Antiseizure Medication for Severe Brain Injury

Overseen By Varina L Boerwinkle, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 4

Sponsor: University of North Carolina, Chapel Hill

Must be taking: Antiseizure medications

Disqualifiers: Epilepsy, Neurological sequels, Brain death, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 2

Duration: 3-13 days

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to explore how antiseizure medications affect brain activity in patients with severe brain injuries and impaired consciousness. Researchers seek to determine if these medications can alter the brain's seizure networks, which might cause seizures, using special brain scans called rs-fMRI. Patients in the ICU who have recently suffered a severe brain injury, such as a stroke or trauma, might be suitable candidates. Participants will take two antiseizure drugs, including Lacosamide Injectable Product (Vimpat) and Levetiracetam, and undergo brain scans before and after to check for changes. As a Phase 4 trial, this research involves FDA-approved treatments and aims to understand how they can benefit more patients.

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 is the safety track record for these treatments?

A previous study found lacosamide safe for treating seizures, even after traumatic brain injury, without harming cognitive skills. Research suggests it may protect the brain if administered before oxygen loss, as demonstrated in studies with newborn rats.

Levetiracetam, another seizure medication, is often used for traumatic brain injuries. It is safe, commonly used in trauma centers to prevent seizures, and performs well compared to similar drugs.

Phenobarbital is recommended for managing brain injuries, particularly to reduce intracranial pressure. It can be used without worsening confusion and may decrease the need for other sedatives.

Phosphenytoin effectively prevents early seizures after traumatic brain injury, especially in adults. Studies show it reduces the risk of seizures soon after the injury.

Valproate sodium may help protect the brain post-injury by reducing brain cell damage and aiding recovery. However, rare cases of nerve damage have occurred, necessitating careful monitoring.

All these medications are FDA-approved for other uses, indicating they are generally well-tolerated. However, like any medication, side effects can occur, so participants are closely monitored during trials. ^{1 2 3 4 5}

Why are researchers enthusiastic about this study treatment?

Researchers are excited about these treatments because they explore various antiseizure medications to manage seizures after severe brain injury. Unlike some standard treatments, such as carbamazepine or topiramate, which have been commonly used for seizures, this trial includes drugs like lacosamide and levetiracetam, each with unique mechanisms of action. Lacosamide, for instance, stabilizes neuronal membranes by enhancing the slow inactivation of sodium channels, offering a potentially different approach to controlling post-injury seizures. Additionally, the injectable formulations of these treatments allow for rapid administration, which is crucial in acute care settings. This trial aims to determine the effectiveness of these drugs in a specific subgroup of patients, helping to refine and optimize treatment strategies for better outcomes.

What evidence suggests that this trial's antiseizure medications could be effective for severe brain injury?

Research shows that these FDA-approved seizure medications can help reduce seizures in people with brain injuries. In this trial, participants in the Seizure Network Positive group will receive two of these medications. Lab studies have found that lacosamide may protect brain cells after an injury. Levetiracetam is considered safe and works like phenytoin to prevent seizures soon after a brain injury. Phenobarbital can decrease pressure inside the skull, which may help after severe injuries, but it might also cause changes in blood pressure. Fosphenytoin is similar to levetiracetam in preventing seizures, especially in young children with brain injuries. Lastly, valproate sodium can lower the risk of early seizures after a severe brain injury and might help protect the brain from further harm. Studies support these treatments, showing their effectiveness in managing seizures after brain injuries. ^{2 4 6 7 8}

Who Is on the Research Team?

Emilio G. Cediel, MD

Principal Investigator

UNC-Chapel Hill

Varina L Boerwinkle, MD

Principal Investigator

UNC-Chapel Hill

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-3 days

Initial Assessment

Participants undergo an initial rs-fMRI to identify seizure networks

1-3 days

1 visit (in-person)

Treatment

Participants with identified seizure networks receive antiseizure medication and undergo a second rs-fMRI

3-13 days

Multiple visits (in-person) for medication administration and assessments

Follow-up

Participants are monitored for changes in seizure networks and typical resting state networks post-treatment

3-13 days

1 visit (in-person) for follow-up assessments

What Are the Treatments Tested in This Trial?

Interventions

• Lacosamide Injectable Product
• Levetiracetam
• Phenobarbital Sodium Injection
• Phosphenytoin
• Valproate Sodium

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.

How Is the Trial Designed?

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 rs-fMRI #1 study, they will receive both loading and maintenance doses of two intervention drug regimens from the study list. For participants with a Glasgow Coma Scale (GCS) of 9 to 12, the research team will choose one of the two selected antiseizure medications (ASMs) and 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 European Union, United States, Canada, Japan for the following indications:

Approved in European Union as Vimpat for:

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

Approved in United States as Vimpat for:

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

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+

Published Research Related to This Trial

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 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]

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]

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]

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 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 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]

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]

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 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]

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]

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Lacosamide

Lacosamide is used to treat focal (partial) seizures in adults and children. To learn more, visit Epilepsy Foundation.