Effect of Antiseizure Medication in Seizure Networks at Early Stages of Acute Brain Injury. The Rs-fMRI, Open-label Pilot Trial
Phase: PHASE4
Conditions: Brain Injuries, Acute, Brain Injuries, Traumatic, Brain Ischemia, Brain Hypoxia, Hypoxia-Ischemia, Brain, Heart Arrest, Stroke, Intracranial Hemorrhages, Coma, Persistent Vegetative State
Sponsor: University of North Carolina, Chapel Hill

 
Effect of Antiseizure Medication in Seizure Networks at Early Stages of 
Acute Brain Injury. The Rs-fMRI, Open-label Pilot Trial. 
 
 
NCT number NCT06081283 
Document Date 10/28/2024 
 

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Master Protocol Document 
 
Title 
Effect of Antiseizure Medication in Seizure 
Networks at Early Stages of Acute Brain Injury. 
The Rs-fMRI, Open-label Pilot Trial. 
Sub-Title 
 
Seizure network treatment in Coma 
 
Principal Investigators 
Varina Boerwinkle, Neurology-Pediatrics/School of Medicine (SOM) 
 (919) 966-9343 
Emilio Garzon Cediel,  Neurology/SOM 
(984) 758-2948 
 
Co-Investigators 
 
 
Statistical  Co-Investigator 
Hongtu Zhu,  Biostatistics 
 
Research Sites 
Neuroscience Intensive Care Unit  
Pediatric Intensive Care Unit 
 
Version Number  7 
October 28, 2024    
 
IRB approval and study ID number: 23-0157 
 
 
I have read, understood, and approved this version of the protocol.    
 
Principal Investigator:      
Varina Louis Boerwinkle 
 
 
Date: October 28, 2024 
 
Principal Investigator:      
Emilio Garzon Cediel  
 
 
Date: October 28, 2024 
 
Statistical Co-investigator:      Hongtu Zhu 
 
 
__ 
 
Date: October 28, 2024 
 
 
 
Statement of Confidentiality and Nondisclosure     This document is a confidential communication.  Acceptance of this document 
constitutes agreement by the recipient that no unpublished information contained herein will be published or disclosed without 
prior written approval of the Principal Investigator or other participating study leadership, except that this document may be 
disclosed in any medium to appropriate investigators, Institutional Review Boards, Scientific Review Committees, and others who 
are directly involved in the study specified herein under the condition that they keep the information confidential. 
 

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Table of Version Changes 
 
Previous 
Version No. 
Affected 
Sections 
Summary of the Changes 
to the Protocol 
Reason for Changes 
1 
1 
The whole protocol synopsis was rearranged, also 
modifications regarding aims, the age and 
intervention were done. 
it was completed and 
modifications were done 
to address imprecisions  
1 
3.1 
We stated that developing prediction models 
epileptogenicity in early SABI was the intention of a 
different future trial. 
To clarify that developing 
prediction models 
epileptogenicity in early 
SABI is outside of the 
scope of this trial 
1 
3.2 
We clarified that the proportions estimation will be 
done on the initial rs-fMRI. 
To make clear the 
temporal relationship with 
the intervention  
1 
3.2 
We clarified that the proportions estimation will be 
done on the initial rs-fMRI. 
To make clear the 
temporal relationship with 
the intervention  
1 
WHOLE 
DOCUMENT 
Age range was corrected to be unified 6-65 years. 
To make clear the 
temporal relationship with 
the intervention  
1 
3.5 
The information inclusion time was restricted to 
specific 14 months after enrollment started. 
To guarantee the study 
duration, because the 
participants' duration for 
this Aim cannot be 
predicted with certainty. 
1 
4.1 
We specified that the clinical team can modify the 
“maintenance” dose before the 2nd rs-fMRI is 
obtained. 
 
For better understanding. 
1 
4.1 
WE clearly stated that our intervention is off-label 
but it meets the requirements to do not require 
submission of an IND to the FDA. 
 
To address the concern 
about use of off-label 
interventions. 
1 
4.1 
We listed al five possible medication combos and 
dose adjustment rules 
To make clear the 
potential regimens. 
1 
 
 
 
 
4.3 
We added comments regarding extended age 
range. 
 
To address the concern 
about the wide age range. 

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1 
4.3 
We added details regarding the EEG recordings. 
 
To address the concern 
about reproducibility. 
1 
5.2 
Contraindications for MRI scan. 
The main study variables 
are based on MRI data. 
E 
5.2 
Inclusion criteria modified: The potential days from 
acute brain injury to enrollment where change 
from 1-45 to 3 (72 Hours)-45. 
The first 72 Hours are 
critical in the stabilization 
of the patients, so this 
improves the homogeneity 
of the subjects. 
1 
5.2 
exclusion criteria modified: “Speaking fluently or at 
their prior reported baseline mental status by 
medical chart review before the intervention 
starts.” 
For better reproducibility 
1 
5.2 
Selection criteria specified: “If there is medical 
history of neurological conditions with concerning 
for impaired independence and the functional 
status of the patient cannot be properly addressed, 
the patient will be excluded from participation.” 
For better reproducibility 
1 
5.3 
I was detailed that Barthel Index Score is asked 
after verbal informed consent for screening. 
For clarity about the 
informed consent for 
screening. 
1 
5.3 
We added “EEG in this protocol does mean 
continuous video EEG, which is the stand of care 
for UNCH ICU patients”. 
For clarity about the 
routine EEG 
1 
5.5 
The screening -enrollment process was further 
explained.  
For clarity about the 
sampling 
1 
6 
Bullet point for the intervention activities. 
To clarify time frames for 
the activities. 

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1 
7.2. & 7.3 
Screening and enrollment were reworded and 
activities list with timeframes where added. 
To clarify time frames for 
the activities. 
1 
7.5 
References to the PASS clinic tests were added. 
It was clearly state that PASS clinic follow-up is 
UNC hospitals SOC, so the information from this 
clinic will be just collected from medical charts. 
To clarify the present study 
is not responsible for the 
schedule or tasks related 
to the PASS clinic. 
1 
7.8 
The dropouts are explained with more detail. 
To clarify the dropouts. 
1 
8.3 
Included an intercept to represent the mean 
difference before and after ASM in the model and 
use the t-test statistic to test. whether the 
intercept is equal to zero for Aims 1a and 1b. 
 to improve the 
interpretation of aim 1. 
1 
8.3 
For Aims 3 and 4 the statistical analysis method 
was changed from linear regression to logistic 
regression.  
the variables EEG 
improvement and RSN 
improvement are binary 
variables. 
1 
4, 5.2, 5.3, 7.2, 
7.3 
The word liaison was replaced for Legal authorized 
representative. 
To match the frequent 
language. 
1 
11 
Blood sample collection and processing was 
included. 
For dose adjustment of 
phenobarbital. 
1 
12.2, 12.3, 12.4 
The independent safety monitor will classify the AE 
and decide which AE require a safety meeting to 
review its classification and generate the report. 
To optimize the report of 
the AEs. 
1 
12.2, 12.4, 12.5 
SAE will pause the trial. The resuming conditions 
were further clarified. 
To make clear situations of 
study pause and study end. 

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1 
13.1.2 
Dispositions for reconsenting subjects that may 
regain decision-making capacity were added.  
Some Subjects may regain 
decision-making capacity.  
1 
13.5 
The ISM was changed. 
To make it different from 
the PI.  
2.1 
4 
We Properly defined SzNET- 
For clarity in the diagrams 
2.1 
1, 3, 8.3 
The aim 5 whas modified from collect to describe 
To describe better what 
we are going to do with 
the data 
2.1 
4 
We added feasibility and confounder variables 
To leverage the study to  
support similar future 
trials’ methods. 
2.1 
1, 3, 4, 8 
We included an additional aim for feasibility 
To leverage the study to  
support similar future 
trials’ methods. 
2.1 
11.3 
It was specified the purpose of the Phenobarbital 
serum levels and their record keeping 
For clarity 
3 
4.3 
Aim 5 variables where changed to Exploratory 
This is more exploratory 
than secondary aim. 
3 
4.1 
All dose regimens where specified for pediatric and 
adult population 
For more precise 
reference 

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3 
12.3 
It was specified that the anatomical MRI sequences 
will be reported by the Radiology department. 
To make the distinction 
from the functional MRI 
sequences reviewed by 
the research team 
3 
5.2 
Exclussion criteria added: Treating physician 
determines the patient is no candidate to receive 2 
of the 5 protocol-specified ASM. 
Specified because of IRB 
request. 
3 
5.2 
Replaced “Speaking fluently or at their prior 
reported baseline mental status by medical chart 
review before the intervention starts” by 
“Following Commands in 3 different exams from at 
least 2 different providers.” 
To have a more 
unequivocal criteria 
3 
4.3 
More explicit etiologies were included among the 
allowed variables. 
To match the CRF design 
which is more descriptive, 
allowing to check multiple 
etiologies by each case.  
3 
1,3,4,5,6,7,8,10 PASS clinic was replaced by “one of the NSICU Post-
Dischrage clinics.” 
To also include the 
follow-up fro patients 
scheduled to any one of 
the NSICU Post-Dischrage 
clinics.   
3 
1, 5, 13 
The Medical ICU  from UNC health was included as 
a place of enrollment 
Most of the hypoxic 
hisquemic SABI patients 
are treated in this ICU 
3 
4.3 
The features to be evaluated by the EEG 
improvement variable were further specified 
To have a more 
standardized definition of 
EEG improvement 
3 
6 
A restriction was added to prevent patients with 
vasospasm detected by transcranial Doppler from 
undergoing the rs-fMRI scan. 
To avoid scanning the 
participant under 
radiological vasospasm 
and enhance findings 
reproducibility. 
4 
1, 2, 3, 4, 5, 7, 
8, 12 
Increase the GCS threshold to GCS<13 in the 
inclusion criteria. 
To allow the participation 
of patients with moderate 
acute brain injury too. 

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4 
1, 2, 5, 7 
Inclussion criteria were reworded  to state that the 
GCS as inclusion criteria will be verified at 
enrollment instead of at admission.  
To allow the participation 
of patients whose 
consciousness 
suppression started after 
ICU admission. 
4 
1, 2, 3, 4, 5, 7, 
8, 12 
Modified the aims to study population with 
moderate to severe acute brain injury (MABI) 
instead of just severe aute brain injury (SABI) 
To increase the 
enrollment rate. 
4 
1, 4, 6, 12 
The intervention regimen options were reduced 
for the subgroup of participants with GCS 9 to 
12, not allowing phenobarbital as one of the 
intervention ASM and indicating that the Loading 
dose of one of the ASM will be omitted. 
To keep a favorable risk-
benefit relationship for 
the participation of that 
subgroup of patients. 
4 
1, 5, 7 
The allowed time from injury to enrollment was 
increased from 3-45 days to 2-90 days. 
To increase the 
enrollment rate. 
4 
4, 6 
A repeated loading dose of phenobarbital is 
indicated in the phenobarbital dosing adjustment 
after the phenobarbital levels. 
To align with the NSICU 
current clinical practice 
and obtain therapeutic 
drug lvels faster.  
4 
1, 5, 13 
three ICUs fron UNC hospitals, were included as 
enrollment sites and will be screened for potential 
participants. 
To increase the 
recruitment rate. 
4 
6 
The timming to upload the rs-fMRI #1 and #2 
reports to EPIC was specified.  
For clarity on the 
procedures. 
5 
4.1, 6 
Oral/enteral maintenance doses regimens were 
included for levetiracetam and lacosamide 
The pharmacodynamics 
are comparable and 
allowing this routes the 
protocol is more aligned 
with the standard of care 
6 
1, 4, 5 
The inclusion criteria extended the enrollment age 
from 18 months up to 70 years. 
To increase the 
enrollment rate. 

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Table of Contents 
Statement of Compliance ................................................................................................................................... 10 
Table of Abbreviations ....................................................................................................................................... 11 
1. 
Protocol Synopsis ................................................................................................................................... 12 
2. 
Introduction ........................................................................................................................................... 15 
2.1. 
Background Information .................................................................................................................... 15 
2.2. 
Scientific Rationale ............................................................................................................................. 17 
3. 
Specific Aims .......................................................................................................................................... 18 
3.1. 
Aim 1 .................................................................................................................................................. 18 
Aim 1a 18 
Aim 1b 18 
3.2. 
Aim 2 .................................................................................................................................................. 18 
3.3. 
Aim 3 .................................................................................................................................................. 19 
3.4. 
Aim 4 .................................................................................................................................................. 19 
3.5. 
Aim 5 .................................................................................................................................................. 19 
3.6. 
Aim 6 .................................................................................................................................................. 19 
Aim 6a 19 
Aim 6b 19 
4. 
Study Design........................................................................................................................................... 19 
4.1. 
Treatment Design ............................................................................................................................... 23 
4.2. 
Experimental Design ........................................................................................................................... 25 
4.3. 
Measurement Design ......................................................................................................................... 25 
5. 
Study Participants .................................................................................................................................. 29 
5.1. 
Numbers of Participants ..................................................................................................................... 29 
5.2. 
Eligibility Criteria ................................................................................................................................ 30 
5.3. 
Enrollment/Selection Strategies ........................................................................................................ 31 
5.4. 
Strategies for Retention ..................................................................................................................... 32 
5.5. 
Matching and Stratification ................................................................................................................ 33 
5.6. 
Randomization  and  Concealment .................................................................................................... 33 
5.7. 
Blinding ............................................................................................................................................... 33 
6. 
Treatment Design: Procedures .............................................................................................................. 34 
7. 
Schedule of Activities and Procedures .................................................................................................. 38 
7.1. 
Table of Events ................................................................................................................................... 38 

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7.2. 
Screening ............................................................................................................................................ 38 
7.3. 
Enrollment .......................................................................................................................................... 39 
7.4. 
Study Visits ......................................................................................................................................... 40 
7.5. 
Final Visit ............................................................................................................................................ 40 
7.6. 
Phone Contacts .................................................................................................................................. 40 
7.7. 
Follow-Up Contact .............................................................................................................................. 41 
7.8. 
Early Discontinuations ........................................................................................................................ 41 
7.9. 
Enrollees May Drop Out ..................................................................................................................... 41 
8. 
Statistical Analysis Plans ........................................................................................................................ 41 
8.1. 
Strategies that Apply to all the Aims .................................................................................................. 41 
8.2. 
Sample Description ............................................................................................................................ 42 
8.3. 
Aim-Specific Plans .............................................................................................................................. 42 
Aim 1a 42 
Aim 1b 42 
Aim 6a 44 
Aim 6b 44 
8.4. 
Planned Interim Analyses ................................................................................................................... 44 
9. 
Sample Size Rationale ............................................................................................................................ 44 
10. 
Data Capture and Database Management ........................................................................................... 44 
10.1. 
Software for Data Capture ................................................................................................................. 44 
10.2. 
Responsibilities for Data Capture and Database Management ......................................................... 44 
10.3. 
Study Records Retention .................................................................................................................... 45 
11. 
Collection and Management of Tissue Specimens ............................................................................... 45 
11.1. 
Use in Current and Future Studies ..................................................................................................... 45 
11.2. 
Sample Preparation ............................................................................................................................ 45 
11.3. 
Record Keeping and Monitoring ........................................................................................................ 45 
11.4. 
Storage and Security .......................................................................................................................... 45 
12. 
Safety Monitoring and Management .................................................................................................... 46 
12.1. 
Risk / Benefit Assessment .................................................................................................................. 46 
12.2. 
Assessment of Safety ......................................................................................................................... 48 
12.3. 
Unanticipated Problems, Adverse Events, Serious Adverse Events ................................................... 49 
12.4. 
Safety Monitoring ............................................................................................................................... 65 
12.5. 
Study Suspension / Early Termination of the Study ........................................................................... 66 
13. 
Regulatory, Ethical, and Study Oversight Specifications ...................................................................... 66 
13.1. 
Informed Consent Process ................................................................................................................. 66 
13.2. 
Study Discontinuation and Closure .................................................................................................... 67 

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13.3. 
Confidentiality and Privacy ................................................................................................................. 68 
13.4. 
Future Use of Stored Specimens and Data ......................................................................................... 68 
13.5. 
Key Roles and Study Governance ....................................................................................................... 69 
13.6. 
Safety Oversight ................................................................................................................................. 69 
13.7. 
Clinical Monitoring Plan (CMP) .......................................................................................................... 69 
13.8. 
Quality Assurance and Quality Control .............................................................................................. 70 
13.9. 
Protocol Deviations ............................................................................................................................ 70 
13.10. Publication and Data Sharing Policy ................................................................................................... 70 
13.11. Conflict of Interest Policy ................................................................................................................... 70 
14. 
Additional Considerations ..................................................................................................................... 71 
15. 
References .............................................................................................................................................. 71 
 
 
 
 
 
 
 
 
 
 
Statement of Compliance 
This study will be conducted as specified in the protocol and in accordance with the International Conference on 
Harmonisation Guidelines for Good Clinical Practice (ICH E6) and the Code of Federal Regulations on the Protection 
of Human Subjects (45 CFR Part 46).  
The protocol, informed consent form(s), recruitment materials, and all participant materials will be submitted to 
the Institutional Review Board (IRB) for review and approval.  Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  In addition, all changes to the consent 
form will be IRB-approved; a determination will be made regarding whether a new consent needs to be obtained 
from participants who provided consent, using a previously approved consent form. 
If required by the IRB, the master protocol document, informed consent form(s), recruitment materials, and all 
participant materials will be submitted to the Scientific Review Committee (SRC) prior to IRB review 
(research.unc.edu/clinical-trials/src). 

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The statistical analysis plans will be consistent with guidance in CONSORT Statement [1] or STROBE Statement [2], 
ICMJE recommendations [3], the 2016 and 2019 statements of the American Statistical Association [4,5], and 
recommendations in Nature [6,7].*  
All personnel involved in the conduct of this study have completed human subjects protection training. 
 
Table of Abbreviations 
AE 
Adverse events 
ASM 
Antiseizure medication 
BIS 
Barthel index score 
BOLD 
Blood oxygen level dependent 
CRF 
Case Report Form 
CI 
Confidence interval 
CICU 
Cardiac  intensive care unit 
CT 
Clinical Trial 
CTICU 
Cardiothoracic surgical intensive care unit 
CTCAE 
Common terminology criteria for adverse events 
DoC 
Disorders of consciousness 
EEG 
Electroencephalogram 
EEG - 
Patients without electrographic seizure, electroclinical seizure or ictal-interictal continuum 
EEG+ 
Patients with electrographic seizure, electroclinical seizure or ictal-interictal continuum 
GCP 
Good clinical practice 
IC 
Independent component 
ICA 
Independent component analysis  
ICH GCP 
International Conference on Harmonisation Good Clinical Practice 
ICF 
Informed consent form 
ICU 
Intensive Care Unit 
IND 
Investigational New drug Application 
ISM 
Independent Safety Monitor 
FDA 
Food and Drug Administration 
fMRI 
Functional Magnetic Resonance Imaging 
IRB 
Institutional Review Board 
LAEP 
Liverpool Adverse Event Profile Test 
LAR 
legally authorized representative 
MD 
Maintenance dose 
MICU 
Medical Intensive Care Unit 
MPD 
Master protocol document 
MRI 
Magnetic resonance imaging 
MSABI 
Moderate to severe acute brain injury 
N 
Number of enrolled participants 
NC TracS  North Carolina Translational and Clinical Sciences 
 
*  [1]   www.consort-statement.org  
   [2]  www.strobe-statement.org  
   [3]  www.icmje.org  
   [4]  Wasserstein RL, et al. (2016), The ASA's Statement on p-Values, The American Statistician, 70:2, 129-133  
   [5]  Wasserstein RL, et al. (2019), Moving to a World Beyond p < 0.05, The American Statistician, 73:sup1, 1-19  
   [6]  Amrhein, et al. (2019) Scientists rise up against statistical significance, Nature 567, 305-307  
   [7]  Editorial (2019) It’s time to talk about ditching statistical significance: Looking beyond a much used and abused measure 
          would make science harder, but better. Nature 567, 283-283. 

