Effect of Antiseizure Medication in Seizure Networks at Early Stages of Acute Brain Injury. The Rs-fMRI, Open-label Pilot Trial
Overview
- Phase
- Phase 4
- Intervention
- Phenobarbital Sodium Injection
- Conditions
- Brain Injuries, Acute
- Sponsor
- University of North Carolina, Chapel Hill
- Enrollment
- 5
- Locations
- 1
- Primary Endpoint
- Pre and Post-intervention Seizure Networks Total Volume Medians
- Status
- Terminated
- Last Updated
- 5 months ago
Overview
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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.
- •2 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.
Exclusion Criteria
- •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
- •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.
Arms & Interventions
Seizure network Positive subjects
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.
Intervention: Phenobarbital Sodium Injection
Seizure network Positive subjects
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.
Intervention: Levetiracetam
Seizure network Positive subjects
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.
Intervention: Lacosamide Injectable Product
Seizure network Positive subjects
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.
Intervention: Valproate Sodium
Seizure network Positive subjects
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.
Intervention: Fosphenytoin
Outcomes
Primary Outcomes
Pre and Post-intervention Seizure Networks Total Volume Medians
Time Frame: At the time of the second study rs-fMRI scan, which acquisition can be from 3 to 13 days after the intervention start date.
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.
Pre and Post-intervention Seizure Networks Power Spectrum Medians
Time Frame: At the time of the second study rs-fMRI scan, which acquisition can be from 3 to 13 days after the intervention start date.
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.
Secondary Outcomes
- 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.)
- Dropout Rate(from enrollment to the second rs-fMRI acquisition time limit which means from 0 to 19 days from enrollment.)
- 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.)
- Enrollment Rate(The day of enrollment of each patient, and this will be collected through study completion, a duration of 1 year)