Antiseizure Medication in Seizure Networks at Early Acute Brain Injury

NCT06081283 | Terminated Phase 4 Results FDA Drug

• 1 other identifier: 23-0157
• Study Type: interventional
• Target: 5
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Brain Injuries, Acute; Brain Injuries, Traumatic; Brain Ischemia; Brain Hypoxia; Hypoxia-Ischemia, Brain; Heart Arrest; Stroke; Intracranial Hemorrhages; Coma; Persistent Vegetative State

Keywords

Coma; Vegetative state; Suppression of consciousness; antiseizure medication; Brain networks; Functional connectivity; Unresponsive wakefulness; Functional MRI; Resting state; Brain Injuries, Acute

Outcome Measures

Primary Outcomes (2)

• Pre and Post-intervention Seizure Networks Power Spectrum Medians

  Power spectral analysis identifies differences in Blood Oxygen Level Dependent (BOLD) changes between different cortical areas, cognitive states, or frequency bands that may reflect a pattern of component frequencies. The power spectrum graph shows the BOLD signal's power density over multiple frequencies, measured in Hz/100. Power Spectrum (PS) is the sum of the PS of the SzNET independent components normalized by their spatial volumes. Functional scans were co-registered to the anatomical T1 image, visually inspected, and subjected to independent component analysis (ICA) using the FMRIB Software Library (FSL) tool MELODIC. ICA was applied to separate the BOLD signal into independent components generated by brain networks, which were evaluated for suspected seizure onset zones (SOZs) based on spatial and temporal features. Pre- and post-intervention Rs-fMRI medians were found from the normalized and volume-adjusted area under the curve of the SzNET PS curve above 6.78 Hz/100.

  At the time of the second study rs-fMRI scan, which acquisition can be from 3 to 13 days after the intervention start date.

• Pre and Post-intervention Seizure Networks Total Volume Medians

  Rs-fMRI data is collected as 2 runs of 10-minute data collection on a 3T MRI scanner. One volume from the fMRI is a complete slice of the brain's activity at a specific point of time. Over the 20-minute period that the rs-fMRI is performed, many volumes are collected at different time points continuously throughout the scan. These volume elements are measured in units of voxels which are a 3D unit of the MRI image. SzNET total volume (TV) is the sum of the volumes of the SzNET independent components, collected through ICA where independent components generated by brain networks were evaluated for suspected seizure onset zones. The medians from the normalized volume of the total seizure networks, of both pre and post-intervention rs-fMRI, were collected from this data.

  At the time of the second study rs-fMRI scan, which acquisition can be from 3 to 13 days after the intervention start date.

Secondary Outcomes (5)

• Presence of Seizure Networks in the First Resting State Functional MRI

  At the time of the first study rs-fMRI scan, which acquisition can be from 1 to 3 days after enrollment.

• Follow-up Electroencephalogram Improvement

  At the time of the follow-up study EEG, which acquisition can be from 3 to 13 days after the intervention start date.

• Connectivity Improvement of Typical Resting State Networks After Intervention

  At the time of the second study rs-fMRI scan, which acquisition can be from 3 to 13 days after the intervention start date.

• Enrollment Rate

  The day of enrollment of each patient, and this will be collected through study completion, a duration of 1 year

• Dropout Rate

  from enrollment to the second rs-fMRI acquisition time limit which means from 0 to 19 days from enrollment.

Study Arms (2)

Seizure network Positive subjects

EXPERIMENTAL

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.

Drug: Phenobarbital Sodium Injection; Drug: Levetiracetam; Drug: Lacosamide Injectable Product; Drug: Valproate Sodium; Drug: Fosphenytoin

Seizure network Negative subjects

NO 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.

Interventions

Phenobarbital Sodium Injection DRUG

\*This drug can only be selected as part of the intervention for the subgroup of patients with a Glasgow Coma Score of 8 or less. Loading dose 20 mg/kg intravenous. Max dose 1000mg Maintenance dose 4mg/kg/day. Max dose 300mg/day. Adult population Loading dose 20 mg/kg intravenous. Maintenance dose 4mg/kg/day.

Also known as: phenobarbital

Seizure network Positive subjects

Levetiracetam DRUG

Pediatric population Loading dose 60 mg/kg intravenous. Max dose 4000mg. Maintenance dose 40mg/Kg/day, Max dose 3000mg/day. Adult population Loading dose 2000mg-4000mg intravenous. Maintenance dose 1500mg to 3000mg/day.

Seizure network Positive subjects

Lacosamide Injectable Product DRUG

Pediatric population Loading dose 10 mg/kg intravenous, Max dose 400mg. Maintenance dose 4mg to 8mg/Kg/day. Max dose 300mg. Adult population Loading dose 200mg to 400mg intravenous. Maintenance dose 200mg to 400mg/day.