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NSICU 
Neuroscience intensive care unit 
NHI 
National Institutes of Health 
NINDS 
National Institutes of Neurological Disorders and Stroke 
NNDI-E 
Neurological Disorders Depression Inventory for Epilepsy 
PI 
Principal investigator 
PICU 
Pediatric intensive care unit 
PROMIS 
Patient Reported Outcome Measurement Information System 
PS 
Power spectrum  
PSI 
Power spectrum improvement ratio 
OHRP 
Office for Human Research Protections 
QC 
Quality Control 
QOLIE 
Quality Of Life In Epilepsy  
RCT 
Randomized controlled trial 
RS 
Resting state 
Rs-fMRI 
Resting state functional MRI 
RSN 
Resting state networks 
SABI 
Severe acute brain injury 
SICU 
Surgical intensive care unit 
SOC 
Standard of care 
SOM 
School of Medicine 
SOP 
Standard operating Procedures 
SzNET 
Seizure networks defined by resting state functional MRI 
SzNET- 
That has presence of Seizure networks observed in resting state functional MRI #1 
SzNET+ 
That has presence of Seizure networks observed in resting state functional MRI #1 
TE 
Echo time 
T-MoCA 
Telefonic Montreal Cognitive Assessment 
TR 
Repetition time 
TraCS 
N.C. Translational and Clinical Sciences Institute   (tracs.unc.edu) 
TV 
Total volume 
TVR 
Total volume reduction 
UNC 
The University of North Carolina 
UNCH 
UNC Hospitals 
UP 
Unanticipated  Problem 
1.   Protocol Synopsis 
 
Title 
Resting state fMRI BOLD Offers Opportunity for Treatment in Coma 
Study Description 
This is an open-label pilot clinical trial in the PICU, NSICU, SICU, CTICU, 
CICU, and MICU at UNCH to characterize the behavior of Seizure 
Networks (SzNET) in 18 months to 70 years old patients with moderate 
to severe acute brain injury (MSABI) and suppression of consciousness. It 
will assess the reduction of SzNET after antiseizure medication (ASM) 
using pre/post-treatment rs-fMRI and compare that response to EEG 
and normal resting state networks (RSN).  
Specific Aims 
(objectives) 
Aim 1.  Estimate the degree of improvement of SzNET in MSABI patients 
after intervention.  
Aim 1a. Measure the improvement of the SzNET total volume in 
MSABI patients after the intervention. 
Aim 1b. Measure the improvement of the SzNET power 
spectrum in MSABI patients after the intervention. 
 

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Aim 2.  Estimate the proportion of EEG- and EEG+ patients presenting 
SzNET on the initial rs-fMRI. 
 
Aim 3.  Investigate association between pre/post-intervention EEG 
improvement and SzNET response. 
 
Aim 4.  Investigate the association between the intervention responses 
of the normal resting state network connectivity and the SzNET 
in MSABI patients. 
 
Aim 5.  Describe  psychosocial functional measure outcomes and 
ambulatory ASM toxicity at 3 months from discharge. 
 
Aim 6.  Assess the trial’s design success regarding participants 
enrollment and retention. 
 
Aim 6a. Measure the enrollment rate. 
Aim 6b. Measure the dropout rate. 
 
 
 
Target Population 
Inclusion Criteria  
1. 
Age from 18 months to 70 years. 
2. 
Suppression of consciousness related to a neurological injury. .  
3.           GCS less than 13. 
 
4. 
Acute brain Injury by TBI, hypoxic-ischemic Insult, cardiac arrest, 
or Stroke. 
5. 
2 to 90 days from MSABI to enrollment. 
6.           Have a routine clinical care surface EEG performed after the 
admission to PICU, NSICU, SICU, CTICU, CICU or MICU. 
7.           Hospitalized at PICU, NSICU, SICU, CTICU, CICU or MICU 
 
Exclusion Criteria  
1. 
Previous medical history of Epilepsy. 
2. 
Previous medical history of neurological conditions that lead to 
dependence greater than expected for age on care for basic 
daily activities given by Barthel Index score (BIS) less than 80. 
3. 
Brain death. 
4. 
Currently able to speak fluently.  
5. 
Currently at one’s prior reported baseline mental status. 
6.           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..  
7.           Prisoner human subjects by medical chart review. 
8.           Pregnant. 
9.           Treating physician determines the patient is no candidate to 
receive 2 of the 5 protocol-specified  ASM. 

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10.         Contraindications for MRI scan. 
Numbers of Enrollees 
Up to 68 individuals will be screened with the goal of enrolling 54 eligible 
individuals and identifying a subset of 22 participants who are SzNET 
positive (see Study Schema, Figure 2). Using a quota sampling strategy, 
11 SzNET+ patients will be recruited consecutively for each EEG+ and 
EEG- strata to ensure the necessary number of patients for the 
interventional phase of the study. 
 
Interventions   
Participants that are SzNET positive will receive a loading ASM 
combination dose of Levetiracetam (60mg/kg) and Phenobarbital (20 
mg/kg), followed by maintenance dosing for weight and age of both 
medications from three to ten days until the repeat rs-fMRI.  
  
If care team considers either of those medications cannot be used, then 
they are allowed to administer any other combination of two ASM from 
the following list as the loading dose: 
1. Phenobarbital 20 mg/kg 
2. Levetiracetam 60mg/kg 
3. Lacosamide 10 mg/kg 
4. Valproate 30 mg/kg 
5. Fosphenytoin 20 mg/kg 
 
Maintenance dose: Standard dosing for weight and age of both 
medications used for the loading dose from three to ten days until the 
repeat rs-fMRI. 
 
Participants with GCS 9 to 12 will not be assigned phenobarbital as one 
of the intervention ASM and the loading dose of one of the two ASM 
selected will be omitted. In this case the ASM list doses remain the 
same, and the recommended intervention will be Levetiracetam with 
loading and maintenance doses and lacosamide only maintenance 
doses.  
 
For all participants, the protocol driven ASM can be continued, 
suspended of modified by the care team after the repeat rs-fMRI is 
obtained. ASM administration after the follow up scan is not considered 
part of the protocol intervention. Step-wise withdrawal is encourage in 
case the care team decides to suspend the ASM given as part of the 
protocol.  
 
Outcome Measures 
Definitions are provided in the abbreviations table. 
 
Aim 1.  Pre and Post treatment SzNET activity 
Aim 1a. Pre and post-treatment SzNET total volume medians 
Aim 1b. Pre and post-treatment SzNET power spectrum medians 
 
Aim 2.   Presence of SzNET in rs-fMRI #1 (binary) 
 
Aim 3.   Follow-up EEG improvement (binary). 

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Aim 4.   Connectivity improvement of typical RSN in MSABI patients after 
intervention (Binary). 
 
Aim 5.   Follow up outcomes (3 months from hospital discharge) 
collected from one of the NSICU Post-Discharge Clinics, include: 
NDDI-E, PROMIS emot. Dist. -Anxiety - Short form, Liverpool Adverse 
Events Profile questionnaire, QOLIE-10-P and MoCA  
 
Aim 6.    
Aim 6a.   Enrollment rate. 
Aim 6b.   Dropout rate. 
 
Statistical Analysis Plans  
for Each Aim  
Aim 1 Plans. Use linear regression to test Aim 1 
Aim 2 Plans. Calculate the proportions and use the two-proportion Z-
test to test their difference. 
 
Aim 3 Plans. Use logistic regression for Aim 3. 
 
Aim 4 Plans. Use logistic regression for Aim 4. 
 
Aim 5 Plans. Calculate the summary statistics for Aim 5. 
 
Aim 6 Plans. Calculate enrollment and dropout rates 
 
Study Duration 
16 Months 
  
Participation Duration 
For main aims 5 to 14 days. Allowed patients for the exploratory aim 
number 5 will have a variable participation duration because of an 
unpredictable hospital discharge time. 
Enrollment Duration 
 1 year  
 
2. Introduction 
2.1.  Background Information 
Disorders of consciousness (DoC) are common in severe acute brain injury (SABI). SABI with prolonged DoC has high 
mortality, morbidity, and long recovery with high costs 1-3. A treatable contributor to DoC in SABI is seizures, with 
30-50% incidence by EEG, and 34% of these are subclinical4-7.  
However, surface EEG monitoring techniques have lower sensitivity for detecting seizures in deep brain locations.   
A significant knowledge gap is what should be done for the patient when the EEG is not conclusive for seizures 
activity (EEG-), and yet the patient’s consciousness is not improving. Because moderate to severe brain injury 
(MSABI) causes injury to deep locations of the brain, there could still be seizures coming from these locations but 
they may not propagate epileptiform activity to the brain’s outer millimeters where the scalp electrodes can sense 
it8. Thus, it is unknown, “To what extent does EEG insensitivity in MSABI causes underestimation of epileptogenic 
activity?”.  Thus, in this situation, a more sensitive technology of epileptogenic network activity in deeply located 
brain regions is needed.  

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Unfortunately, a current non-invasive and safe means of determining if seizures are reducing consciousness in 
MSABI is not established. The impact of this clinical gap has resulted in the lack of professional societies’ guidelines 
with evidence-based recommendations for antiseizure medication (ASM) in those with SABI and EEG-9,10. This 
knowledge gap and its consequences has long been recognized by physicians, resulting in widely accepted use of 
empirical ASM, hoping for the patient to improve when other reasons for coma have been ruled-out.  
 
One noninvasive and safe solution to address this problem is seizure networks (SzNET) detection by resting-state 
functional MRI (rs-fMRI). Rs-fMRI is sensitive to seizure network activity in deep locations primarily during interictal 
periods11-13. SzNET are pathological in those with known seizures, which is supported by the improvement of 
epilepsy surgery outcomes when SzNET are targeted14, and SzNET normalization correspondingly with the post-
operative seizure reduction13.  
 
However, what this abnormal connectivity in MSABI is caused by is not 
established. Multiple contributors to the abnormal connectivity in MSABI are 
possible. In addition to seizures, others include increased intracranial pressure 
from edema, hemorrhage, or hydrocephalus, or alternatively, cortical 
spreading depolarizations 15,16. If the abnormal network patterns in MSABI 
correspond to those seen in seizure networks of epilepsy and are modulated 
by antiseizure medication, then there may be a relationship with 
epileptogenic 
brain 
activity. While this is 
not definitive proof of 
epileptogenic 
causation or change in 
outcome, instead ASM 
delivery in those with 
MSABI 
and 
seizure 
networks is an initial 
logical perturbation of this complex network system to determine 
if further investigation is warranted.  
In our preliminary retrospective SABI data in adults and children 
(N=63), 30% were EEG- and SzNET+ (Fig. 1).  Regarding initial 
evidence of SzNET response to ASM in SABI, of the 63 SABI 
patients who received rs-fMRI, 27 (42%) had SzNet; of these, 6 
received ASM therapy driven by clinician interpretation of rs-fMRI 
results described in Table 2 with network and outcome 
improvement. 
In epilepsy, SzNET also disrupt the RSN, impacting the patient phenotype, such as memory capacity reduction17,18. Since 
Resting State Networks (RSN) connectivity is associated with consciousness recovery in DoC19,20, then SzNET may also be 
disrupting RSN connectivity in MSABI, producing prolonged DoC. In our case series SABI- SzNET treatment experience 
described in Table 1, the RSN connectivity also improved with therapy. Thus, it is also possible that by tracking not only 
the therapy impact on SzNET but also the RSNs, especially the default mode network, that is highly associated with SABI 
DoC recovery21,22, we may better understand the link of SzNET disruption of RSN and possible mechanism of prolonged 
DoC in SABI.  
Our long-term goal for this research line, aimed to be through the support of the NINDS, is to evaluate if and how SzNET 
and RSNs are linked to epileptogenic activity and connectivity in consciousness-supporting networks in SABI, thereby 
elucidating the opportunity for DoC SzNET-guided therapy, and potential for improved outcomes of this subset of DoC.  
Supportively, the goal of this initial proposal is to allow for the opportunity to acquire adequate pilot data to inform the 
  
Table 2. Treated SzNET  
Treatment: 5 of 6 patients with 
phenobarbital load 20 mg/kg x 3 days 
and 1 patient with levetiracetam load 
60 mg/kg 
EEG- 
60% 
DoC improvement* 
100% 
SzNet improvement 
100% 
EEG improvement in 
those EEG+ 
100% 
*DoC improvement defined by care teams’ 
documentation of patient exam improving by 
one level of DoC within 14 days of therapy. 
Example 
from 
coma 
to 
unresponsive 
wakefulness syndrome (UWS), or from UWS to 
minimal responsiveness syndrome (MCS). 
 
Figure. 1. Adult and Peds SABI EEG and Seizure Network (SN) 
prevalence (N=63). EEG-SN+ comprise 30% of the SABI 
population.  

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larger planned and more rigorous trial, which will be a double-blinded placebo controlled clinical trial of ASM in SABI 
patients who are EEG- and SzNet+.  
Thus, we hypothesize that SzNET may hinder the improvement of coma, by reducing typical resting state network 
connectivity.  
 
2.2.  Scientific Rationale 
Study Proposal:  This is an uncontrolled two-arm open-label single-center interventional clinical trial that will be 
used to prepare for a full-scale randomized, placebo-controlled trial by investigating the feasibility of the study and 
proposed measures collection. It will explore changes in SzNET, RSNs, and EEG data, before, and after combination 
drug therapy with levetiracetam and phenobarbital (or a combination of two other ASM drugs (see section 4.1) and 
psychometric measures at 3 months after hospital discharge based on a sample of 54 patients with MSABI and DoC.  
Our long-term goal for this research line is to determine if SzNET are linked to epileptogenic activity in SABI to 
improve the endotype characterization of its DoC and better guide targeted treatments. 
 
Rational for specific aims and outcome measures:  The purpose of this study is to determine the occurrence of a 
specific biomarker called SzNET in patients with MSABI and investigate the effects of ASM on SzNET. The study also 
aims to find any correlation between EEG and SzNET in patients who experience seizures on EEG. 
The study outcome measures will focus on quantifiable changes in SzNET and RSNs with therapy. It is difficult to 
isolate the effects of early therapy on outcomes due to the high rate of withdrawal of life sustaining therapy in the 
early weeks of MSABI and the potential secondary injuries. Therefore, this study will take a conservative approach 
and focus on quantifiable changes in SzNET and RSNs with therapy. If there are no significant changes in the 
networks after therapy, it may not be necessary to further investigate the relationship between SzNET and 
outcomes. The feasibility of collecting outcomes and trends in relation to SzNET will be tested as part of this pilot 
study through ICU exams and follow-up clinics, including side effects of medication, morbidity, and mortality, to 
identify any positive trends.  
Rational for study inclusion/exclusion criteria:  This study focuses on patients with brain damage severe enough 
to impair consciousness but with the potential to recover in the absence of epileptogenic activity. The inclusion 
criteria have been chosen to identify patients with this level of brain damage. 
 
To be eligible for the study, patients must have a suppression of consciousness related to a neurological injury with 
Glasgow Coma Scale of less than 13  and be hospitalized at the ICU. This brain injury severity score indicates that 
the patient has a moderate to severe consciousness compromise, which is the intended target population. Patients 
who have recovered their baseline mental status or the ability to follow commands prior to therapy are excluded 
from the study or withdrawn if they were already consented into the study. This exclusion ensures that eligible 
participants still has a disorder of consciousness severe enough to warrant the risk of the study therapy. Patients 
who are brain dead are also excluded from the study because their lesions are so severe that recovery is not 
possible, regardless of the treatment.  
 
Rational for study intervention:   
The relationship between SzNET, EEG, and epileptogenic activity in patients with MSABI is not yet fully understood. 
To validate SzNET, it is necessary to explore its meaning in patients who are EEG-negative, as they are the population 
that could potentially benefit from it the most, given the possibility of epileptogenic activity overlooked by EEG. 
Validating seizure-biomarkers in surface EEG-negative patients is challenging, as the alternative gold standard 
validation methods should be the intracranial EEG which would propose higher risk in the target population for  
increased bleeding and infection risks. By administering an ASM and observing the induced changes in SzNET and 
RSN we may document a response like the observed in the  patients referenced in table 2. If we can gather 

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preliminary information consistent with our pilot findings, that may justify conducting a larger randomized 
controlled trial (RCT).   
 
Rational for two ASMS and dosage:   
When the EEG is positive, we can track a patient's response to medication, but we won't have a similar bedside 
measure of immediate improvement in patients who are EEG-negative but have positive SzNET. If SzNET is 
contributing to a patient's depressed mental status as occurs during non convulsive status epilepticus, Its severity 
could be similar. 
 
Since we cannot measure improvement by EEG, and because more than one medication is often required in status 
epilepticus, we need a strategy with a high likelihood of controlling epileptogenic activity. Dual loading doses of 
ASM have been shown to provide a more definitive response in known cases of status epilepticus than using only 
one medication23,24. The selection of phenobarbital is due to its relatively high efficacy in status epilepticus25,26.   The 
primary concerning side effect of phenobarbital is ventilatory depression. However, this effect is less relevant in 
this population as many of these patients already have a secure airway due to the ongoing depression in mental 
status and required mechanical ventilation. Therefore, this is not a significant concern for patients who are already 
under mechanical ventilation due to their low neurological response.  
 
 
 
3. Specific Aims 
 
3.1. Aim 1 
 
Obtain a preliminary estimate of the seizure networks (SzNET) changes in moderate to severe acute brain 
injury (MSABI) patients after the research  intervention  with antiseizure medication (ASM) to support a 
future larger placebo controlled resting state-fMRI (rs-fMRI) clinical trial for prediction models of 
epileptogenicity in early SABI. The preliminary data of primary interest is the magnitude of the functional 
imaging SzNET response to high-efficacy pharmacological treatments in this clinical setting. 
 
Aim 1a 
Measure the improvement of the SzNET spatial total volume (TV) in MSABI patients after the intervention. 
The estimand of interest is the SzNET spatial TV median before and after the intervention in the target 
population. The intrasubject TV change ratio will be expressed as total volume reduction (TVR). 
 
Aim 1b 
Measure the improvement of the SzNET temporal power spectrum (PS) in MSABI patients after the 
intervention. The estimand of interest is the SzNET temporal PS median before and after the intervention 
in the target population. The intrasubject PS change ratio will be expressed as power spectrum 
improvement (PSI) 
 
3.2. Aim 2 
Estimate the frequency of EEG- and EEG+ patients presenting with SzNET on their initial rs-fMRI prior to the 
study intervention. The estimands of interest are the proportions and differences of proportions of patients 
with SzNET among EEG- and EEG+ patients in this clinical setting. 
 

