lacosamide in the treatment of epilepsy]. [2018]

7. New Zealand pubmed.ncbi.nlm.nih.gov

Lacosamide: A Review in Focal-Onset Seizures in Patients with Epilepsy. [2019]

8. United States pubmed.ncbi.nlm.nih.gov

An overview of third-generation antiseizure drugs: Clobazam, lacosamide, rufinamide, and vigabatrin. [2020]

9. United States pubmed.ncbi.nlm.nih.gov

Levetiracetam Prophylaxis for Children Admitted With Traumatic Brain Injury. [2022]

10. Scotland pubmed.ncbi.nlm.nih.gov

The use of antiepileptic medication in early post traumatic seizure prophylaxis at a single institution. [2020]

11. United States pubmed.ncbi.nlm.nih.gov

Valproate therapy for prevention of posttraumatic seizures: a randomized trial. [2022]

12. England pubmed.ncbi.nlm.nih.gov

Controlled trial of sodium valproate in severe epilepsy. [2019]