Brain Injuries, Acute, Brain Injuries, Traumatic, Brain Ischemia, Brain Hypoxia, Hypoxia-Ischemia, Brain, Heart Arrest, Stroke, Intracranial Hemorrhages, Coma, Persistent Vegetative State
Conditions
Keywords
Coma, Vegetative state, Suppression of consciousness, antiseizure medication, Brain networks, Functional connectivity, Unresponsive wakefulness, Functional MRI, Resting state, Brain Injuries, Acute
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.
Interventions
\*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.
DRUGLevetiracetam
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.
DRUGLacosamide 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.
DRUGValproate 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
DRUGFosphenytoin
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.
Sponsors
University of North Carolina, Chapel Hill
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention 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
Eligibility
Sex/Gender
ALL
Age
18 Months to 70 Years
Healthy volunteers
No
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 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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Pre and Post-intervention Seizure Networks Power Spectrum Medians | 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. |
| Pre and Post-intervention Seizure Networks Total Volume Medians | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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. | Binary variable obtained by expert's opinion comparison between the typical resting state networks of the pre and post-intervention resting state functional MRIs |
| 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. | Binary Variable. The total amount of participants for this outcome measure will include only the subjects enrolled until the first sampling quota is completed. Only the two SzNET+ groups have a minimum enrollment goal. Thus, enrollment will stop once each of the two SzNET+ groups enroll ten patients. |
| Dropout Rate | from enrollment to the second rs-fMRI acquisition time limit which means from 0 to 19 days from enrollment. | Number of dropout participants divided by the amount of enrolled participants. |
| Enrollment Rate | The day of enrollment of each patient, and this will be collected through study completion, a duration of 1 year | Number of participants enrolled divided by the amount of eligible participants screened. |
| 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. | 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; and Ictal-interictal continuum. |
Countries
United States
Participant flow
Pre-assignment details
No participants were enrolled with a Glasgow Coma Scale (GCS) score of 9 to 12. The intervention phase occurs between resting state functional magnetic resonance imaging (rs-fMRI#1) and the day of follow-up rs-fMRI#2 and repeated EEG. The intervention is considered complete and the follow-up tests can be done if the patient received the study antiseizure medication (ASM) for at least 72 hours after the loading dose, and the second scan was done within 72 hours of the last intervention ASM dose.
Participants by arm
| Arm | Count |
|---|---|
| Seizure Network Positive Subjects Participants in this group include all SzNET-Positive subjects, whether EEG-Positive or EEG-Negative. Within six days of their initial rs-fMRI study, they will receive both loading and maintenance doses of two intervention drug regimens from the study's list. For participants with a GCS of 9 to 12, the research team will choose one of the two selected ASMs, and will 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.
The possible intervention drug regimens used were: Phenobarbital Sodium Injection, Levetiracetam, Lacosamide Injectable Product, Valproate Sodium, and fosphenytoin. For further specifics on loading and maintenance dosages please refer to the Arms and Interventions section of the Protocol Record. | 3 |
| 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. | 2 |
| Total | 5 |
Baseline characteristics
| Characteristic | Seizure Network Negative Subjects | Total | Seizure Network Positive Subjects |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 4 Participants | 2 Participants |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment United States | 2 Participants | 5 Participants | 3 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 1 Participants | 3 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 3 | 2 / 2 |
| other Total, other adverse events | 0 / 3 | 0 / 0 |
| serious Total, serious adverse events | 0 / 3 | 0 / 0 |
Outcome results
Primary
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.
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.
Population: This outcome does not apply to the Seizure Network Negative Subjects; therefore, no data were collected for this group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Seizure Network Positive Subjects | Pre and Post-intervention Seizure Networks Power Spectrum Medians | Pre-intervention rs-fMRI | 1.66 Hz/10^2 |
| Seizure Network Positive Subjects | Pre and Post-intervention Seizure Networks Power Spectrum Medians | Post-intervention rs-fMRI | 0.061 Hz/10^2 |
Primary
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.
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.
Population: This outcome does not apply to the Seizure Network Negative Subjects; therefore, no data were collected for this group.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Seizure Network Positive Subjects | Pre and Post-intervention Seizure Networks Total Volume Medians | Pre-intervention rs-fMRI | 3733.89 voxels |
| Seizure Network Positive Subjects | Pre and Post-intervention Seizure Networks Total Volume Medians | Post-intervention rs-fMRI | 3734.00 voxels |
Secondary
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
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.
Population: Connectivity of typical resting state networks only includes Seizure Network Positive Subjects; therefore, no data were collected for the Seizure Network Negative Subjects arm.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Seizure Network Positive Subjects | Connectivity Improvement of Typical Resting State Networks After Intervention | Connectivity improvement | 2 Participants |
| Seizure Network Positive Subjects | Connectivity Improvement of Typical Resting State Networks After Intervention | No connectivity improvement | 1 Participants |
Secondary
Dropout Rate
Number of dropout participants divided by the amount of enrolled participants.
Time frame: from enrollment to the second rs-fMRI acquisition time limit which means from 0 to 19 days from enrollment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Seizure Network Positive Subjects | Dropout Rate | 2 Participants |
| Seizure Network Negative Subjects | Dropout Rate | 2 Participants |
Secondary
Enrollment Rate
Number of participants enrolled divided by the amount of eligible participants screened.
Time frame: The day of enrollment of each patient, and this will be collected through study completion, a duration of 1 year
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Seizure Network Positive Subjects | Enrollment Rate | 5 Participants |
Secondary
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; and Ictal-interictal continuum.
Time frame: At the time of the follow-up study EEG, which acquisition can be from 3 to 13 days after the intervention start date.
Population: Follow-up EEG activity only includes Seizure Network Positive Subjects; therefore, no data were collected for the Seizure Network Negative Subjects arm.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Seizure Network Positive Subjects | Follow-up Electroencephalogram Improvement | With improvement | 0 Participants |
| Seizure Network Positive Subjects | Follow-up Electroencephalogram Improvement | Without improvement | 3 Participants |
Secondary
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. Only the two SzNET+ groups have a minimum enrollment goal. Thus, enrollment will stop once each of the two SzNET+ groups enroll ten patients.
Time frame: At the time of the first study rs-fMRI scan, which acquisition can be from 1 to 3 days after enrollment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Seizure Network Positive Subjects | Presence of Seizure Networks in the First Resting State Functional MRI | Seizure networks present | 3 Participants |
| Seizure Network Positive Subjects | Presence of Seizure Networks in the First Resting State Functional MRI | Seizure networks absent | 0 Participants |
| Seizure Network Negative Subjects | Presence of Seizure Networks in the First Resting State Functional MRI | Seizure networks present | 0 Participants |
| Seizure Network Negative Subjects | Presence of Seizure Networks in the First Resting State Functional MRI | Seizure networks absent | 2 Participants |