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3.3. Aim 3 
Investigate association between post-intervention EEG improvement and SzNET response. The estimand of 
interest is the relative risk of EEG improvement in patients with more than 50% improvement of their SzNET 
by TVR and PSI. 
3.4. Aim 4 
Investigate the association between the post-intervention typical resting state networks (RSN) connectivity 
improvement and the SzNET response. The estimand of interest is the relative risk of improvement of the 
RSNs in the patients with more than 50% of improvement of their SzNET by TVR and PSI. 
3.5. Aim 5 
Describe psychosocial functional measure outcomes and ambulatory ASM toxicity at 3 months from 
hospital discharge.  The estimates of interest will be the PROMIS Emotional Distress—Anxiety— Short 
Form, the Neurological Disorders Depression Inventory for Epilepsy (NNDI-E), the QOLIE-10-P, the 
Telephonic Montreal Cognitive Assessment, and the Liverpool adverse event profile test. All will be 
assessed at the 3 month follow up visit by one of the NSICU Post-Dischrage clinics. This aim only applies to 
the patients that are discharged alive from the hospital and will include results from visits until 14 months 
after the enrollment start. 
3.6. Aim 6 
Assess the trial's design feasibility success in enrollment and retention for our actual institutional context 
by evaluating the enrollment rate and dropout rate among participants at the end of the trial. it will be 
composed by two sub aims. 
Aim 6a 
Measure the participants enrollment rate during the hole study enrolling months. The estimand of interest will 
be the rate of enrolled patients per month. 
 
Aim 6b 
Measure the participants dropout rate among participants. The estimand of interest will the dropout rate 
from the total enrolled participants at the end of the study. 
 
 
 
4. Study Design 
 
This is a prospective interventional, uncontrolled, open-label, single center pilot study in moderate to severe acute 
brain injury (MSABI) patients with suppression of consciousness. The study main outcomes require pre and post-
intervention rs-fMRI data collection to characterize the evolution of SzNET, a physiological measure of brain 
function. Clinical implementation of rs-fMRI is still novel, not frequently performed at early stages of MSABI, and 
has few medical indications as a follow-up test. As this data is infrequently generated during the standard of care 
(SOC), a prospective interventional study with an ASM intervention and a research funded rs-fMRIs is needed.  
 
The target population is in the UNC intensive care unit, and to prioritize the human subjects’ wellbeing, the patients 
will receive their standard clinical monitoring and therapy per the local care team, including EEG, antiseizure 
therapy, and head imaging as clinically indicated.  Once stable for MRI, subjects will receive the study-related rs-
fMRI #1. If SzNET are detected (SzNET+), the subject will start the study treatment protocol, followed by post-
treatment repeat rs-fMRI (rs-fMRI#2) and EEG. Those patients negative for SzNET in the rs-fMRI#1 (SzNET-) will not 

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have intervention or research follow up EEG and rs-fMRI, but if they are followed by one of the NSICU Post-
Dischrage clinics, the information obtained from their assessments will be collected as part of this study.  
 
Rationale for intervention with ASM  
The purpose of this study is to test the correlation of SzNET in MSABI with epileptogenic activity. To benchmark this 
correlation, we will compare the response of SzNET to ASM with well-known effect in the epileptogenic activity. 
Previous data in epilepsy shows that SzNET improvement is related to clinical improvement13, and those clinical 
effect sizes of seizure improvement have been measured for multiple pharmacological treatments including the 
ones listed for this protocol intervention26,27. We hypothesize that SzNET improvement will be similar to the effect 
size expected for the selected ASM. If we are correct, SzNET could help predict clinical outcomes related to 
epileptogenic activity. To achieve this, we need treatment protocols with proven consistent clinical response and a 
large effect size. The recommended protocol for a effective response is a combination of intravenous phenobarbital 
and levetiracetam at loading doses26. However, since the main outcome measures are quantitative and smaller 
effect size responses could still be detected, for this pilot trial we allow a list of alternative ASM protocols with 
anticipated similar efficacy. The purpose of this alternative options is that the care team can use a different protocol 
if it is more appropriate given the patient's particular characteristics. 
  
Rationale for stratification by EEG 
Restated:  Seizure network activity could be the cause of suppressed conscious in acute brain injury. The EEG, which 
is the best current test for detection of seizure, may not detect this activity, if it is occurring in deep brain locations.  
SzNET by rs-fMRI may be a biomarker of abnormal activity in acute brain injury that could be responsive to ASM.    
In ICU patients with suppression of consciousness, we will use the EEG to stratify patients into two groups, EEG+ 
and EEG-. EEG+ will be defined by either electrographic seizure, electroclinical seizure or ictal-interictal continuum 
as defined by the American clinical Neurophysiology Society's Standardized Critical Care EEG Terminology28, 
whereas EEG- will be lacking these features. Further, we will observe the rate of SzNET by rs-fMRI in both groups, 
and response of the SzNET and EEG to study intervention. 
To ensure rapid recruitment, the study will use a quota sampling strategy. Specifically, eleven SzNET+ patients will 
be recruited consecutively for each EEG+ and EEG- strata to ensure the necessary number of patients for the 
interventional phase of the study.   
 
Data collection 
First, informed consent will be obtained from the subject’s legally authorized representative (LAR). Then, baseline 
variables will be collected by interview and review of medical charts. After subjects are scanned, the rs-fMRI images 
are uploaded to the UNCH MRI PACS system by an MRI technician and accessed through the UNCH secure PACS 
portal by study personnel, through download onto the UNC SOM secure system. There, the rs-fMRI processing and 
analysis are accomplished, and information is deidentified for storage in the PI’s UNC-OneDrive. Clinical and 
demographic data will be collected by the study research coordinator and stored in a REDCap file. Once the study 
data collection is completed, the deidentified REDCap database will be used for analysis and stored at the PI’s UNC-
OneDrive. A separately stored subject key code in a SOM-stored research excel file will link the research subject’s 
codes and MRN until five years after study completion. Hospital discharged patients will be followed through one 
of the NSICU Post-Dischrage clinics, and that data will be stored in the same study REDCap file. 
 
End-of-study criteria and discontinuation criteria for the participant. 
Patients that need to discontinue the study treatments during the intervention phase because of medical reasons 
will be withdrawn from the study, unless they can be assigned to one of the alternative combination-drug protocols 
and continue to meet eligibility criteria. 
  
End-of-study criteria or stopping-rules for the entire study.  

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If a severe adverse event related to study participation occurs (e.g., transportation to the MRI scan, side-effect of 
the ASM intervention), the study will be suspended pending review by the IRB and implementation of an approved 
Corrective and Preventative Action Plan.  
 
Based on pilot data, SzNET is common in patients who are EEG+, but only present in about 30% of patients who are 
EEG-. After enrolling 40 patients, we will review the results of rs-fMRI #1, and the study will stop because of futility 
if we observe one the following criteria: 
• 
SzNET are detected in less than 70% of the patients classified as EEG+ or less than 10% of the patients in 
the EEG- group. 
• 
More than 50% of the subjects from the intervention group do not show a change in SzNET after the study 
treatment. 
 
 
 

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Figure 2.  Study Flow Diagram.  
 
 
• 
  
• 
Prescreening 
• 
 
• 
 
• 
 
 
 
• 
  
• 
Screening and 
• 
 Recruitment 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
Verification of Eligibility 
• 
and  Enrollment 
• 
 
• 
 
• 
 
• 
 
• 
In-hospital  
• 
assessment 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
 
• 
In- hospital 
• 
 intervention 
• 
 
• 
 
• 
 
• 
In-hospital  
• 
Assessment 2 
• 
 
• 
 
• 
 
• 
Visit at 
• 
one of the NSICU 
• 
Post-Dischrage  
• 
clinics (3months post 
• 
 hosp discharge) 
 
Obtain verbal informed consent to screen with Barthel Index    
Obtain screening data (Barthel Index assessment) and baseline 
data. 
Review and verify current eligibility criteria  
Follow-up Studies: Rs-fMRI#2 and EEG 
Intervention (Combination ASM Drug Therapy) 
SzNET- 
(EEG+ & EEG-) 
N=32 
Rs-fMRI #1 and allocation by results 
Written informed consent 
Enrollment of Eligible Patients 
Final follow-up  
assessments of outcome measures and safety. 
Participation completed.  
SzNET+ 
EEG+ 
N=11 
Tracking possible candidates  
Apply inclusion and exclusion criteria. 
Contact care team and families  
Review Clinical Care EEG  
EEG+ 
EEG - 
SzNET+ 
EEG- 
N=11 

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4.1. Treatment Design 
The intervention and its compliance criteria are defined as receiving treatment by minimum 72 hours since loading 
dose start time or up to ten complete days with administration of two of the following ASM regimens:  
 
Phenobarbital: 
Pediatric population 
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. Max dose 600mg/day.   
  
Levetiracetam 
Pediatric population 
Loading dose 60 mg/kg intravenous. Max dose 4000mg. 
Maintenance dose 40mg/Kg/day, Max dose 3000mg/day intravenous or enteral. 
Adult population 
Loading dose 60 mg/kg intravenous. Max dose 4500mg.  
Maintenance dose 1500mg to 4000mg/day intravenous or enteral.   
  
Lacosamide 
Pediatric population 
Loading dose 10 mg/kg intravenous, Max dose 400mg. 
Maintenance dose 4mg to 8mg/Kg/day. Max dose 300mg intravenous or enteral. 
Adult population 
Loading dose 200mg to 400mg intravenous 
Maintenance dose 200-400mg/day intravenous or enteral. 
  
Valproate 
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 40 mg/kg intravenous. Max dose 3000mg   
Maintenance dose 15-30mg/Kg/day, Max dose 3000mg/day.    
  
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 4-7mg PE/Kg/day. Max dose 400mg PE/day 
 
All maintenance doses are given every 12 hours,  starting 12 hours after the loading dose. 
Participants with GCS 9 to 12 will not receive phenobarbital as one of the intervention ASM, and the loading dose 
of one of the two selected ASMs will be omitted. 

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All patients with an identified SzNET in rs-fMRI#1 will be included in the intervention group. Within one and six days 
after the first scan, the care team will decide and start the intervention with two ASM agents from the list. The 
intervention phase occurs between 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 ASM for 
at least 72 hours after the loading dose start, and the second scan must be done within 72 hours of the last 
intervention ASM dose. The treatment protocol can continue up to a maximum of ten days to improve the 
opportunity to schedule the scan. Thus, the rs-fMRI #2 must be done at a time between 73h and 312h (the fourth 
and thirteenth days) after the intervention phase starts, and the subject can still be receiving the intervention at 
that time.   
Once the rs-fMRI #2 is obtained, the subject’s ASM treatment can be continued or changed for clinical reasons 
depending entirely on the care team’s decision, then it will not be considered part of the study’s intervention phase 
or be related to the research team. 
The intervention aims to validate the epileptogenic background of the SzNET by using an ASM that is known to be 
effective.  We expect the intervention will influence the improvement of the SzNET. We hypothesize that the 
intervention will selectively modulate the networks caused by epileptogenic activity, while having less to no impact 
on abnormal networks caused by other phenomena. 
The length of the intervention is designed to be adequate for pharmacological modulation of epileptogenic activity. 
The six-day time frame between the minimum and the maximum treatment protocol time facilitates a window for 
the rs-fMRI schedule that is a realistic schedule time frame in the ICU.  
From the different ASM options the key intervention and first option to be considered as intervention will be 
phenobarbital + levetiracetam. This specific ASM combination will be communicated clearly to the ICU care teams 
as the first line of the study intervention. However, for clinical reasons the care team will be free to select any 
combination of two or more study listed ASM regimens. On day two of maintenance dosing, the phenobarbital 
serum level will be measured if it is one of the selected medications, and a new loading dose will be given to aim 
for a level of 40mcg/ml.  
The dual ASM loading dose approach is designed to increase the likelihood of a timely response to SzNET, as 
compared to using only one ASM and its rational use is supported by the better response suggested in Status 
epilepticus23,24. With a gentler medication regimine of single agent, given the data, should be less likely to see an 
impact on the SzNET.  If we go this route and we don’t see an effect, then we are also unlikely to get any further 
funding to repeat such a study with dual agent, given the competitive nature of grant application and the clinical 
team may also loose appetite for supporting more studies. 
Phenobarbital is included specifically because of its high efficacy in treating epileptogenic activity25,26. Phenobarbital 
can cause ventilatory depression.  However, the patients with SABI during the study timeframe are expected to be 
intubated with good airway and ventilatory control, and thus less likely to require significant escalation of airway 
or ventilatory support.  Furthermore, all ICU patients are monitored with all necessary safety considerations for 
airway management and ventilation. ASM maintenance dosing can be modify by the care team during the 
intervention phase and still be compliant, as long as the dose remain equal or higher than the minimum dosage 
stated in the insert. The care team may adjust ASM based on clinical determinants after the second rs-fMRI without 
compromising the protocol, as the main outcome measures are based on data collected on that day.  
The short term-use of dual ASM that we would be giving to patients with suspected non-convulsive status 
epilepticus or subclinical seizures with coma in the ICU is off-label because the intervention is not given to treat 
confirmed seizures by their standard definition. However, the possibility of deleterious epileptogenic activity cannot 
be discarded in the eligible patients and the routes of administration and concomitant dosage levels are appropriate 
for status epilepticus (see appendix B to F), not increasing the risk of the intervention compare to the regular use 
of the listed ASM.  The study’s intervention does not significantly increase the selected subjects’ risks leading to a 
discouraging risk-benefit relationship because these subjects are already at very high risk of death if they do not 
wake up from their coma. Thus, any opportunity to try to improve the chances of waking up from coma is worth 

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the risk of the antiseizure medication. That risk benefit relationship is the reason why empiric antiseizure 
medication is often given in SABI patients with DoC.   
Participants with a GCS of 9 to 12 are at lower risk compared to those with a GCS of less than 9 and may not require 
ventilatory support. To maintain a favorable risk-benefit ratio for their participation, these participants will not 
receive phenobarbital as one of the intervention ASM, and the loading dose of one of the two selected ASMs will 
be omitted. 
The present study and its results are not intended to try to support changes in the indications, the labeling or the 
advertising of medical devices use or drugs. The study’s informed consent will describe the purpose and the 
procedures and interventions described in this trial. Taking into account the statements in this protocol we are not 
submitting an FDA “ Investigational New drug Application (IND)” because according to 21 CFR 312.2(b)(1), the 
clinical investigation of a marketed drug or biologic does not require submission of an IND if all six of the following 
conditions are met: 
i. 
 it is not intended to be reported to FDA in support of a new indication for use or to support any other 
significant change in the labeling for the drug; 
ii. 
it is not intended to support a significant change in the advertising for the product; 
iii. 
it does not involve a route of administration or dosage level, use in a subject population, or other factor 
that significantly increases the risks (or decreases the acceptability of the risks) associated with the use of the drug 
product; 
iv. 
it is conducted in compliance with the requirements for IRB review and informed consent [21 CFR parts 56 
and 50, respectively]; (revision by the IRB and compliance with the protection of human subjects) 
v. 
it is conducted in compliance with the requirements concerning the promotion and sale of drugs [21 CFR 
312.7]; and 
vi. 
it does not intend to invoke 21 CFR 50.24.29 
 
4.2.  Experimental Design    
This pilot study is a stratified interventional study that will evaluate the response of an exploratory biomarker. There 
will be no placebo-controlled groups, and the study main intervention will be systematically assigned to all subjects 
with SzNET identified by the first rs-fMRI. Patients without SzNET will not receive the study treatment and will 
continue their medical therapy as directed by their care team. They will be included in the required analysis for aim 
2 and 5. Two specialists will assess the two post-intervention follow-up studies, the rs-fMRI#2 and the repeat EEG, 
providing the only blinding needed. These study design elements will ensure the technical requirements necessary 
to calculate the sample size required for a larger trial in EEG-negative patients with SzNET-positive and explore two 
important aspects of the biomarker SzNET: its correlation with the EEG response of patients and the effect size of 
its response to the intervention ASM. 
4.3.  Measurement Design   
Table 2.  Variables of interest: their occasions of evaluation, their uses for the aims, their roles in the study 
Variables within Domains 
Scale1 
Occasions2  
Aims3 
Main Roles 
Identifiers 
 
 
 
 
Participant’s unique ID 
nominal 
all 
all 
identifier 

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Intervention 
categorical 
E 
All, 
except 
aim 2 
intervention 
Clinical Health Profile 
 
 
 
 
Spontaneous ventilation 
Binary 
E, 2 
Aim 1 
Exploratory uses 
Glasgow Coma Scale (GCS)  
Ordinal 3-15 
S, E, 2 
-- 
Screening  
weight  
kg 
E 
-- 
dosing 
height 
cm 
E 
-- 
dosing 
body mass index (BMI) 
kg/cm2 
E 
-- 
dosing 
body surface area (BSA) 
kg/m2 
E 
-- 
dosing 
Supratentorial decompressive craniectomy 
Binary 
S, E, 2 
-- 
Exploratory uses 
age   
decimal yrs 
S 
-- 
screening 
sex 
categorical 
S 
-- 
Exploratory uses 
Pre-MSABI BIS (appendix a) 
Ordinal 0-100 
S 
-- 
screening 
Medical Records 
 
 
 
 
Presumed etiologies of disorder of consciousness 
Categorical 
S 
-- 
screening  
co-morbidities list 
nominal 
S 
-- 
screening 
Clinical tests 
 
 
 
 
2HELPS2B Score 
Ordinal 0-7 
S 
-- 
Exploratory uses 
pre-intervention EEG status (EEG monitoring 
Seizures) 
Binary 
E 
All 
classification 
Research tests 
 
 
 
 
SzNET presence 
Binary 
E 
All 
Classification and 
primary outcome 
Total Volume (TV)  
continuous 
2 
Aim 1a 
primary outcome 
Total Volume Reduction (TVR)  
continuous 
2 
Aim 1a, 
3, 4 
primary outcome 
Power Spectrum (PS)  
continuous 
2 
Aim 1b 
primary outcome 
Power Spectrum Improvement (PSI)  
continuous 
2 
Aim 1a, 
3, 4 
primary outcome 
Typical RSN improvement 
Binary 
2 
Aim 4 
Secondary outcome 
EEG improvement 
Binary 
2 
Aim 3 
Secondary outcome 
Protocol Time Frames 
 
 
 
 
Days of antiseizure medication 
Days (discrete) 
2 
- 
Confounder 
Time from MSABI to rs-fMRI#1 (days) 
Days (discrete) 
2 
- 
Confounder 
Time from MSABI to rs-fMRI#2 (days) 
Days (discrete) 
2 
- 
Confounder 
Time from MSABI to treatment protocol start 
(days) 
Days (discrete) 
2 
- 
Confounder 
Time from enrollment to rs-fMRI#1 
Days (discrete) 
2 
- 
Secondary outcome 
Questionnaires/survey instruments4 
 
 
 
 
Anxiety: PROMIS Emotional Distress—Anxiety— 
Short Form (appendix H) 
Ordinal 7-35 
3 
Aim 5 
Exploratory outcome 

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Depression: Neurological Disorders Depression 
Inventory for Epilepsy (NNDI-E) (appendix I) 
Ordinal 6-24 
3 
Aim 5 
Exploratory outcome 
Quality of Life: QOLIE-10-P (appendix J) 
Ordinal 1-10 
3 
Aim 5 
Exploratory outcome 
Telephonic Montreal Cognitive Assessment 
(appendix K) 
Ordinal 0-15 
3 
Aim 5 
Exploratory outcome 
ASM toxicity: Liverpool adverse event profile test 
(appendix L) 
Ordinal 19-76 
3 
Aim 5 
Exploratory outcome 
Safety Monitoring 
 
Any time 
(AT) After 
E 
 
 
Adverse event related with the transportation to 
the MRI scan. 
Ordinal 1-5 
AT after E 
- 
safety monitoring 
Adverse event related with the transportation to 
the MRI scan. Description 
nominal 
AT after E 
- 
safety monitoring 
Adverse event related with the intervention 
Ordinal 1-5 
AT after E 
- 
safety monitoring 
Adverse event related with the intervention. 
Description 
nominal 
AT after E 
- 
safety monitoring 
Dropout 
binary 
AT after E 
Aim 6 
Secondary outcome 
Dropout date 
ordinal 
AT after E 
Aim 6 
Secondary outcome 
Dropout cause 
nominal  
AT after E  
- 
safety monitoring 
Feasibility 
 
 
 
 
Informed consent acceptance 
Binary 
E 
Aim 6 
confounder 
 
 
1 Units of measurement or the scale. 
 
 
2 Occasions of evaluation or retrieval:     S = screening,  E = enrollment,  2 = rs-fMRI#2, 
 
 
 
 
 
                             3 = 3 months      
 
 
3 The specific aims in which the variable will play a role in data analyses. 
 
 
4 will be collected by one of the NSICU Post-Discharge clinics.  
 
