Antiseizure Medication in Seizure Networks at Early Acute Brain Injury

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

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.

Study Overview

• Status: Recruiting
• Conditions: Stroke; Brain Ischemia; Brain Injuries, Traumatic; Heart Arrest; Intracranial Hemorrhages; Brain Hypoxia; Coma; Hypoxia-Ischemia, Brain; Persistent Vegetative State; Brain Injuries, Acute
• Intervention / Treatment: Drug: Phenobarbital Sodium Injection; Drug: Levetiracetam; Drug: Lacosamide Injectable Product; Drug: Valproate Sodium; Drug: Phosphenytoin

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Emilio G. Cediel, MD; Phone Number: 9847582948; Email: egcediel@email.unc.edu
• Study Contact Backup: Name: Varina L Boerwinkle, MD; Phone Number: 9199669343; Email: Varina_Boerwinkle@med.unc.edu

Study Locations

• United States
  • North Carolina
    • Chapel Hill, North Carolina, United States, 27599
      • Recruiting
      • UNC Health
      • Contact: Varina L Boerwinkle, MD; Phone Number: 9199669343; Email: Varina_Boerwinkle@med.unc.edu
      • Contact: Emilio G Cediel, MD; Phone Number: 984-758-2948; Email: egcediel@email.unc.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Seizure network Positive subjects; 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; 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.; Other Names: phenobarbital; Drug: Levetiracetam; 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.; Drug: Lacosamide Injectable Product; 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.; Drug: Valproate Sodium; 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; Other Names: Valproate; Drug: Phosphenytoin; 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.
No Intervention: Seizure network Negative subjects; 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?

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.

Collaborators and Investigators

• Sponsor: University of North Carolina, Chapel Hill
• Investigators: Principal Investigator: Emilio G. Cediel, MD, UNC-Chapel Hill; Study Chair: Varina L Boerwinkle, MD, UNC-Chapel Hill

Study record dates

Study Major Dates

• Study Start (Actual): November 20, 2023
• Primary Completion (Estimated): November 1, 2024
• Study Completion (Estimated): February 1, 2025

Study Registration Dates

• First Submitted: September 28, 2023
• First Submitted That Met QC Criteria: October 6, 2023
• First Posted (Actual): October 13, 2023

Study Record Updates

• Last Update Posted (Actual): November 29, 2023
• Last Update Submitted That Met QC Criteria: November 27, 2023
• Last Verified: September 1, 2023

More Information

Terms related to this study

• Keywords: Functional connectivity; Functional MRI; Coma; Vegetative state; Brain networks; Resting state; Suppression of consciousness; antiseizure medication; Unresponsive wakefulness; Brain Injuries, Acute
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Neurobehavioral Manifestations; Brain Damage, Chronic; Craniocerebral Trauma; Trauma, Nervous System; Signs and Symptoms, Respiratory; Unconsciousness; Consciousness Disorders; Brain Ischemia; Ischemia; Brain Injuries; Wounds and Injuries; Hemorrhage; Brain Injuries, Traumatic; Seizures; Heart Arrest; Intracranial Hemorrhages; Hypoxia; Hypoxia, Brain; Hypoxia-Ischemia, Brain; Persistent Vegetative State; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Enzyme Inhibitors; Excitatory Amino Acid Antagonists; Excitatory Amino Acid Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Hypnotics and Sedatives; GABA Modulators; GABA Agents; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Antimanic Agents; Cytochrome P-450 Enzyme Inducers; Cytochrome P-450 CYP3A Inducers; Nootropic Agents; Cytochrome P-450 CYP2B6 Inducers; Valproic Acid; Lacosamide; Levetiracetam; Phenobarbital
• Other Study ID Numbers: 23-0157

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Deidentified individual data that supports the results will be shared beginning 9 to 36 months following publication provided the investigator who proposes to use the data has approval from an Institutional Review Board (IRB), Independent Ethics Committee (IEC), or Research Ethics Board (REB), as applicable, and executes a data use/sharing agreement with UNC.
• IPD Sharing Time Frame: beginning 9 and continuing for 36 months following publication
• IPD Sharing Access Criteria: Investigator has approved IRB, IEC, or REB and an executed data use/sharing agreement with UNC.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No