Seizure network Positive subjects

Valproate Sodium DRUG

Pediatric population Loading dose 30mg/kg intravenous. Max dose 3000mg Maintenance dose 20mg to 30mg/Kg/day, Max dose 3000mg/day. Adult population Loading dose 30 mg/kg intravenous. Maintenance dose 20mg to 30mg/Kg/day

Also known as: Valproate

Seizure network Positive subjects

Fosphenytoin DRUG

Pediatric population Loading dose 20 mg phenytoin equivalents (PE)/kg intravenous. Max dose 1500mg PE Maintenance dose 4mg PE/Kg/day. Max dose 300mg PE/day. Adult population Loading dose 20 mg/kg intravenous. Max dose 1500mg PE Maintenance dose 4mg PE/Kg/day.

Seizure network Positive subjects

Eligibility Criteria

• Age: 18 Months - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Currently ICU hospitalized.
• Suppression of consciousness related to a neurological injury by medical chart review.
• Glasgow Coma Scale of less than 13 at enrollment by medical chart review.
• Diagnosis of Acute brain injury by traumatic brain injury (TBI), hypoxic-ischemic insult, cardiac arrest, or stroke by medical chart review.
• to 90 days from acute brain injury to enrollment time by medical chart review.
• Have a surface EEG performed after the current ICU admission
• Clinically stable to undergo MRI scan, This stability is defined by care team concept, which should be stated in the medical records.

You may not qualify if:

• Previous medical history of Epilepsy by medical chart review.
• Previous medical history of neurological sequels that lead to dependence on care for basic daily activities, by Barthel index score less than 80.
• Known allergy/Hypersensitivity or medical contraindications (like porphyria or cardiac arrhythmias) to the treatment protocol options, leaving no potential combination of drugs for the intervention without concerns for adverse events related to known preexistent conditions.
• Considered with Brain death by the care team in the medical record, at any time.
• Speaking fluently or at their prior reported baseline mental status by medical chart review before the intervention starts.
• Contraindications for MRI scan.
• Prisoner human subjects by medical chart review.
• Confirmed currently pregnant by medical history or by positive blood or urine pregnancy test done in the present hospital admission.
• Treating physician determines the patient is no candidate to receive 2 of the 5 protocol-specified ASM.

Sponsors & Collaborators

• University of North Carolina, Chapel Hill: lead

Study Sites (1)

UNC Health

Chapel Hill, North Carolina, 27599, United States

Location

MeSH Terms

Conditions

Brain Injuries; Brain Injuries, Traumatic; Brain Ischemia; Hypoxia, Brain; Hypoxia-Ischemia, Brain; Heart Arrest; Stroke; Intracranial Hemorrhages; Coma; Persistent Vegetative State

Interventions

Phenobarbital; Levetiracetam; Valproic Acid; fosphenytoin

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Craniocerebral Trauma; Trauma, Nervous System; Wounds and Injuries; Cerebrovascular Disorders; Vascular Diseases; Cardiovascular Diseases; Hypoxia; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Heart Diseases; Hemorrhage; Pathologic Processes; Unconsciousness; Consciousness Disorders; Neurobehavioral Manifestations; Neurologic Manifestations; Brain Damage, Chronic

Intervention Hierarchy (Ancestors)

Barbiturates; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines; Pentanoic Acids; Valerates; Fatty Acids, Volatile; Fatty Acids; Lipids

Results Point of Contact

• Title: Meitra Kazemi
• Organization: University of North Carollina at Chapel Hill

meitra_kazemi@med.unc.edu

919-914-9579

Study Officials

• Emilio G. Cediel, MD

  UNC-Chapel Hill

  PRINCIPAL INVESTIGATOR

• Varina L Boerwinkle, MD

  UNC-Chapel Hill

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Subjects will be enrolled irrespective of their electroencephalogram (EEG) results, whether positive(+) or negative(-) for epileptogenic activity. All enrolled subjects will undergo an initial resting-state functional MRI (rsfMRI). The results will categorize the patients based on the presence or absence of seizure networks (SzNET), resulting in 2 groups: SzNET+ and SzNET-. SzNET- participants will not undergo further interventions or tests, while SzNET+ subjects will be assigned to the intervention arm and will receive follow-up rsfMRI and EEG. The study aims to fill 2 quotas in its intervention arm: Participants who are both SzNET+ and EEG+, and another for those SzNET+ but EEG-. Once either of these quotas is complete, the study will cease screening subjects with EEG results falling into that quota. The subjects discharged from hospital on antiseizure medications for medical reasons will be followed up at 3 months post-discharge to collect exploratory data

Study Record Dates

• First Submitted: September 28, 2023
• First Posted: October 13, 2023
• Study Start: November 20, 2023
• Primary Completion: December 22, 2024
• Study Completion: January 22, 2025
• Last Updated: November 14, 2025
• Results First Posted: November 14, 2025

Record last verified: 2025-07

Data Sharing

• IPD Sharing: Will share
• Time Frame: beginning 9 and continuing for 36 months following publication
• Access Criteria: Investigator has approved IRB, IEC, or REB and an executed data use/sharing agreement with UNC.

Locations

US (1)