 
In Table 2, the treatment regimens must include two from:   
6. Phenobarbital  
7. Levetiracetam  
8. Lacosamide  
9. Valproate  
10. Fosphenytion  
 
In Table 1, the allowed Presumed etiologies of disorder of consciousness are:   
1. Hypoxia/anoxia (i.e., respiratory arrest with preserved circulation) 
2. Hypoxic-ischemic injury (i.e., cardiac arrest). 
3. Ischemic stroke. 
4. Intracerebral hemorrhage. 
5. Subarachnoid hemorrhage. 
6. Subdural hemorrhage 
7. Epidural hemorrhage 
8. Traumatic brain injury (penetrating). 
9. Traumatic brain injury (non-penetrating). 
10. Venous sinus thrombosis/cortical vein thrombosis 
 
    

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Baseline Variables: 
- 
The Medical record domain variables will focus on retrieving information to screen patients and verify 
inclusion-exclusion criteria. Thus, the previous history of epilepsy and neurological problems that could lead 
to functional dependence greater than expected for age are relevant confounders that will be avoided in 
this pilot trial. The presumed etiology of DoC are the inclusion criteria, and we expect to evaluate the rs-
fMRI for exploratory purposes in subgroup analysis. Glasgow coma scale GCS is a baseline variable that will 
be collected in more time points. 
- 
The presence of SzNET will classify the patients that will receive intervention corresponding to the protocol 
and those that will only continue medical treatment according to care team indications in case of the 
presence or the absence of SzNET in the first MRI, accordingly. Outcomes will be reported as proportions 
and differences of proportions of patients with SzNET among EEG- and EEG+.  
- 
Surface EEG monitoring pre-intervention (Seizures) is a binary variable collected from the total available 
surface EEG monitoring before rs-fMRI#1 with EEG+ and EEG- as possible values and retrieved by the 
investigators from the medical record or direct communication with the Epileptologist, which later must be 
supported in the medical records. EEG+ is defined as surface EEG with the presence of electrographic 
seizure, electroclinical seizure or ictal-interictal continuum. 
Outcome Variables: 
Each SzNET is made of one or more BOLD signal independent components that share atypical temporal or spatial 
features 11. 
 
- 
SzNET total volume (TV) is the sum of the volumes of the SzNET independent components. The TV change 
from before to after the intervention is a ratio expressed as the TV reduction (TVR), and is given by: 
𝑇𝑇𝑇𝑇𝑇𝑇= 1 −
∑
𝑃𝑃𝑖𝑖
𝑛𝑛
𝑖𝑖=𝑛𝑛
∑
𝐸𝐸𝑖𝑖
𝑛𝑛
𝑖𝑖=𝑛𝑛
 
Where P is the volume of a post-treatment SzNET, E is the spatial volume of an initial SzNET and n is the amount 
of SzNET in each rs-fMRI. 
- 
Power Spectrum (PS) is the sum of the power spectrum of the SzNET independent components normalized 
by their spatial volumes. The PS change from before to after the intervention is a ratio expressed as the PS 
improvement (PSI) and is given by: 
 
𝑃𝑃𝑃𝑃𝑃𝑃= 1 −
∑
[𝑃𝑃∫
𝑓𝑓(𝑠𝑠)
27.12
6.78
]𝑖𝑖
𝑛𝑛
𝑖𝑖=1
∑
[𝐸𝐸∫
𝑓𝑓(𝑠𝑠)
27.12
6.78
]𝑖𝑖
𝑛𝑛
𝑖𝑖=1
 
Where F(S) is the power spectrum curve. 
- 
EEg improvement Binary variable categorized in "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. This 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: 
o Epileptiform Discharges 
o Rythmic and periodic patterns 
o Electrographic and electroclinical seizures. 
o Ictal-interictal continuum. 
It will be used to investigate the association in patients with a clear improvement of their SzNET. Such 
improvement will be defined as more than 0.5 TVR or 0.5 PSI threshold.  
- 
RSN improvement is a binary variable collected by the study coordinator based on clinical records of the rs-
fMRI#2, taking into consideration the spatial and temporal features and the number of canonical RSN 

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observed in the rs-fMRI#2. It will be used to investigate association in patients with a clear improvement of 
their SzNET; such improvement will be defined as more than 0.5 TVR or 0.5 PSI threshold.  
- 
All the variables listed as exploratory will be studied for association in patients with clear improvement of 
their SzNET, such improvement will be defined as more than 0.5 TVR or 0.5 PSI threshold. 
- 
 
Comments regarding extended age range: 18 months to 70 years of age had heterogeneity of brain function related 
to both neurodevelopment and old-age related degenerative processes.  However, the impact of seizure on brain 
networks that causes suppression of consciousness is similar through these age groups.  For example when seizure 
occurs we expect reduction in consciousness in both young and old who have either epilepsy or acute brain injury. 
Patient’s age may have impact on the clinical outcomes and connectivity aspects of resting state networks, for that 
reason we will analyze seizure networks (SzNET) different to the typical resting state networks (RSN). The analytical 
approach to SzNET that depend mostly on the ictal activity will be quantitative, but RSN improvement is a binary 
variable based on experts opinion judging the presence or absence of these normal networks that are described 
and used for neuroprognostication across different age groups30-32 
 
Safety and Feasibility Variables: 
These variables will be collected as part of the safety monitoring. Some of these variables also aim to determine 
how practical and viable is the study design, recruitment strategies, and participant retention in our institutional 
actual context. By closely monitoring the enrollment rate, which measures the efficiency of the recruitment process, 
and the dropout rate, which indicates the probability of the participants to continue with the study. Valuable 
insights can be gained regarding the feasibility of conducting a similar study on a larger scale. This findings will 
provide crucial information for refining future study protocol and improving recruitment and retention strategies 
to ensure the successful implementation of future research projects with similar conditions. 
5. Study Participants 
5.1. Numbers of Participants 
 
5.1.1. Number to be screened: N=68  
 
 
5.1.2. Number to be enrolled:   N = 54 
Rationale of Number Expected to be Screened:   
The Study will employ a quota sampling method to enroll four groups of patients, designated as: SzNET+/EEG+, 
SzNET+/EEG-, SzNET-/EEG+, and SzNET-/EEG-. Importantly, only the two SzNET+ groups have a minimum enrollment 
goal. Thus, enrollment will stop once each of the two SzNET+ groups enroll ten patients. The logic behind the patient 
screening and enrollments is as below.  

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1. 
SzNET+/EEG- Strata:  To successfully complete the 
study treatment in 10 EEG- subjects, who would eventually be 
found to be SzNET+, we need to enroll 11 subjects, as we 
anticipate a 1 in 10 subject attrition. In our preliminary SABI 
data (Fig 2), of those who would meet inclusion/exclusion 
criteria, 30% with EEG- were SzNET+. Thus, we expect to need 
to enroll approximately 37 EEG- patients with completed good 
quality studies. Lastly, due to the ICU environment and the 
Barthel score required, we expect 80% of the subjects eligible 
for enrollment, thus 46 EEG- patients will be screened to fulfill 
this group’s recruitment goal. 
2. 
SzNET+/EEG+ Strata:  To successfully complete 
treatment in 10 EEG+ subjects, who would eventually be found 
to be SzNET+, we need to enroll 11 patients, as we anticipate a 
1 in 10 subject attrition. In our preliminary SABI data (Fig 2), of 
those who would meet inclusion/exclusion criteria, 67% of the 
EEG+ were SzNET+. Thus, we expect to need to enroll approximately 17 EEG+ patients with completed good studies. 
Lastly, due to the ICU environment and the Barthel score required, we expect 80% of the subjects eligible for 
enrollment. Thus, 22 EEG+ patients will be screened to fulfill this group’s recruitment goal.   
Participants who drop out, are withdrawn, or have missing data will not be replaced until second aim’s data is 
complete, afterwards we will continue recruitment until we meet the two strata proposed enrollment. The subjects 
analyzed for the second aim will only include those scanned until the time when the first group of SzNET+/EEG+ or 
SzNET+/EEG- recruitment will be completed. By this strategy, the initial estimate of the proportion of SzNET+ 
subjects by EEG subgroup could be less biased, and we will guarantee the required number of subjects to start the 
interventional phase of the study while optimizing the total amount of initial rs-fMRI needed.    
Sources of recruitment:  UNCH PICU, NSICU, SICU, CTICU, CICU or MICU patients meeting study inclusion and 
exclusion criteria.  Potential research subjects will be identified by the study team members chart screening of all 
the patients with EEG orders from ICU, for eligibility.   
Interventional Study numbers of enrollees expected to receive the treatment regimen:  Since this is a non-controlled 
interventional open-label pilot study, and we need a total of 20 subjects successfully to receive the study therapy 
AND repeat rs-fMRI, then due to intra-study attrition of 1:10, we expect to treat a total of 22 patients with the study 
therapy. 
 
5.2. Eligibility Criteria 
This study will be done in moderate to severe acute brain injury (MSABI) patients aged 18 months to 70 years, at 
risk of epileptogenic activity and presenting with coma. The target population is recruited at Pediatric ICU (20 beds) 
and the Neuroscience ICU (22 beds) from UNC health at Chapel Hill, which acts as a tertiary referral center for 
patients from North Carolina and surrounding states. The Pediatric ICU treats an average of 109 patients/year with 
primary ICD codes for traumatic brain injury, arrest and encephalopathies & coma, which are the main codes for 
the target population.  
In the United States, 795,000 people experience a stroke (ischemic or hemorrhagic) every year33, and TBI causes 
approximately  282,000 hospitalizations and about 56,000 deaths each year 34. SABI from TBI, stroke, and other 
neurological problems require treatment in the ICU, where the incidence of Seizures is approximately 35%5,35. 
 
 
5.2.1. Inclusion Criteria  
 
Fig. 1. Adult and Peds SABI EEG and Seizure Network (SN) 
prevalence (N=63). EEG-SN+ comprise 30% of the SABI 
population.  

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In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
• 
Age from 18 months to 70 years at ICU admission by medical chart review.  
• 
Suppression of consciousness related to a neurological injury by medical chart review.  
• 
GCS less than 13 at enrollment.  
• 
Diagnosis of Acute brain injury by 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 routine clinical surface EEG performed after the admission to PICU, NSICU, SICU, CTICU, CICU or 
MICU. 
• 
Clinically stable to undergo MRI scan, This stability is defined by care team concept, which should be 
stated in the medical records. 
• 
Hospitalized in NSICU, PICU, SICU, CTICU, CICU or MICU 
 
 
5.2.2. Exclusion Criteria  
Any individual who meets one or more of the following criteria will be excluded from participation: 
• 
Previous medical history of Epilepsy by medical chart review.   
• 
Previous medical history of neurological conditions that lead to dependence on care for basic daily 
activities, by BIS less than 80, examined with the patient’s LAR at the time of the in person interview 
for obtaining the informed consent. If there is medical history of neurological conditions with 
concerning for impaired independence and the functional status of the patient cannot be addressed  
properly the patient will be excluded from participation. 
• 
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.  
• 
Is following Commands in 3 different exams from at least 2 different providers. 
• 
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. 
 
5.3. Enrollment/Selection Strategies 
 
5.3.1.  Prospective Recruitment   
The recruitment for this study is based on three steps as shown in Figure 3. The initial prescreening does not imply 
additional activities to the standard of care and is designed to provide an opportune identification of potential 
research subjects while they are stable enough to meet the inclusion criteria. The screening period is planned to be 
short with the application of one additional screening test before enrollment and driven by interaction between 
the research team and the legally authorized representative (LAR) of the research subject.  
By enrollment criteria, the patients from the target population for this study are not able to give consent on their 
own. Thus, the LAR will be in charge of giving consent on behalf of all the human subjects, including the children. 
The particularly vulnerable populations of pregnant subjects and prisoners will be excluded from the study. In the 
particular case of pregnant subjects they will be excluded due to higher risk of study-related pregnancy 
complications.   

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Relevant aspects regarding the protection of particularly vulnerable subjects: This research is considered to 
involve greater than minimal risk but presents the prospect of direct benefit to the individual subjects, thus in the 
case of children, the consent of one of their parents will be required.  
Language recruitment barriers: Informed consent form in Spanish, and Spanish-spoken in-person interview and 
phone calls by study personnel will be an available alternative for the non-English speaking population that might 
prefer Spanish to reduce language recruitment barriers. 
The recruitment strategy process is described in Figure 3.  
 
 
 
5.3.2. Screen Failures    
We expect less than 5% of potential subjects will be screen failures because individuals will be screened and enrolled 
on the same day. That is possible because most of the eligibility criteria will be previously reviewed during the 
prescreening process. The only screening test is the application of the Barthel Index, which will be done after verbal 
consent for screening at the time of the in-person interview for the study informed consent. At that time, the 
screening list will be complete, and the final decision of eligibility for enrollment will be taken before asking for 
informed consent for the study. Patients deemed ineligible during the interview will not be able to re-screen. 
5.4. Strategies for Retention 
The primary strategy to prevent dropout during the treatment phase is to keep frequent direct communication with 
the care team to schedule rs-fMRI #2 as soon as possible by the indicated time frame. 
The average SABI patient volume treated last 3 years at the NeuroICU and the PICU at UNC health was 1238 and 
109 patients/year respectively (via UNCH operation analyst), for which an adequate volume to cover enrollment is 
 

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expected. UNC health has previously enrolled MSABI patients on research and has all the necessary equipment and 
resources to complete the eligibility evaluations for this study.  
5.5.  Matching and Stratification 
In ICU patients with suppression of consciousness, we will use the routine care EEG to stratify patients into two 
groups, EEG+ and EEG- during the prescreening. EEG+ will be defined by either electrographic seizure, electroclinical 
seizure or ictal-interictal continuum as defined by the American clinical Neurophysiology Society's Standardized 
Critical Care EEG Terminology28, whereas EEG- will be lacking these features. EEG in this protocol does mean 
continuous video EEG, which is the stand of care for UNCH ICU patients. 
To select the patients for screening and enrollment, we will use a quota sampling strategy. Specifically, we will 
recruit eleven SzNET+ patients consecutively for each EEG+ and EEG- group. Once one of those group’s enrollment 
is complete, we will continue screening only patients from the EEG category that could be enrolled in the incomplete 
SzNET+ group.  
As this is a pilot study, including a wide range of age, the study design does not include matching.  
5.6.  Randomization  and  Concealment 
This is an open label, nonrandomized study.  Not applicable.   
5.7.  Blinding 
The Follow-up EEG will be assessed by an epileptologist blinded to rs-fMRI#2 results. Those results will not be posted 
in the medical records or commented with personnel outside the clinical rs-fMRI service until the follow up EEG and 
its comparison results should be collected. This blinding doesn’t need to be removed to reassure the patient SOC.   
 
 

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6. Treatment Design: Procedures 
Description   For this uncontrolled, open-label, interventional trial, the intervention will be assigned to all 
enrolled patients with SzNET+ by the first rs-fMRI. The intervention and its compliance criteria are defined as 
receiving treatment for three to ten complete days with at least two of the following ASM regimens, 
simultaneously:  
1. Phenobarbital 20 mg/kg intravenous loading dose 
2. Levetiracetam 60mg/kg intravenous loading dose 
3. Lacosamide 200 mg intravenous loading dose 
4. Valproate 30 mg/kg intravenous loading dose 
5. Fosphenytion 20 mg/kg intravenous loading dose 
 
All the maintenance dose regimens will start the next day to loading dose, and dosing wil be calculated for weight 
and age of both medications within the combination group, until the repeat rs-fMRI. As soon as possible, the 
research team will inform the care team that the patient has been allocated to the intervention branch so they can 
decide on two ASM regimens from the previous list to start the treatment. On the same day, the research team will 
confirm by medical charts the two ASM selected and the date and the time of the first loading dose infusions. The 
intervention phase takes the time between rs-fMRI#1 and follow-up rs-fMRI and EEG. The rs-fMRI#2 must be 
performed after at least three complete days of treatment and no later than eleven days after the beginning of the 
intervention phase, but in case of ASM withdrawal, the rs-fMRI#2 must be done no later than 72 hours from the 
last dose. As outcome measures are based on data collected the day of the second rs-fMRI, after that day, the care 
team will be free to adjust ASM according to what better fits the patient without compromising the protocol.  
The study’s main intervention option consists of the Phenobarbital and Levetiracetam regimens. However, the 
clinical team can select any combination of two or more ASM regimens from the list provided, for clinical reasons. 
On day two of intervention, the phenobarbital serum level will be measured if it was one of the selected 
medications, and a new loading dose will be given to aim for a serum level of 40mcg/ml.  
Participants with GCS 9 to 12 will not receive phenobarbital as one of the intervention anti-seizure medications 
(ASM), and the loading dose of one of the two selected ASMs will be omitted. For these participants the study’s 
main intervention option consists of the Levetiracetam and Lacosamide regimens, omitting the Lacosamide loading 
dose. 
 
Rs-fMRI schedule (Day 0-1 of Enrollment) 
 
Order Pre-Intervention research-related rs-fMRI#1 
Time from enrollment to intervention start (Days 1-6 of Enrollment) 
o Scan should be performed within 3 days from enrollment. 
o To undergo any study indicated rs-fMRI, the participant should not have been diagnosed with 
vasospasm based on their most recent transcranial Doppler examination, conducted within the 
last 3 days. 
o The time frame between fMRI scan and intervention start will range from 1 to 6 days. 
o Obtain (research driven) fMRI 
 
What is rs-fMRI 
 
MRI generates images based on the interaction of the body with potent 
electromagnetic fields. 
 
Rs-fMRI uses BOLD signal to identify vascular reflexes related to neuronal 
activation. 

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 
What is the process of transporting the patient to the fMRI? 
 
As SOC at UNC Health, a transport team made of two nurses, one fellow physician 
and one respiratory therapist gathers with the patients at ICU and checks to have 
the required equipment for transportation. 
 
