Antiseizure Medication in Seizure Networks at Early Acute Brain Injury

Study Overview
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Brief Summary
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The goal of this clinical trial is to explore the effect of FDA-approved antiseizure drugs in the brain connectivity patterns of severe 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.

Official Title
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Effect of Antiseizure Medication in Seizure Networks at Early Stages of Acute Brain Injury. The Rs-fMRI, Open-label Pilot Trial

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

Intervention / Treatment
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* Drug: Phenobarbital Sodium Injection
* Drug: Levetiracetam
* Drug: Lacosamide Injectable Product
* Drug: Valproate Sodium
* Drug: Phosphenytoin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Currently ICU hospitalized. Glasgow Coma Scale of less than 9 at ICU admission by medical chart review. Diagnosis of Acute brain injury by TBI, hypoxic-ischemic insult, cardiac arrest, or stroke by medical chart review. 3 to 45 days from acute brain injury to enrollment time by medical chart review. 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 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.

Ages Eligible for Study
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Minimum Age: 6 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: 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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Seizure network Positive subjects<br>Participants in this group encompass all SzNET-Positive subjects, including those who are EEG-Positive and EEG-Negative. Within six days of their initial rs-fMRI study, they will receive both loading and maintenance doses of two of the intervention drug regimens from the study's list. Maintenance doses should be administered every 12 hours, commencing 12 hours after the loading dose, with a maximum of 19 maintenance doses allowed. A second rs-fMRI and EEG will be conducted after participants have received at least five maintenance doses. Following these follow-up rs-fMRI and EEG assessments, the use of the intervention drugs as part of the research intervention will be discontinued. However, if medically necessary, these drugs can continue as part of regular therapy. It's important to note that repeat EEG and rs-fMRI assessments cannot be conducted if more than 72 hours have passed since the last dose of the intervention drug regimen. | Drug: Phenobarbital Sodium Injection<br>* 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.<br>* Other names: phenobarbital;Drug: Levetiracetam<br>* 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.<br>Drug: Lacosamide Injectable Product<br>* 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.<br>Drug: Valproate Sodium<br>* 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<br>* Other names: Valproate;Drug: Phosphenytoin<br>* Pediatric population Loading dose 20 mg 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.<br>|
| No Intervention: Seizure network Negative subjects<br>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. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pre and post-intervention seizure networks power spectrum medians | the medians from the normalized and volume-adjusted, area under the curve of the seizure networks power spectrum curve above 6.78 Hz/100, of both pre and post-intervention rs-fMRI | 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 | the medians from the normalized volume of the total seizure networks, of both pre and post-intervention rs-fMRI | 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 Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Presence of seizure networks in the first resting state functional MRI | Binary Variable. The total amount of participants for this outcome measure will include only the subjects enrolled until the first sampling quota is completed. | 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 | Binary variable categorized as with improvement or without improvement, obtained by expert's overall qualitative assessment comparing the follow-up study EEG and the clinically indicated EEG considered at the enrollment time. The qualitative assessment will be based on the EEG's background and the presence of electrophysiological signs of ictal or interictal activity. These signs are described by the American Clinical Neurophysiology Society as: Epileptiform Discharges Rhythmic and periodic patterns Electrographic and electroclinical seizures. Ictal-interictal continuum. | 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 | Binary variable obtained by expert's opinion comparison between the typical resting state networks of the pre and post-intervention resting state functional MRIs | 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 | Number of participants enrolled divided by the amount of eligible patients screened. | The day of enrollment of each patient, and this will be collected through study completion, a duration of 1 year | 
| Dropout rate | Number of dropout participants divided by the amount of enrolled patients. | from enrollment to the second rs-fMRi acquisition time limit which means from 0 to 19 days from enrollment. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Functional MRI, Resting state, Coma, Vegetative state, Suppression of consciousness, antiseizure medication, Brain networks, Functional connectivity, Unresponsive wakefulness, Brain Injuries, Acute