The subject is transported by the transport team from the ICU to the MRI Scan 
within the hospital, located on the first floor or the basement of the same ICU 
building, according to the MRI scanner availability. 
 
Once the rs-fMRI scanning is acquired the transport team transports the subject 
back to the ICU. 
 
How long does the fMRI routinely last? 
 
Around 25 minutes for the scanning 
 
Variable transportation times, from ICU to scanner and from scanner to ICU 
 
What are the risks associated with the fMRI? 
 
Patients meeting eligibility criteria do not have risk of adverse events related to 
the electromagnetic fields 
 
Rs-fMRI does not require contrast agents to be administered. 
 
In case of tattoos with suspected high levels of ferromagnetic compounds cold 
compresses can be apply to prevent heating. 
 
Transportation through the hospital to perform the MRI scan can be associated 
with mechanical risks and support devices malfunction. Trained personnel is in 
charge of the process, which is supervised by a physician. 
 
o SzNET Stratification of rs-fMRI 
 
SzNET (-): with EEG (+) or EEG (-). 
 
N=32 
 
No protocol Intervention-driven, combined ASM is administered. 
 
They will not receive the second fMRI. 
 
They will only be followed at the 3 months post discharge visit if they are 
scheduled to one of the NSICU Post-Dischrage clinics. 
 
MRI scan transportation related AE Review. 
 
SzNET(+): with EEG(+). 
 
N=11 
 
Proceed with combined ASM Intervention. 
 
Intervention must start within 1 to 6 days after enrollment. 
 
AE Review. 
 
SzNET(+):with EEG(-) 
 
N=11 
 
Proceed with combined ASM Intervention. 
 
Intervention must start within 1 to 6 days after enrollment. 
 
AE Review. 
o Study team will inform the family of the rs-fMRI results and upload the official report to EPIC. 
Intervention start (Days 1-6 from Enrollment) 
• 
Clinical Care Team will choose the intervention regimen.  
o If participant was already on two of the protocol-approved ASM, the participant will be required 
to start the intervention by administering the protocol-driven loading dose infusions outlined for 

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each of the combined ASMs, or by administering the loading dose for any of the other 5 listed 
ASM options. A third option in this case is to administer protocol-driven loading dose of one of 
the current medications and add another of the 5 ASM loading dose and maintenance regimen. 
o If participant was already on one of the protocol-approved ASM, the participant will be required 
to start the intervention by administering the protocol-driven loading dose outlined for the ASM 
that the participant was previously receiving along with another protocol-driven ASM loading 
dose from the ones listed on the protocol. 
o If participant was not receiving any of the protocol approved ASM, the participant will be 
administered a loading dose of two of the 5 protocol approved ASM. 
o If the clinical care team does not want to use a combination of two of the 5 protocol-approved 
ASMs, they will not be enrolled into the study. 
• 
Reasearch Team will  
o Review adverse events 
o Review participant medical record to confirm which combined ASM was decided by the clinical 
care team and charge it into EPIC. 
o Document date and time of first intervention-related loading dose infusions. 
Maintenance Dose (Up to 3 to 10 Days from loading dose start) 
• 
Research Team will charge to EPIC the maintenance doses and verify ASM Administration. 
o The maintenance protocols must be administered for at least 72 hours from the start time of the 
loading dose infusion. 
o The MD can continue for up to 10 days while the second fMRI is trying to be scheduled and 
obtained. 
o The ASM can be continued beyond 10 days but would no longer be considered in the protocol-
driven intervention phase. 
o The Post-Intervention assessment scans can be obtained, even if the participant remains on ASM 
beyond the maintenance dose period. 
o To undergo any study indicated rs-fMRI, the participant should not have been diagnosed with 
vasospasm based on their most recent transcranial Doppler examination, conducted within the 
last 3 days. 
o If one of the combined doses administered is phenobarbital 
 
On Day 2 of the MD:  
 
Specimen Collection (phenobarbital serum level  UNC Hospitals Test ID LAB30) will 
be ordered by the research team. 
 
The research team reconvenes the maintenance dosing with the medical care 
team to aim for a level of 40mcg/ml. 
o Review any AEs associated with ASM 
o Review Dropout data (if applicable) 
• 
Medical Care Team will decide if the patient continues with the study’s antiseizure medication regimens. 
In this case, they will continue to provide the medication, and thepatient will be responsible for expenses. 
 
Acquisition, storage and preparation:   The present study does not employ experimental compounds, all the 
medications related to the study follow the same standard Storage rules of the medications regularly used at the 
ICUs of UNCH.      

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Administration: IV and enteral administration with infusion times and observation according to the internal 
protocols for each medication at the patient’s corresponding ICU. 
Rescue Procedures/Medications    
• 
If emergent adjustments to the treatment plan are needed those will be decided by the care team. 
• 
Administration of additional ASM to the study intervention is allowed as determined by the clinical team.  
Adherence Monitoring/Evaluations   the intervention’s ASM timing and dosing will be checked from the 
medical charts. On day two, the phenobarbital serum level will be measured if it was one of the selected 
medications, and a new loading dose will be given to aim for a serum level of 40mcg/ml.    
Concomitant Therapies   There are no prohibited or recommended concomitant therapies. Calcium channel 
blockers must be used with precaution when administering some of the protocol ASM (see appendix B & E).   
Follow-up tests (Days 3-13 from Start of Loading Dose) 
• 
Order Post-Intervention research-related rs-fMRI (#2) 
o 
Scan must be performed after completing a minimum of 72h of intervention ASM protocol (including 
loading and maintenance doses). 
o 
Scan must be completed within 72hrs of last intervention ASM dose. 
o To undergo any study indicated rs-fMRI, the participant should not have been diagnosed with 
vasospasm based on their most recent transcranial Doppler examination, conducted within the 
last 3 days. 
o 
Post scan, the participant can continue on their current ASM regimen or be changed based on 
routine clinical care decisions. 
o 
The official results repport will be uploaded to EPIC after the post-intervention research-related EEG 
has been reported. 
o 
AE Review:  
o 
Review Dropout data (if applicable) 
o 
Collect GCS Score  
• 
Obtain Post-Intervention research-related EEG 
o 
EEG characteristics 
 
The EEG is a non-invasive medical test with very low risk of adverse events. Very rare 
complications could be associated with skin reactions to the conducting material used for 
the electrodes and malfunction of the device.  
 
Bedside monitoring. 
 
Minimum 1 hour run.  
 
Without Photostimulation. 
o 
EEG recording must be obtained within 72hrs of last intervention ASM dose. 
o 
Post the EEG, the participant can continue on their current ASM regimen or be changed based on 
routine clinical care decisions. 
o 
EEG will be reviewed by a blinded epileptologist for rs-fMRI (#2) results. 
o 
For ethical reasons the results will be shared with the care team. 
    

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7. Schedule of Activities and Procedures 
7.1. Table of Events 
 
Procedure 
ICU 
Range days 
Since 
MSABI 
event 
(-1 to -90) 
prescreening 
Screening/Enrollment 
interview 
(Must be stable to 
transport and scan) 
 
Study 
baseline 
(Time 
frame from 
enrollment, 
1 to 3 days) 
Intervention 
Phase 
Between rs-
fMRI #1&#2 
(Time frame 
from 
enrollment, 
1 to 16 days) 
Follow up 
Studies 
RANGE 
study day: 
Between 
3th to 13th 
of the 
intervention 
start 
(Time frame 
from 
enrollment, 
3 to 19 
days) 
One of 
the 
NSICU 
Post-
Dischrage 
clinics 
At 
3 
Months 
from 
discharge 
Recruitment 
Eligibility 
assessments by 
medical chart review 
X 
X 
 
 
 
 
Informed consent 
 
X 
 
 
 
 
Enrollment and rs-
fMRI Schedule 
 
X 
 
 
 
 
Allocation 
 
 
X 
 
 
 
Patient or 
LAR surveys 
BIS Pre-MSABI 
 
X 
 
 
 
X 
NDDI-E 
 
 
 
 
 
X 
PROMIS emot. Dist. -
Anxiety – Short form 
 
 
 
 
 
X 
Liverpool AEP 
 
 
 
 
 
X 
QOLIE-10-P 
 
 
 
 
 
X 
MoCA 
 
 
 
 
 
X 
Treatment 
Study protocol 
treatment 
 
 
 
X* 
 
 
Standard care 
treatment 
X 
X 
X 
X 
X 
X 
Physical  
Exams 
Glasgow Coma Scale 
X 
X 
X 
 
X* 
 
Neurological exam  
 
 
 
 
 
X 
Safety 
Monitoring 
Review of adverse 
events reported. 
 
 
 
X 
X* 
 
Clinical 
tests 
Pregnancy test  
X 
 
 
 
 
 
Surface EEG 
X 
 
 
 
 
 
Research 
tests 
Rs-fMRI  
 
 
X 
 
X* 
 
Follow-up EEG 
 
 
 
 
X* 
 
Phenobarbital serum 
levels 
 
 
 
X* 
 
 
*Activities including only SzNET + patiens. 
7.2.  Screening 
Patients meeting eligibility criteria will be followed by the research personnel to check with the care team the time 
when the clinical condition of the patient is stable enough to be transported, and MRI scanned. The communication 
between the research team and the care team will be telephonic. Once the care team accepts and informs that the 
patient can be screened, the study personnel will check the compliance with inclusion/exclusion criteria listed, call 
the Patient’s family or LAR to inform them about the study and will ask for verbal informed consent to screen the 

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patient. If the family agrees, the study personnel will schedule the screening/enrollment interview as soon as 
possible. 
Prescreening Assessments Activities (days -90 to -1): The research team will only perform medical chart review of 
the patients that have an EEG requested. 
• 
Assessing for an ordered clinical care EEG. 
 
2HELPS2B Assessment reviewed from the baseline EEG. 
 
Stratification of Pre-Screening EEG Data (retrieved from medical record review). 
• 
EEG(+): had a presence of electrographic seizure, electroclinical seizure or ictal-
interictal continuum. 
• 
EEG(-): was negative for electrographic seizure, electroclinical seizure or ictal-
interictal continuum. 
 
• 
Medical chart review: Presumed etiologies of disorder of consciousness, Epilepsy antecedent, other co-
morbidities list, current spontaneous ventilation, height, weight, BMI, BSA, age, sex, pregnancy condition, 
supratentorial decompressive craniectomy, GCS score and current neurological responsiveness. 
• 
Contacting care team to ask for clinical stability to MRI scan and authorization to contact the LAR.  
 
Contacting the LAR to obtain verbal consent to administer the BIA. 
 
Screening/enrollment interview (Day 0) 
The screening will involve the in-person interview time period because the Barthel Index score is an additional test 
required to determine study eligibility. Thus, screening and enrollment will be performed on the same day, which 
is essential to reduce drop out during the screening period because the clinical state of these patients varies day by 
day. This strategy is also designed to reduce the anxiety of the families/LAR. The time frame to schedule the 
screening/enrollment interview after the phone call is flexible only to the extent that it must still meet the max 90 
days enrollment deadline from MSABI. That means the available time to schedule the interview depends on the 
time since MSABI started, to meet the eligibility criteria. On the day of the telephonically scheduled interview with 
the LAR, the eligibility criteria by medical chart review will be double checked before the interview. If the patient is 
still eligible, the meeting will proceed. After presenting the study and its purpose, the study personnel will complete 
the Barthel Index (see appendix A) with the help of the LAR. If the score does not exclude the patient, the 
interviewer will explain potential risks and benefits and ask for consent for the study.        
7.3. Enrollment  
Once informed consent is obtained and the patient is enrolled, the coordinator will double-check previous history 
of porphyria, allergies, and hypersensitivity to the potential ASM listed in the study to provide a list of the treatment 
protocols that could be used for the patient if allocated to intervention. On the same day, the study coordinator 
will schedule the rs-fMRI for the following days and inform the research and the care teams of the scheduled date. 
This date should be within three days at maximum, and the intervention allocation must be done within six days 
from enrollment. Considering those dates, the minimum and maximum times from MSABI to the first rs-fMRI are 
4, and 48 days correspondingly. The minimum and maximum times from MSABI to the intervention are 5 and 51 
days, correspondingly. The family will be told that all the rs-fMRI results will be provided and explained after the 
follow-up research tests, and no further instructions are needed.   
Screening/enrollment interview Activities (Day 0) 
• 
BIS assessment for score (>80) through interview with potential LAR. 
• 
Written Informed Consent Obtained from LAR. 

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o Consent must be obtained within 90 days from the participant’s MSABI. 
o Confirming baseline variables are collected through medical chart review. 
 
Supratentorial decompressive craniectomy, current GCS score, presence of spontaneous 
ventilation. 
o Verify with the LAR about: porphyria, co-morbidities, medical implants or contraindications for MRI, 
allergies, and hypersensitivity to the potential ASM. 
o Provide a list of the treatment ASMs recommended for this participant that could be used if 
allocated to intervention. 
 
• 
Notify Clinical Team about participant enrollment. 
o Verify with study team about which 2 combined ASMs could be administered in case of allocation 
to treatment. 
1. Phenobarbital 20 mg/kg loading dose 
2. Levetiracetam 60mg/kg loading dose 
3. Lacosamide 10 mg/kg loading dose 
4. Valproate 30 mg/kg loading dose 
5. Fosphenytion 20 mg/kg loading dose 
       
7.4.  Study Visits 
This study is designed for in-hospital patients; no additional research team visits are planned. Clinical information 
after enrollment will be collected from medical charts (Glasgow coma score at the rs-fMRI#2 day), and the last data 
collection date at the outpatient clinic will be collected from medical records from the subjects that were discharged 
alive on ASM and scheduled to follow-up by one of the NSICU Post-Dischrage clinics. That visit is described under 
the next final visit section No. 7.5.  For details about the in-hospital research activities visit Treatment Design section 
No. 6.     
7.5. Final Visit 
3 Months Post Day of Hospital Discharge 
• 
Patients who are discharged will be seen in one of the NSICU Post-Dischrage clinics.  
• 
The visits are scheduled at 3 months after hospital discharge. 
• 
This visit is not scheduled by the research staff, and its information will only be obtained through medical 
chart review. 
• 
The scales that are performed in patients that are seen in one of the NSICU Post-Dischrage clinics will 
evaluate functional, cognitive, and behavioral/psychiatric outcomes:  
o ASM toxicity: Liverpool adverse event profile test (LAEP) – If the patient is on ASM36,37 
o Cognitive outcome: Telephonic Montreal Cognitive Assessment (T-MoCA- 5mins protocol)38 
o Anxiety: PROMIS Emotional Distress—Anxiety— Short Form39 
o Depression: Neurological Disorders Depression Inventory for Epilepsy (NNDI-E)40 
o Quality of Life: QOLIE-10-P41  
 
 
7.6.  Phone Contacts  
Not applicable.       
    

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7.7.  Follow-Up Contact  
The subjects will continue follow-up by their care team as appropriate, no research follow up subject visit is required 
beyond the 3-month from hospital discharge NSICU Post-Dischrage clinic visit listed in section 7.5.           
7.8.  Early Discontinuations 
Data to be Collected   The care team may adjust the treatment plan of all patients to ensure optimal medical 
management, including the study intervention. Patients who do not meet the treatment criteria (which requires 
treatment with two of the ASM regimens specified in the protocol for at least 72h from loading dose) or who are 
unable to undergo the rs-fMRI#2 after completing the minimum intervention time and within 72 hours of their last 
dose of the intervention protocol will be considered dropouts. For these patients, only the clinical data available at 
the time of enrollment and their initial rs-fMRI data will be collected for analysis of aim #2. However, this data 
cannot be used for other outcomes analysis. Nonetheless, we will still collect information about the reason for 
dropping out and any reported adverse events.  
Subjects missing follow-up after rs-fMRI#2 and repeat EEG are performed will have all the study data already 
collected except for the data asked at one of the NSICU Post-Dischrage clinics for exploratory outcomes.        
Criteria for Intervention Discontinuation    
• 
Changes in the medical condition that contraindicate the use of at least two of the medications mentioned 
in the valid intervention list.  
• 
Developing a medical condition that does not allow the rs-fMRI#2 scan. 
• 
Presenting a grade 4 AE. 
• 
Presenting a grade 2 to 3 AE without adequate measures to solve the event and prevent its study-related 
recurrence. 
Requiring more aggressive ASM treatment because of seizures worsening or the need to change one ASM from the 
protocol list for another listed ASM is allowed.  
7.9. Enrollees May Drop Out 
Participants and/or their LARs may voluntarily withdraw from participation at any time, for any reason, with no 
penalty or loss of rights, or indicated treatment. The reasons for drop-out and missing data will be documented in 
the database. Drop-out from the study during the intervention phase will probably not imply patients leaving the 
hospital because of the intervention's short time frame and the target population's characteristic clinical condition. 
For those cases, we will schedule a personal interview between the research team and the LAR to solve doubts if 
the LAR accept by phone call. No efforts will be made to follow up with patients who drop out after the follow-up 
tests were taken because, after that time, the data collected is not relevant for the major outcomes of interest.    
8. Statistical Analysis Plans 
8.1. Strategies that Apply to all the Aims 
All statistical procedures will be performed in SAS and R. Biostatistician Dr. Hongtu Zhu will oversee all data 
analyses.  
(i) 
All data will be scored and rescored by separate staff members and checked for accuracy prior to double 
entry into our database. All datasets are backed up daily. 

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(ii) 
Prior to statistical modeling, we will perform descriptive analyses and data visualizations to examine 
the distributions of all measures. Appropriate transformations to obtain approximate normality will be 
performed; where necessary, additional nonparametric tests will confirm results.   
(iii) 
 Linear regression model and nonparametric tests (e.g., Wilcoxon rank sum test) will be the primary 
analytic tools for testing our a priori hypotheses. Model selection methods (e.g., Bayesian information 
criterion) and sensitivity analysis methods will be used to select models and assess various model 
assumptions. We will consider the use of appropriate covariates as detailed below in all aims.  
(iv) 
We will record the reasons for drop-outs, missing / censored data values, and protocol departures in 
the database.  We will appropriately handle drop-outs and missing data (e.g., missing responses and/or 
covariates) by using imputation or other estimation methods (e.g., missing completely at random), 
while considering anticipated causes. We will carry out sensitivity analysis to evaluate different missing 
mechanisms.  
(v) 
We will use test statistics (e.g., likelihood ratio test) to test the hypotheses. To identify significant 
component terms in each of the models, we will examine the parameter estimates, 95% confidence 
intervals, and p-values of the component terms in an analysis of fixed effects for the final regression 
models.  All statistical estimates of population parameters will be tabulated along with corresponding 
confidence intervals (CIs) and/or standard errors (SEs) to convey levels of precision / imprecision.  
We will use graphical methods such as forest plots to visualize the analysis results.  We will also include outcome-
dependent exploratory analyses to generate new hypotheses.       
 
     
8.2.  Sample Description 
We will use graphical figures (e.g., forest plots with tabulations, scatter plots, histograms, box-and-whisker plots, 
etc.) and descriptive statistical methods to describe the sample of individuals studied; they include graphical 
figures, counts, frequencies, sample means, sample standard deviations, percentiles, min, max, and standardized 
differences.      
We will compare SzNET+/EEG+ with SzNET+/EEG- in terms of baseline/pre-treatment characteristics.  
 
8.3.  Aim-Specific Plans 
Plans for Aim 1. 
Aim 1 is to obtain preliminary data about the degree of improvement of seizure networks (SzNET) in moderate to 
severe acute brain injury (MSABI) patients after intervention’s antiseizure medication (ASM).  
 
Aim 1a 
 
Measure the improvement of the SzNET total volume in MSABI patients after the intervention’s ASM. The 
primary outcome of interest is the SzNET total volume median before and after the intervention’s ASM in the 
target population. 
 
H0: there will be no difference in the SzNET total volume median in MSABI patients before and after the 
intervention’s ASM.  
H1: SzNET total volume median in MSABI patients before ASM will be smaller than after the intervention’s ASM. 
 
 
Aim 1b 
 
Measure the improvement of the SzNET power spectrum in MSABI patients after ASM. The outcome of 
interest is the SzNET power spectrum median before and after ASM in the target population. 
 

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H0: there will be no difference in the SzNET power spectrum median in MSABI patients before and after the 
intervention’s ASM.  
H1: SzNET power spectrum median in MSABI patients before ASM will be higher than after ASM. 
 
We plan to recruit 11 patients with SzNET+EEG+ and 11 subjects with SzNET+EEG-. Therefore, 22 subjects with 
measurements before and after the intervention’s ASM will be used in Aims 1a and 1b.  We will fit linear regression 
models with dependent variables as follows.  We calculate the changes of the SzNET total volume and the SzNET 
power spectrum before and after the intervention’s  ASM and use them as the primary dependent variables. Due 
to the small number of subjects, we only include an intercept to represent the mean difference before and after 
the intervention’s ASM in the model, and we use the t-test statistic to test whether the intercept is equal to zero 
for Aims 1a and 1b. Moreover, we may consider demographic variables and pre-intervention EEG status (EEG+ or 
EEG-) if necessary. 
 
Plans for Aim 2.  
Estimate the frequency of EEG- and EEG+ patients presenting SzNET. The outcomes of interest are the proportions 
and differences of proportions of patients with SzNET among EEG- and EEG+ patients in this clinical setting.  
For aim 2, we sequentially recruit SzNET+ subjects until the number of subjects in either SzNET+EEG+ or SzNET+EEG- 
first reaches 11 subjects. We will calculate the proportions of patients with SzNET among EEG- and EEG+ patients. 
and use the two-proportion Z-test to test their difference.   
 
Plans for Aim 3.  
Investigate association between post-intervention EEG improvement and SzNET response. The outcome of interest 
is the relative risk of EEG improvement in patients with more than 50% improvement of their SzNET by TVR and 
PSI.  
 
H0: there will be no difference in the EEG improvement between the patients with and without more than 50% 
improvement of their SzNET.  
H1: EEG improvement will be greater in the patients with more than 50% of SzNET improvement. 
 
There are 22 subjects used in Aim 3. We will fit logistic regression model to characterize the association between the 
EEG improvement with the patients with and without more than 50% improvement of either PSI or TVR. We will use 
the Wald test and likelihood ratio test statistics to test the null and alternative hypotheses.  
 
Plans for Aim 4.  
Investigate association between the post-intervention typical resting state networks (RSN) connectivity 
improvement and the SzNET response. The outcome of interest is the relative risk of improvement of the typical 
RSN in the patients with more than 50% of improvement of their SzNET by TVR and PSI.  
 
H0: there will be no difference in the typical resting state networks connectivity improvement between the patient 
with and without more than 50% improvement of their SzNET.  
H1: Median typical resting state networks connectivity improvement will be greater in the patients with more than 
50% of SzNET improvement. 
 
There are 22 subjects used in Aim 4.  We will fit logistic regression model to correlate the RSN improvement with 
the patients with and without more than 50% improvement of either PSI or TVR and use the Wald test and likelihood 
ratio statistics to test the null and alternative hypotheses.  
 
Plans for Aim 5.   

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Describe psychosocial functional measure outcomes and ambulatory ASM toxicity at 3 months from discharge.  The 
outcomes of interest will be the PROMIS Emotional Distress—Anxiety— Short Form, the Neurological Disorders 
Depression Inventory for Epilepsy (NNDI-E), the QOLIE-10-P, the Telephonic Montreal Cognitive Assessment, and 
the Liverpool adverse event profile test. All will be assessed at the 3 month follow-up visit to one of the NSICU Post-
Dischrage clinics. 
 
Plans for Aim 6. 
Aim 6 is to assess the trial's design feasibility success in enrollment and retention by evaluating the enrollment rate 
and dropout rate among participants at the end of the trial.  
 
Aim 6a 
 
Measure the enrollment during all the months of study enrollment. The primary outcome of interest is 
the rate of monthly enrolled patients. 
 
Aim 6b 
 
Measure the participants dropout among participants during the study. The primary outcome of interest 
is the dropout rate among the total number of enrolled participants at the end of the study. 
 
 
We will calculate the summary statistics of these measurements.  
8.4.  Planned Interim Analyses 
No interim analyses will be performed.  
9. Sample Size Rationale 
 
There is no preliminary data for effect size estimation using the paradigm and patient population suggested in this 
study. In Aim 1, a paired t-test is used to test measurement differences before and after ASM.  A effect size 0.806 
can be detected for a 1-sided test at a power of 80% and a Type I error at 0.05 with the total of 11 subjects before 
and after  ASM.  In Aim 4, a transformed Z-test is used to test correlation between two variables.  A correlation size 
0.506 can be detected for a 1-sided test at a power of 80% and a Type I error at 0.05 with the total of 22 subjects. 
10. Data Capture and Database Management 
10.1. Software for Data Capture 
The study personnel will enter the study data into a REDCap spreadsheet.  REDCap is a HiPAA-compliant data 
capture system provided by the NC TraCS Institute at UNC. The data system includes password protection and 
internal quality checks, such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate.  Study data will be entered directly from the medical chart, Rs-fMRI report, Core Disease CRF (appendix 
G) and one of the NSICU Post-Dischrage clinics forms (appendix H, I, J, K, L). 
  
10.2. Responsibilities for Data Capture and Database Management 
Data collection is the responsibility of the research staff at the site under the supervision of the PI. The PI is 
responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. The study 

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coordinator or the coinvestigators that performs the consent interview will be responsible of interrogating the 
premorbid Barthel Index, initial filling up the Core Disease CRF and give it to the research staff to collect those data 
into the database.  
 
All source documents will be completed in a neat, legible manner to ensure accurate interpretation of data.   
Data recorded in the electronic case report form (eCRF) derived from source documents should be consistent with 
the data recorded on the source documents.  
 
Clinical data including adverse events (AEs), concomitant medications, and expected adverse reactions data) and 
research test data will be entered into REDCap, a HiPAA compliant data capture system provided by the NC TraCS. 
The data system includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered directly from the 
source documents. 
 
10.3. Study Records Retention 
Study documents should be retained until at least 5 years have elapsed since the formal discontinuation of clinical 
development of the study intervention. These documents should be retained for a longer period, however, if 
required by local regulations. No records will be destroyed without the written consent of the UNC Neurology 
Department and the Director of the UNC Clinical Resting State fMRI service.  
 
11. Collection and Management of Tissue Specimens 
11.1. Use in Current and Future Studies 
If one of the combined doses administered is phenobarbital, on Day 2 the MD a blood sample will be collected for 
phenobarbital serum level (UNC Hospitals Test ID LAB30) to adjust the phenobarbital dose, aiming for a serum 
concentration of 40mcg/ml. The specimen collection will be ordered by the research team. 
11.2. Sample Preparation 
For thePhenobarbital serum levels measure  2 mL of blood are withdrawn by corresponding ICU nurse personnel 
from a central or arterial line using aseptic technic. If no adequate lines in place are available, the blood is 
acquired by phlebotomy performed by lab personnel. Immediately after withdrawal the blood is stored in a royal 
blue top tube or plain red top tube (no gel). After proper labeling with the research subjects MRN, it is 
transported at room temperature to the Core Laboratory for spin within 4 hours and further processing. 
11.3. Record Keeping and Monitoring 
The results will be informed and kept as regular tests done for clinical purposes. The results will not be stored by 
the research team, but will be used for safety purposes to provide a one time feedback to the care team in order 
to adjust dosing if deemed necessary.  
11.4. Storage and Security 
The sample will be stored, processed and discarded according to the usual standard procedures of UNC health 
Hem Onc Laboratory. It will not be kept for future research purposes.     

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12. Safety Monitoring and Management 
12.1.  Risk / Benefit Assessment 
No psychological, social, legal or economic risks are anticipated with the study for the patients or the community.  
Main Potential Risks (Based on frequency and severity): 
Potential Risks: Physical risk of accidents during transportation to MRI scanner and scanning time. 
This includes but is not limited to intravenous access displacements, falls, contusions, mechanical ventilation 
decoupling or displacement of medical devices.   
Frequency: Uncommon to Rare. 
Severity: Mild to severe, being rare the severe ones. 
This risk is reduced by transport monitoring and care by a fellow physician, one respiratory therapist and two 
nurses. Enough clinical stability to transport to MRI scan by care team criteria is required.   
Potential Benefits: For the individual participant the information acquired from the MRI scan can help guide 
treatment and can also provide useful information for neuro-prognostication. It also is the exam that defines 
the classification into intervention and no intervention groups. 
 
 
Phenobarbital 
Potential Risks: Physical risk of unknown hypersensitivity or unexpected reaction.  
This includes non-dose dependent reactions like serious dermatologic reactions or drug reactions with 
eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity, and dose dependent adverse 
effects presented while on the adequate range for age and weight like prolongation of QT. 
Electrocardiographic monitoring is standard of care for the ICU patients, which improves the safety of this 
drug use. Patients with porphyria will not be allocated to treatment with phenobarbital. Sedation or 
ventilatory depression by Phenobarbital are not relevant risks in this study because it would only be 
administered to patients that require ventilatory support. The risk of abuse and dependence on Phenobarbital 
is associated with use for prolonged periods of time so it also is not going to be considered. 
Frequency of dermatologic reactions or hypersensitivity: Rare. 
Severity: Mild to severe, being rare the severe ones. 
Source: FDA labeling (appendix E) 
 
Potential Benefits: As the rationale of this study explains, this medication could improve the control over 
epileptogenic activity, improving normal brain connectivity and clinical outcome, and in the context of the 
present study, will be administered to patients with abnormal resting state networks that are suspected of 
having an epileptogenic correlate. The available alternative options in the current clinical practice for MSABI 
patients with persistent consciousness compromise, risk of epileptogenic activity, and no 
electroencephalographic indication of increasing the ASM in their treatments are: 
1. Wait for the clinical evolution assuming there is no additional benefit for stronger ASM and 
consciousness compromise is not related to the epileptogenic activity. 
2. Increase the ASM regimen strength to test the hypothesis that epileptogenic activity might be 
involved in the consciousness compromise.  
Levetiracetam 
Potential Risks: Physical risk of unknown hyper sensibility or unexpected reaction.  
This includes non-dose dependent reactions like serious dermatologic reactions or drug reactions with 
eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity, and dose dependent adverse effects 
presented while on adequate range for age and weight like hematologic abnormalities. 
Frequency of dermatologic reactions or hypersensitivity: Rare. 
Severity: Mild to severe, being rare the severe ones. 

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Source: FDA labeling (appendix D)  
Potential Benefits: As the rationale of this study explains, this medication could improve the control over 
epileptogenic activity, improving normal brain connectivity and clinical outcome, and in the context of the 
present study, will be administered to patients with abnormal resting state networks that are suspected of 
having an epileptogenic correlate. The available alternative options in the current clinical practice for MSABI 
patients  with persistent consciousness compromise, risk of epileptogenic activity, and no 
electroencephalographic indication of increasing the ASM in their treatments are: 
1. Wait for the clinical evolution assuming there is no additional benefit for stronger ASM and 
consciousness compromise is not related to the epileptogenic activity. 
2. Increase the ASM regimen strength to test the hypothesis that epileptogenic activity might be 
involved in the consciousness compromise.  
Lacosamide 
Potential Risks: Physical risk of unknown hyper sensibility or unexpected reaction.  
This includes non-dose dependent reactions like serious dermatologic reactions or drug reactions with 
eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity, and dose dependent adverse 
effects presented while the on adequate range for age and weight like cardiac rhythm and conduction 
abnormalities. 
Frequency of dermatologic reactions or hypersensitivity: Rare. 
Severity: Mild to severe, being rare the severe ones. 
Source: FDA labeling (appendix C)  
 Potential Benefits: As the rationale of this study explains, this medication could improve the control over 
epileptogenic activity, improving normal brain connectivity and clinical outcome, and in the context of the 
present study, will be administered to patients with abnormal resting state networks that are suspected of 
having an epileptogenic correlate. The available alternative options in the current clinical practice for MSABI 
patients with persistent consciousness compromise, risk of epileptogenic activity, and no 
electroencephalographic indication of increasing the ASM in their treatments are: 
1. Wait for the clinical evolution assuming there is no additional benefit for stronger ASM and 
consciousness compromise is not related to the epileptogenic activity. 
2. Increase the ASM regimen strength to test the hypothesis that epileptogenic activity might be 
involved in the consciousness compromise. 
Valproate 
Potential Risks: Physical risk of unknown hyper sensibility or unexpected reaction.  
This includes non-dose dependent reactions like serious dermatologic reactions or drug reactions with 
eosinophilia and systemic symptoms (DRESS)/multiorgan hypersensitivity, and dose dependent adverse 
effects presented while on the adequate range for age and weight like Hepatotoxicity and pancreatitis. 
Frequency of dermatologic reactions or hypersensitivity: Rare. 
Severity: Mild to severe, being rare the severe ones. 
Source: FDA labeling (appendix F)  
 Potential Benefits: As the rationale of this study explains, this medication could improve the control over 
epileptogenic activity, improving normal brain connectivity and clinical outcome, and in the context of the 
present study, will be administered to patients with abnormal resting state networks that are suspected of 
having an epileptogenic correlate. The available alternative options in the current clinical practice for MSABI 
patients  with persistent consciousness compromise, risk of epileptogenic activity, and no 
electroencephalographic indication of increasing the ASM in their treatments are: 
1. Wait for the clinical evolution assuming there is no additional benefit for stronger ASM and 
consciousness compromise is not related to the epileptogenic activity. 
2. Increase the ASM regimen strength to test the hypothesis that epileptogenic activity might be 
involved in the consciousness compromise. 
Fosphenytoin 

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Potential Risks: Physical risk of unknown hyper sensibility or unexpected reaction.  
This includes non-dose dependent reactions like serious dermatologic reactions or drug reactions with 
eosinophilia systemic symptoms (DRESS)/multiorgan hypersensitivity, and administration rate dependent 
adverse effects like cardiac arrythmias. Hematologic complications and local toxicity have been reported. It 
will not be administered in patients with porphyria. 
Frequency of dermatologic reactions or hypersensitivity: Rare. 
Severity: Mild to severe, being rare the severe ones. 
 
Frequency of cardiac arrhythmia: rare at infusion rates of 150 mg phenytoin sodium equivalents (PE) per 
minute in adults and 2 mg PE/kg/min (or150 mg PE/min, whichever is slower) in pediatric patients. 
Severity: Can be severe.  
Source: FDA labeling (appendix B)  
 Potential Benefits: As the rationale of this study explains, this medication could improve the control over 
epileptogenic activity, improving normal brain connectivity and clinical outcome, and in the context of the 
present study, will be administered to patients with abnormal resting state networks that are suspected of 
having an epileptogenic correlate. The available alternative options in the current clinical practice for MSABI 
patients with persistent consciousness compromise, risk of epileptogenic activity, and no 
electroencephalographic indication of increasing the ASM in their treatments are: 
1. Wait for the clinical evolution assuming there is no additional benefit for stronger ASM and 
consciousness compromise is not related to the epileptogenic activity. 
2. Increase the ASM regimen strength to test the hypothesis that epileptogenic activity might be 
involved in the consciousness compromise. 
 
The comprehensive mention of additional recognized AE related to the ASM listed on the protocol is included 
under section 12.3, “Grading the Severity of Adverse Events and Events of ‘Special Interest’”. 
 
12.2. Assessment of Safety 
The present study includes vulnerable populations unable to give consent which is addressed by LAR’s 
informed consenting process. It does not involve experimental drugs and employs clinical safety measures to 
prevent complications during the transport and scanning of the patients. Nonetheless the potential AE of 
diagnostic procedures and the ASM used for the intervention will be assessed by the following strategies: 
• 
Eligibility criteria that imply checking for hypersensitivity or contraindications to the treatment protocol 
options that could be selected as the patient’s intervention. A selection of the non-contraindicated list of 
ASM for potential intervention use since the enrollment time reinforces this approach.  
• 
Clinically indicated routine blood cells count, hepatic function, and renal function. 
• 
Implementation of the clinical monitoring plan. 
• 
Frequent direct communication between the care team and the research team. 
• 
Severe adverse events (SAE) in enrolled subjects will pause the trial enrollment. 
• 
The Independent Safety Monitor (ISM) will classify and report the AE. He will decide in which cases a 
meeting with the research or the care teams is needed for that task, and the assistants to the meeting. In 
case of mild to moderate adverse events found to be related, the research personnel will present a 
mitigating strategy. In the case of a SAE, the ISM will decide the conditions required to resume the trial or 
study end. 
• 
Collection and analysis of safety variables to reassure and evaluate AE non-repetition strategies. 
As criteria for individual research stopping, SAE will lead to retirement from the study as well as grade 2 to 3 
AE without adequate measures to solve the event and prevent its study-related recurrence. Other events that 

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render the subject non-compliant with the enrollment criteria such brain death will retire the patient even if 
their occurrence was not triggered by the research activities. 
 
12.3. Unanticipated Problems, Adverse Events, Serious Adverse Events 
Unanticipated Problems: An unanticipated problem is any incident, experience or outcome that meets all 
three Office for Human Research Protections (OHRP) criteria (1) unexpected (in severity, specificity, 
frequency, or nature), (2) related or possibly related to the research, and (3) indicates that subjects or others 
are at a greater risk of physical, psychological, economic, legal, or social harm, as defined in UNC Office of 
human Research Ethics SOP. 
 
Adverse Event (AE) Definitions: Any untoward or unfavorable occurrence in a human subject, including any 
abnormal sign (for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the transportation and scanning time for the rs-fMRI#1 or rs-fMRI #2, or with the 
administration of one of the ASM listed as possible treatment protocol during the intervention phase, 
whether or not considered related to the subject’s participation in the research.    
 
Serious Adverse Events (SAE) Definition: Adverse event or suspected adverse reaction which is considered 
“serious” if, in the view of either the research team or the Neurology department, it results in any of the 
following outcomes:  
 
• 
Death   
• 
A life-threatening adverse event   
• 
Prolongation of existing hospitalization, a persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions.  
• 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include severe dermatological reactions or 
blood dyscrasias.     
 
Grading the Severity of Adverse Events and Events of ‘Special Interest’: AE non classified as unrelated will  be 
classified according to the Common Terminology Criteria for Adverse Events (CTCAE) scale v5.0 (appendix M) 
as follows:    
 
Phenobarbital 
Respiratory, thoracic and mediastinal disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 

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Respiratory, 
thoracic and 
mediastinal 
disorders - 
Other, 
specify 
Asymptomatic 
or mild 
symptoms; 
clinical or 
diagnostic 
observations 
only; 
intervention not 
indicated  
Moderate; 
minimal, local or 
noninvasive 
intervention 
indicated; 
limiting age-
appropriate 
instrumental 
ADL 
Severe or medically 
significant but not 
immediately life-
threatening; 
hospitalization or 
prolongation of 
existing 
hospitalization 
indicated; limiting 
self-care ADL  
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
 
Skin and subcutaneous tissue disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Stevens-
Johnson 
syndrome 
- 
- 
Skin sloughing 
covering <10% 
BSA with 
associated 
signs (e.g., 
erythema, 
purpura, 
epidermal 
detachment, 
and mucous 
membrane 
detachment) 
Skin sloughing 
covering 10 - 
30% BSA with 
associated 
signs (e.g., 
erythema, 
purpura, 
epidermal 
detachment 
and mucous 
membrane 
detachment) 
Death 
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The 
syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes.   
Toxic 
epidermal 
necrolysis  
- 
- 
- 
Skin sloughing 
covering 
>=30% BSA 
with associated 
symptoms 
(e.g., 
erythema, 
purpura, or 
epidermal 
detachment)  
Death 
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The 
syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes.   
 
General disorders and administration site conditions 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Edema face 
Localized facial 
edema 
Moderate 
localized facial 
edema; limiting 
instrumental 
ADL 
Severe 
swelling; 
limiting self-
care ADL 
  
  

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Definition: A disorder characterized by swelling due to excessive fluid accumulation in facial 
tissues. 
Edema limbs 
5 - 10% inter-
limb 
discrepancy in 
volume or 
circumference 
at point of 
greatest visible 
difference; 
swelling or 
obscuration of 
anatomic 
architecture on 
close inspection 
>10 - 30% inter-
limb 
discrepancy in 
volume or 
circumference 
at point of 
greatest visible 
difference; 
readily 
apparent 
obscuration of 
anatomic 
architecture; 
obliteration of 
skin folds; 
readily 
apparent 
deviation from 
normal 
anatomic 
contour; 
limiting 
instrumental 
ADL 
>30% inter-
limb 
discrepancy 
in volume; 
gross 
deviation 
from normal 
anatomic 
contour; 
limiting self-
care ADL 
  
  
Definition: A disorder characterized by swelling due to excessive fluid accumulation in the 
upper or lower extremities. 
Fever 
38.0 - 39.0 
degrees C 
(100.4 - 102.2 
degrees F) 
>39.0 - 40.0 
degrees C 
(102.3 - 104.0 
degrees F) 
>40.0 
degrees C 
(>104.0 
degrees F) 
for <=24 hrs 
>40.0 degrees C 
(>104.0 degrees 
F) for >24 hrs 
Death 
Definition: A disorder characterized by elevation of the body's temperature above the upper 
limit of normal. 
Infusion site 
extravasation 
Painless edema 
Erythema with 
associated 
symptoms (e.g., 
edema, pain, 
induration, 
phlebitis) 
Ulceration or 
necrosis; 
severe tissue 
damage; 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by leakage of the infusion into the surrounding tissue. Signs 
and symptoms may include induration, erythema, swelling, burning sensation and marked 
discomfort at the infusion site. 

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lnjection site 
reaction 
Tenderness 
with or without 
associated 
symptoms (e.g., 
warmth, 
erythema, 
itching) 
Pain; 
lipodystrophy; 
edema; 
phlebitis 
Ulceration or 
necrosis; 
severe tissue 
damage; 
operative 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an intense adverse reaction (usually immunologic) 
developing at the site of an injection. 
Localized 
edema 
Localized to 
dependent 
areas, no 
disability or 
functional 
impairment 
Moderate 
localized edema 
and 
intervention 
indicated; 
limiting 
instrumental 
ADL 
Severe 
localized 
edema and 
intervention 
indicated; 
limiting self-
care ADL 
  
  
Definition: A disorder characterized by swelling due to excessive fluid accumulation at a specific 
anatomic site. 
Navigational Note: Prior to using this term consider specific edema areas: General disorders 
and administration site conditions: Edema face, Edema limbs, Edema trunk, or Edema neck; 
Nervous system disorders: Edema cerebral; Reproductive system and breast disorders: Genital 
edema; Respiratory, thoracic and mediastinal disorders: Laryngeal edema or Pulmonary edema; 
Skin and subcutaneous tissue disorders: Periorbital edema; Vascular disorders: Lymphedema 
Pain 
Mild pain 
Moderate pain; 
limiting 
Severe pain; 
limiting self-
care 
  
  
instrumental 
ADL 
ADL 
Definition: A disorder characterized by the sensation of marked discomfort, distress or agony. 
Navigational Note: Prior to using this term consider using a specific body part pain term found 
throughout the CTCAE (over 40 different pain terms). 
 
Investigations 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Electrocardiogram 
QT corrected 
interval prolonged 
Average QTc 
450 - 480 
ms 
Average 
QTc 481 - 
500 ms 
Average 
QTc >= 501 
ms; >60 ms 
change 
from 
baseline 
Torsade de 
pointes; 
polymorphic 
ventricular 
tachycardia; 
signs/symptoms 
of serious 
arrhythmia 
  
Definition: A finding of a cardiac dysrhythmia characterized by an abnormally long corrected QT 
interval. 
 
Psychiatric disorders  
CTCAETerm 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 

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Suicidal 
ideation 
increased 
thoughts of 
death but no 
wish to kill 
oneself 
Suicidal 
ideation with 
no specific 
plan or intent 
Specific plan to 
commit suicide 
without serious 
intent to die 
which may not 
require 
hospitalization 
Specific plan to 
commit suicide with 
serious intent to die 
which requires 
hospitalization 
- 
Definition: A disorder characterized by thoughts of taking one's own lite. 
Suicide 
attempt 
  
  
Suicide attempt 
or gesture 
without intent 
to die 
Suicide attempt with 
intent to 
Death 
Definition: A disorder characterized by self-inflicted harm in an attempt to end one's own lite 
 
Levetiracetam: 
Psychiatric Disorders 
CTCAETem 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Agitation 
Mild mood 
alteration 
Moderate 
mood 
alteration 
Severe agitation; 
hospitalization 
not indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
- 
Definition: A disorder characterized by a state of restlessness associated with unpleasant 
feelings of irritability and tension  
Anxiety 
Mild 
symptoms; 
interventio
n not 
indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting 
self-care ADL; 
hospitalization 
indicated 
Life-threatening 
consequences; 
urgent intervention 
indicated 
- 
Definition: A disorder characterized by apprehension of danger and dread accompanied by 
rest lessness, tension, tachycardia, and dyspnea unattached to a clearly identifiable 
stimulus. 
Depression 
Mild 
depressive 
symptoms 
Moderate 
depressive 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
depressive 
symptoms; 
limiting self-
care ADL; 
hospitalization 
not indicated 
Life-threatening 
consequences, 
threats of harm to 
self or others; 
hospitalization 
indicated 
Death 
 
 
Definition: A disorder characterized by melancholic feelings of grief or unhappiness. 
Personality 
change 
Mild 
personality 
change 
Moderate 
personality 
change 
Severe 
personality 
change; 
hospitalization 
not indicated 
Lite-threatening 
consequences, 
threats of harm 
to self or 
others; 
hospitalization 
indicated 
- 

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Definition: A disorder characterized by a conspicuous change in a person's behavior and 
thinking. 
Irritability  
Mild; easily 
consolable 
Moderate; 
limiting 
instrumental 
ADL; 
increased 
attention 
indicated 
Severe abnormal 
or excessive 
response; 
limiting self care  
ADL; 
inconsolable; 
medical or 
psychiatric 
intervention 
indicated 
- 
- 
Definition: A disorder characterized by an abnormal responsiveness to stimuli or physiological 
arousal; may be in response to pain, fright, a drug, an emotional situation or a medical 
condition. 
psychosis 
Mild psychotic 
symptoms 
Moderate 
psychotic 
symptoms 
(e.g., 
disorganized 
speech; 
impaired 
reality 
testing) 
Severe 
psychotic 
symptoms (e.g., 
paranoid, 
extreme 
disorganization)
; hospitalization 
not indicated; 
new onset 
Lite-
threatening 
consequences
, threats of 
harm to self 
or others; 
hospitalizatio
n indicated 
 
 
Death 
Definition: A disorder characterized by personality change, impaired functioning, and loss of 
touch with reality. lt may be a manifestation of schizophrenia, bipolar disorder or brain tumor. 
 
Nervous system disorders 
CTCAE Tem 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Somnolence Mild but more 
than usual 
drowsiness or 
sleepiness 
Moderate 
sedation; 
limiting 
instrument
al ADL 
Obtundation or 
stupor 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by characterized by excessive sleepiness and drowsiness. 
Ataxia 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention 
no indicated 
Moderate 
symptoms; 
limiting 
instrument
al ADL 
Severe 
symptoms; 
limiting self-
care ADL; 
mechanical 
assistance 
indicated 
- 
- 
Definition: A disorder characterized by lack of coordination of muscle movements resulting in 
the impairment or inability to perform voluntary activities  
 
General disorders 

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CTCAE Tem 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Fatigue 
Fatigue 
relieved by 
rest 
Fatigue not 
relieved by 
rest; limiting 
instrumental 
ADL 
Fatigue not 
relieved by rest, 
limiting self care 
ADL 
- 
- 
Definition: A disorder characterized by a state of generalized weakness with a pronounced 
inability to summon sufficient energy to accomplish daily activities. 
 
lmmune system disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Anaphylaxis 
- 
- 
Symptomatic 
bronchospasm, with 
or without urticaria; 
parenteral 
intervention 
indicated; allergy-
related 
edema/angioedema; 
hypotension 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by an acute inflammatory reaction resulting from the release 
of histamine and histamine-like substances from mast cells, causing a hypersensitivity immune 
response. Clinically, it presents with breathing difficulty, dizziness, hypotension, cyanosis and loss 
of consciousness and may lead to death. 
 
Skin and subcutaneous tissue disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Stevens-
Johnson 
syndrome 
- 
- 
Skin sloughing 
covering <10% 
BSA with 
associated signs 
(e.g., erythema, 
purpura, 
epidermal 
detachment, 
and mucous 
membrane 
detachment) 
Skin sloughing 
covering 10 - 
30% BSA with 
associated signs 
(e.g., erythema, 
purpura, 
epidermal 
detachment 
and mucous 
membrane 
detachment) 
Death 
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The 
syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes.        

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Toxic 
epidermal 
necrolysis  
- 
- 
- 
Skin sloughing 
covering >=30% 
BSA with 
associated 
symptoms (e.g., 
erythema, 
purpura, or 
epidermal 
detachment)  
Death 
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The 
syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes.        
 
Investigations 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Neutrophil count 
decreased 
<LLN - 1500/ 
mm3 ; <LLN - 
1.5 X 10e9 /L 
<1500 - 1000/ 
mm3; <1.5 - 
1.0 X 10e9 /L 
<1000 - 
500/mm3; 
<1.0 - 0.5 x 
10e9 /L 
<500/ mm3; 
<0.5 x 10e9 /L 
 - 
Definition: A finding based on laboratory test results that indicate a decrease in number of 
neutrophils in a blood specimen. 
White blood cell 
decreased 
<LLN - 
3000/mm3; 
<LLN - 3.0 X 
10e9 /L 
<3000 - 2000/ 
mm3; <3.0 - 
2.0 X 10e9 /L 
<2000 - 
1000/mm3; 
<2.0 - 1.0 X 
10e9 /L 
<1000/ mm3; 
<1.0 x 10e9 /L 
 - 
Definition: A finding based on laboratory test results that indicate an decrease in number of white 
blood cells in a blood specimen. 
 
Lacosamide 
 
Psychiatric disorders  
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Suicidal 
ideation 
increased 
thoughts of 
death but no 
wish to kill 
oneself 
Suicidal 
ideation with 
no specific 
plan or intent 
Specific plan to 
commit suicide 
without serious 
intent to die 
which may not 
require 
hospitalization 
Specific plan to 
commit suicide with 
serious intent to die 
which requires 
hospitalization 
- 
Definition: A disorder characterized by thoughts of taking one's own lite. 
Suicide 
attempt 
  
  
Suicide attempt 
or gesture 
without intent 
to die 
Suicide attempt with 
intent to 
Death 
Definition: A disorder characterized by self-inflicted harm in an attempt to end one's own lite 
 

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Nervous system disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Dizziness 
Mild 
unsteadiness 
or sensation of 
movement 
Moderate 
unsteadiness or 
sensation of 
movement; 
limiting 
instrumental 
ADL 
Severe 
unsteadiness or 
sensation of 
movement; 
limiting self 
care ADL 
- 
- 
Definition: A disorder characterized by a disturbing sensation of lightheadedness, unsteadiness, giddiness, 
spinning or rocking. 
Ataxia 
Asymptomatic; 
clinical or 
diagnostic 
observations 
only; 
intervention 
no indicated 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self 
care ADL; 
mechanical 
assistance 
indicated 
- 
- 
Definition: A disorder characterized by lack of coordination of muscle movements resulting in the 
impairment or inability to perform voluntary activities  
Syncope 
- 
- 
Fainting; 
orthostatic 
collapse 
- 
- 
Definition: A disorder characterized by spontaneous loss of consciousness caused by insufficient 
blood supply to the brain. 
 
Cardiac disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Atrioventricular 
block first 
degree 
Asymptomatic, 
intervention 
not indicated 
Non-urgent 
intervention 
indicated 
  
  
  
Definition: A disorder characterized by a dysrhythmia with a delay in the time required for the 
conduction of an electrical impulse through the atrioventricular (AV) node beyond 0.2 seconds; 
prolongation of the PR interval greater than 200 milliseconds. 
Mobitz type I 
Asymptomatic, 
intervention 
not indicated 
Symptomatic; 
medical 
intervention 
indicated 
Symptomatic 
and 
incompletely 
controlled 
medically, or 
controlled 
with device 
(e.g., 
pacemaker) 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 

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Definition: A disorder characterized by a dysrhythmia with a progressively lengthening PR interval 
prior to the blocking of an atrial impulse. This is the result of intermittent failure of atrial electrical 
impulse conduction through the atrioventricular (AV) node to the ventricles. 
Mobitz (type) II 
atrioventricular 
block 
Asymptomatic, 
intervention 
not indicated 
Symptomatic; 
medical 
intervention 
indicated 
Symptomatic 
and 
incompletely 
controlled 
medically, or 
controlled 
with device 
(e.g., 
pacemaker); 
new onset 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by a dysrhythmia with relatively constant PR interval prior to 
the block of an atrial impulse. This is the  result of intermittent  failure  of atrial electrical impulse 
conduction through the atrioventricular (AV) node to the ventricles. 
Atrioventricular 
block complete   
Non-urgent 
intervention 
indicated 
Symptomatic 
and 
incompletely 
controlled 
medically, or 
controlled 
with device 
(e.g., 
pacemaker); 
new onset 
Life-threatening 
consequences; 
urgent intervention 
indicated 
Death 
Definition: A disorder characterized by a dysrhythmia with complete failure of atrial electrical 
impulse conduction through the AV node to the ventricles. 
Ventricular 
arrhythmia 
Asymptomatic, 
intervention 
not indicated 
Non-urgent 
medical 
intervention 
indicated 
Urgent 
intervention 
indicated 
Life-threatening 
consequences; 
hemodynamic 
compromise 
Death 
Definition: A disorder characterized by a dysrhythmia that originates in the ventricles. 
  
Ventricular 
tachycardia 
  
Non-urgent 
medical 
intervention 
indicated 
Symptomatic, 
urgent 
intervention 
indicated 
Life-threatening 
consequences; 
hemodynamic 
Death 
compromise 
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats per 
minute that originates distal to the bundle of His. 
Valproate 
 
Hepatobiliary disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hepatic 
failure 
  
  
Asterixis; mild 
encephalopathy; 
drug induced liver 
injury (DILI); limiting 
self-care ADL 
Life-threatening 
consequences; 
moderate to severe 
encephalopathy; 
coma 
Death 

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Definition: A disorder characterized by the inability of the liver to metabolize chemicals in the 
body. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic 
dehydrogenase, alkaline phosphatase, aminotransferase, and/or prolongation of prothrombin 
time (INR.) Drug-induced liver injury (DILI) as defined by Hy's Law. 
 
Gastrointestinal disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Pancreatitis 
  
Enzyme 
elevation ; 
radiologic 
findings only 
Severe pain; 
vomiting; 
medical 
intervention 
indicated (e.g., 
analgesia, 
nutritional 
support) 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by inflammation of the pancreas with no documented 
pancreas infection. 
 
Nervous system disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Somnolence 
Mild but more 
than usual 
drowsiness or 
sleepiness 
Moderate 
sedation; 
limiting 
instrumental 
ADL 
Obtundation or 
stupor 
Life-
threatening 
Death 
consequences; 
urgent 
intervention 
indicated 
Definition: A disorder characterized by characterized by excessive sleepiness and drowsiness. 
Encephalopathy Mild symptoms 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
Severe 
symptoms; 
limiting self-
care ADL 
Life-
threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by a pathologic process involving the brain. 
Depressed level 
of consciousness 
Decreased level 
of alertness 
Sedation; slow 
response to 
stimuli; limiting 
instrumental 
ADL 
Difficult to 
arouse 
Life-
threatening 
consequences; 
coma; urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by a decrease in ability to perceive and respond 
Lethargy 
Mild symptoms; 
reduced 
alertness and 
awareness 
Moderate 
symptoms; 
limiting 
instrumental 
ADL 
 - 
 - 
 - 

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Definition: A disorder characterized by a decrease in consciousness characterized by mental and 
physical inertness. 
Cognitive 
disturbance 
Mild cognitive 
disability; not 
interfering with 
work/school/life 
performance; 
specialized 
educational 
services/devices 
not indicated 
Moderate 
cognitive 
disability; 
interfering with 
work/school/life 
performance but 
capable of 
independent 
living; 
specialized 
resources on 
part time basis 
indicated 
Severe cognitive 
disability; 
significant 
impairment of 
work/school/life 
performance 
 - 
 - 
Definition: A disorder characterized by a conspicuous change in cognitive function. 
 
lnvestigations 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Platelet count 
decreased 
<LLN - 75,000/ 
mm3; <LLN - 
75.0 X 10e9 /L 
<75,000 - 
50,000/ mm3; 
<75.0 - 50.0 X 
10e9 /L 
<50,000 - 
25,000/ mm3; 
<SO.O - 25.0 X 
10e9 /L 
<25,000/mm3; 
<25.0 x 10e9/L 
  
Definition: A finding based on laboratory test results that indicate a decrease in number of 
platelets in a blood specimen. 
 
General disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hypothermia 
 - 
35 - >32 
degrees C; 95 
- >89.6 
degrees F 
32 - >28 
degrees C; 
89.6 ->82.4 
degrees F 
<=28 degrees C; 
82.4 degrees F; 
life-threatening 
consequences 
(e.g., coma, 
hypotension, 
pulmonary 
edema, acidemia, 
ventricular 
fibrillation) 
Death 
Definition: A disorder characterized by an abnormally low body temperature. Treatment is 
required when the body temperature is 35C (95F) or below. 
 
Fosphenitoin 
 
Cardiac disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 

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Atrioventricular 
block first 
degree 
Asymptomatic, 
intervention not 
indicated 
Non-urgent 
intervention 
indicated 
  
  
  
Definition: A disorder characterized by a dysrhythmia with a delay in the time required for the 
conduction of an electrical impulse through the atrioventricular (AV) node beyond 0.2 seconds; 
prolongation of the PR interval greater than 200 milliseconds. 
Mobitz type I 
Asymptomatic, 
intervention not 
indicated 
Symptomatic; 
medical 
intervention 
indicated 
Symptomatic 
and 
incompletely 
controlled 
medically, or 
controlled 
with device 
(e.g., 
pacemaker) 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by a dysrhythmia with a progressively lengthening PR 
interval prior to the blocking of an atrial impulse. This is the result of intermittent failure of atrial 
electrical impulse conduction through the atrioventricular (AV) node to the ventricles. 
Mobitz (type) II 
atrioventricular 
block 
Asymptomatic, 
intervention not 
indicated 
Symptomatic; 
medical 
intervention 
indicated 
Symptomatic 
and 
incompletely 
controlled 
medically, or 
controlled 
with device 
(e.g., 
pacemaker); 
new onset 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by a dysrhythmia with relatively constant PR interval prior 
to the block of an atrial impulse. This is the result of intermittent failure of atrial electrical 
impulse conduction through the atrioventricular (AV) node to the ventricles. 
Atrioventricular 
block complete 
 - 
Non-urgent 
intervention 
indicated 
Symptomatic 
and 
incompletely 
controlled 
medically, or 
controlled 
with device 
(e.g., 
pacemaker); 
new onset 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by a dysrhythmia with complete failure of atrial electrical 
impulse conduction through the AV node to the ventricles. 
Ventricular 
fibrillation 
 - 
 - 
 - 
Life-threatening 
consequences; 
hemodynamic 
compromise 
Death 

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Definition: A disorder characterized by a dysrhythmia without discernible QRS complexes dueto 
rapid repetitive excitation of myocardial fibers without coordinated contraction of the ventricles  
Ventricular 
tachycardia 
 - 
Non-urgent 
medical 
intervention 
indicated 
Symptomatic, 
urgent 
intervention 
indicated 
Life-threatening 
consequences; 
hemodynamic 
compromise 
Death 
Definition: A disorder characterized by a dysrhythmia with a heart rate greater than 100 beats 
per minute that originates distal to the bundle of His. 
Sinus 
bradycardia 
Asymptomatic, 
intervention not 
indicated 
Symptomatic, 
intervention 
not indicated; 
change in 
medication 
initiated 
Symptomatic, 
intervention 
indicated 
Life-threatening 
consequences; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by a dysrhythmia with a heart rate less than 60 beats per 
minute that originates in the sinus node. 
 
Skin and subcutaneous tissue disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Stevens-
Johnson 
syndrome 
- 
- 
Skin sloughing 
covering <10% 
BSA with 
associated 
signs (e.g., 
erythema, 
purpura, 
epidermal 
detachment, 
and mucous 
membrane 
detachment) 
Skin sloughing 
covering 10 - 
30% BSA with 
associated 
signs (e.g., 
erythema, 
purpura, 
epidermal 
detachment 
and mucous 
membrane 
detachment) 
Death 
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The 
syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes.     
Toxic 
epidermal 
necrolysis  
- 
- 
- 
Skin sloughing 
covering 
>=30% BSA 
with associated 
symptoms 
(e.g., 
erythema, 
purpura, or 
epidermal 
detachment)  
Death 
Definition: A disorder characterized by less than 10% total body skin area separation of dermis. The 
syndrome is thought to be a hypersensitivity complex affecting the skin and the mucous membranes.     
 

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Hepatobiliary disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Hepatic 
failure 
  
  
Asterixis; mild 
encephalopathy; 
drug induced liver 
injury (DILI); 
limiting self-care 
ADL 
Life-threatening 
consequences; 
moderate to severe 
encephalopathy; 
coma 
Death 
Definition: A disorder characterized by the inability of the liver to metabolize chemicals in the 
body. Laboratory test results reveal abnormal plasma levels of ammonia, bilirubin, lactic 
dehydrogenase, alkaline phosphatase, aminotransferase, and/or prolongation of prothrombin 
time (INR.) Drug-induced liver injury (DILI) as defined by Hy's Law. 
Blood 
bilirubin 
increased 
>ULN - 1.5 x 
ULN if 
baseline was 
normal; > 
1.0 - 1.5 x 
baseline if 
baseline was 
abnormal 
>l.5 - 3.0 x 
ULN if 
baseline 
was 
normal; 
>l.5 - 3.0 x 
baseline if 
baseline 
was 
abnormal 
>3.0 - 10.0 x ULN if 
baseline was 
normal; >3.0 - 10.0 x 
baseline if baseline 
was abnormal 
>10.0 x ULN if 
baseline was 
normal; >10.0 x 
baseline if baseline 
was abnormal 
  
Definition: A finding based on laboratory test results that indicate an abnormally high level of 
bilirubin in the blood. Excess bilirubin is associated with jaundice 
 
Investigations 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Electrocardiogram QT 
corrected interval 
prolonged 
Average QTc 
450 - 480 ms 
Average 
QTc 481 - 
500 ms 
Average 
QTc >= 501 
ms; >60 ms 
change from 
baseline 
Torsade de 
pointes; 
polymorphic 
ventricular 
tachycardia; 
signs/symptoms of 
serious arrhythmia 
 - 
Definition: A finding of a cardiac dysrhythmia characterized by an abnormally long corrected QT 
interval. 
Alanine 
aminotransferase 
increased 
>ULN - 3.0 x 
ULN if 
baseline was 
normal; 1.5 - 
3.0 x 
baseline if 
baseline was 
abnormal  
>3.0 - 5.0 x 
ULN if 
baseline 
was normal; 
>3.0 - 5.0 x 
baseline if 
baseline 
was 
abnormal  
>5.0 - 20.0 x 
ULN if 
baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline 
was 
abnormal 
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal  
- 
Definition: A finding based on laboratory test results that indicate an increase in the level of 
alanine aminotransferase (ALT or SGPT) in the blood specimen.   

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Aspartate 
aminotransferase 
increased  
>ULN - 3.0 x 
ULN if 
baseline was 
normal; 1.5 - 
3.0 x 
baseline if 
baseline was 
abnormal  
>3.0 - 5.0 x 
ULN if 
baseline 
was normal; 
>3.0 - 5.0 x 
baseline if 
baseline 
was 
abnormal  
>5.0 - 20.0 x 
ULN if 
baseline 
was normal; 
>5.0 - 20.0 x 
baseline if 
baseline 
was 
abnormal  
>20.0 x ULN if 
baseline was 
normal; >20.0 x 
baseline if baseline 
was abnormal  
- 
Definition: A finding based on laboratory test results that indicate an increase in the level of 
aspartate aminotransferase (AST or SGOT) in a blood specimen.   
 
Blood and lymphatic system disorders 
CTCAE Term 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Grade 5 
Eosinophilia 
>ULN and 
>Baseline 
  
Steroids 
initiated 
  
  
Definition: A disorder characterized by laboratory test results that indicate an increased number 
of eosinophils in the blood. 
Leukocytosis 
  
  
>100,000/mm3 
Clinical 
manifestations 
of leucostasis; 
urgent 
intervention 
indicated 
Death 
Definition: A disorder characterized by laboratory test results that indicate an increased number 
of white blood cells in the blood. 
 
  
Relatedness Definition: The research team, the clinical team and the independent safety monitor (ISM) will 
assess the likelihood of every SAE to be related to the research procedures and will classify the AE as: 
• 
Unrelated 
• 
Unlikely related 
• 
Possibly related  
• 
Probably related  
• 
Definitely related 
Non-SAE AE will be classify just by the ISM, and in both cases (SAE and non-SAE), to do so they will consider 
the following criteria: 
• 
The AE has been previously reported for the suspected relatedness of ASM 
• 
The temporal association between the ASM administration time and the AE is consistent with 
evidence-based literature. 
• 
Other potential causes for the suspected AE were considered. 
AE not classified as Unrelated will be considered to intervene with protective measures. 
    
Expectedness Definition:  The study personnel will evaluate if the related AE/SAE was expected. AEs different 
from transitory ventilatory decoupling are not expected during transport to MRI scans. The incident, 
experience, or outcome potentially related to one ASM listed is expected if reported in the FDA Online Label 
Repository in terms of nature, severity and frequency (see appendix B to F), and it is congruent with the 
subject’s clinical condition.     
 

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AE and SAE Assessment, Follow-up Procedures: Multimodal monitoring and the daily paraclinical test 
indicated by the patient’s clinical care will provide the means to detect the eventual AE. The research team 
and the ISM will actively search the medical charts for reported AE or concerning findings and establish direct 
communication with the care team to verify those findings to be considered an AE. Clinical conduct, including 
treatments required because an AE will be provided as needed by the care team, according to clinical 
management institutional guidelines. Meanwhile, the research team will verify the subjects’ criteria to 
continue in the trial. For patients still able to continue in the study that presents an AE related to a specific 
intervention ASM, the care team and the research team will look to replace the related ASM with another 
from the protocol if that is safe for the patient and could let to complete the intervention criteria to perform 
the follow up tests. The clinical follow up required will be indicated by the care team and specific aims related 
follow up will be decided by the research team.  
 
Reporting and Documentation Procedures: After the ISM analysis of each AE, the research team will 
report the event to the Neurology Department and the IRB by an NIH Clinical Research Toolbox Adverse event 
Form v2.0 (Appendix N). If the AE was classified as severity grade 4 or 5, or meets the UNC criteria for 
Promptly reportable information, it will be reported within seven days from the event; otherwise, the report 
will be stored at the clinical Resting State fMRI service and provided to the Neurology Department and the IRB 
as applicable. All those reports will be input in the corresponding safety variables and will be collected by the 
research team at the reporting time. 
The Research team and the independent safety monitor will also look for any unanticipated problem (UP), which 
the study monitor will report it to the IRB and the Neurology Department with an NIH UP form (Appendix O), within 
seven days of the observed problem.   
Participant Notification of New Information: Any new safety information known by the Research team 
will be provided to the actively enrolled subject or his LAR within five days and this communication will be 
reported in the electronic medical charts.  
The anatomical MRI series will be reviewed and reported by the Radiology department of UNC health 
including whichever incidental finding. That anatomical image won't be reviewed in 
detail by the research team, but will be used as part of the analysis process of the functional MRI 
sequences (BOLD). The functional MRI sequences (BOLD) won't give incidental findings, it would inform the 
state of resting state networks detected in the Subject. the presence of networks with features compatible 
with seizure networks will be disclosed to family and care team, because that finding will prompt the 
intervention arm allocation.   
12.4. Safety Monitoring 
The intervention phase of this study will occur while the participant is in the ICU, where constant medical care and 
observation are provided, so initial responses to adverse events will be in charge of the care team because they 
are the best suited for an on-time reaction. If emergent adjustments to the treatment plan are needed, those will 
be decided by the care team in direct communication with the research team when the time allows it. This 
communication will ensure compliance with the intervention criteria whenever possible, even if it implies 
switching an ASM for another one listed on the intervention protocol. Every adverse event related to a study 
subject being reported to the SAFE reporting system or identified by other non-specified means will be tracked by 
the study coordinator, who will inform the research team and the ISM, who will first decide if there is an 
identifiable unanticipated problem involved with the AE and then review the event to define its grade, its 
likelihood of being related to the study, the potential risk of recurrence, and how to prevent it. The ISM is free to 
schedule a meeting to complete those tasks, with the assistance of whom he determines.  After the adverse event 
analysis, a study AE report classifying the event will be created (appendix N), and the AE that are not classified as 

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unrelated will be included in the reported safety variables. In case of severe adverse events, the meeting will also 
state the necessary conditions to resume the study or its definite early termination.  
12.5. Study Suspension / Early Termination of the Study 
The Study will be suspended and potentially prematurely terminated in the following situations: 
• 
A severe adverse event occurs, and there is a concern for the risk of recurrence without an immediate and 
reliable preventive strategy.  
• 
Happen three recurrent grade 2 to 3 AE of the same type implying noncompliance or inefficacy of the 
corrective measures. 
• 
Notice of an unanticipated problem that implies an unfavorable risk benefit relationship for the intervention 
to the target population. 
• 
The 25 percent of the maximum number of subjects to be enrolled have had the rs-fMRI#1 and no SzNET 
have been detected. 
• 
A cumulative number of five enrolled patients allocated to the intervention do not reach to complete the 
intervention phase and get the research follow up tests. 
• 
Any determination of serious or continuing noncompliance by the reviewing IRB. 
 
If any of these situations is identified, it will prompt an asynchronous meeting or in person meeting, as 
determined by the ISM, for the research team to present an action plan to the Vice Chair of Research of the 
Department of Neurology. The Vice Chair will then assess the conditions for resuming the study, consider early 
termination if necessary, or convene a broader meeting as deemed appropriate. For those AE involving 
suspension and determination of being study-related, the resuming asynchronous or in person meeting will 
include the assistance of the ISM and whoever s/he determines as appropriate for the AE analysis. 
 
 
13. Regulatory, Ethical, and Study Oversight Specifications 
 
13.1. Informed Consent Process 
 
The informed consent for the BIS screening test will be obtain verbally and the study’s informed consent will be 
obtained using the informed consent form. Please see further details in section 13.1.2 
 
 
13.1.1. 
Consent/Assent and Documents Provided to Participants 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the participant 
and written documentation of informed consent is required prior to starting intervention/administering study 
intervention.  The following consent materials are submitted with this protocol: 
• 
Appendix P. Informed consent form. 
• 
Appendix B FDA insert of Fosphenytion 
• 
Appendix C FDA insert of Lacosamide 
• 
Appendix D FDA insert of Levetiracetam  
• 
Appendix E FDA insert of Phenobarbital  
• 
Appendix F FDA insert of Valproate  
 
 
13.1.2. 
Consent Procedures and Documentation 

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Informed consent is a process that is initiated prior to the individual’s or their LAR’s agreeing to participate in the 
study and continues throughout the individual’s study participation. 
The first approach to the patient’s LAR will be by telephone, presenting the researcher as non-care team personnel, 
part of a research team from the neurology department, and explaining the purpose of the call with a general idea 
of the study; then will ask for consent to schedule a personal interview to give further details of the study and the 
screening procedures. If the LAR accepts, an interview will be scheduled soon, in English or Spanish, according to 
the LAR preferences. The interview can be performed by one of the study investigators or by the research 
coordinator who will be trained to perform this activity. 
At the interview, the screening process and the Barthel Index will be explained, if the LAR agree to continue the 
screening, the Barthel Index will be completed. For patients with a Barthel score of 75 or less the researcher will 
explain that the patient is not eligible for the study, in the case of a Barthel score of 80 or more the researcher will 
continue with the informed consent process to enroll the patient.  
 
Consent forms will be Institutional Review Board (IRB)-approved and the participant’s LAR will be asked to read and 
review the document. The investigator will explain the research study to the participant’s LAR and answer any 
questions that may arise. A verbal explanation will be provided in terms suited to the LAR’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  Participant’s LAR 
will have the opportunity to carefully review the written consent form and ask questions prior to signing. The 
participant’s LAR should have the opportunity to discuss the study with their family and think about it prior to 
agreeing to authorize the participation. The participant’s LAR will sign the informed consent document prior to any 
procedures being done specifically for the study. Participant LAR must be informed that participation is voluntary 
and that subjects may withdraw from the study at any time, without prejudice. A copy of the informed consent 
document will be given to the participant LAR for their records. The informed consent process will be conducted 
and documented in the source document (including the date), and the form signed, before the participant 
undergoes any study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to their LAR that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. In case a research subject regains capacity to consent by neurological and mental medical 
exam, the research team will explain to the subject their current situation in the study and will explain all the study 
dispositions mentioned before to request for new consent. If the participant doesn’t want to continue in the study, 
no further research studies will be performed, or new information collected, but the information obtained until that 
moment will be included in the study analyses. 
13.2. Study Discontinuation and Closure 
This study may be temporarily suspended or prematurely terminated if defined stopping rules are met.  Written 
notification, documenting the reason for study suspension or termination, will be provided by the suspending or 
terminating party to the study participant’s LAR, the Neurology Department and the IRB.    
If the study is prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and Neurology department and will provide the reason(s) for the 
termination or suspension. Active study participants or their LAR will be contacted and informed of changes to the 
study. 
  
Examples of circumstances that may warrant termination or suspension of the study include: 
• 
Criteria established in the Master protocol document (MPD) for early termination of the study have been 
satisfied 
• 
Detection of an unexpected unacceptable level of risk to participants 
• 
Futility due to insufficient adherence to protocol requirements. 
• 
Unexpected inability to recruit participants. 
 

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The study may resume once concerns about safety, protocol compliance, and data quality are addressed, and meets 
the requirements of the UNC Neurology department and the IRB. 
13.3. Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by the UNC Clinical Resting State fMRI Service, the 
PICU, the NSICU, the SICU, the CICU, the CTICU, the MICU, and the Neurology Department. This confidentiality is 
extended to cover EEG recordings and rs-fMRI data in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized third party 
without prior written approval of UNC.  
 
All research activities will be conducted in as private a setting as possible. 
 
The Neurology Department and representatives of the Institutional Review Board (IRB may inspect all documents 
and records required to be maintained by the investigator, including but not limited to, medical records (office, 
clinic, or hospital) and pharmacy records for the participants in this study. The clinical study site will permit access 
to such records. 
 
The study participant’s contact information will be securely stored at UNC Health information system site for 
internal use during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB and the Institutional policies requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will be 
transmitted to and stored at the PI’s UNC OneDrive account. This will not include the participant’s contact or 
identifying information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical site and by the UNC 
clinical resting state fMRI service research staff will be secured and password protected. At the end of the study, all 
study databases will be de-identified and archived in SOM Dept of Neurology Protected Research Database. 
 
 
 
13.3.1. 
Certificate of Confidentiality 
Not Apply. 
13.4. Future Use of Stored Specimens and Data 
Data collected for this study will be analyzed and stored at the PI’s UNC OneDrive and The School of Medicine drive.  
After the study is completed, the de-identified, archived data will be transmitted to and stored at a private folder 
for the UNC Clinical resting State fMRI Service in the official School of Medicine drive, for use by other researchers 
including those outside of the study.  
Permission to transmit data to the School of Medicine drive should be included in the informed consent. With the 
participant’s approval and as approved by local Institutional Review Boards (IRBs), de-identified biological data will 
be stored at the School of Medicine drive.  The files at the School of Medicine drive will also be provided with a 
code-link that will allow linking the biological recordings (MRI imaging and EEG recordings)  with the phenotypic 
data from each participant, maintaining the blinding of the identity of the participant. The blood samples collected 
for medication serum levels will not be stored, the results will be used just for treatment-dose adjustment purposes 
and not collected as research variables. This phenobarbital serum level information will be stored and managed in 
the same fashion as the patient’s clinical information. 
 

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13.5. Key Roles and Study Governance 
Principal Investigator,  
 
Principal Investigator 
Varina L. Boerwinkle MD 
 
Emilio G. Cediel 
University of North Carolina at Chapel Hill 
 
 University of North Carolina at Chapel Hill  
Address: 170 Manning Drive 
 
Address: 115 Mason Farm Rd. Lab 7113 
919 9668178 
 
984 7582948 
Varina_Boerwinkle@med.unc.edu 
 
Egcediel@email.unc.edu 
Research Coordinator 
 
Independent Safety Monitor (ISM) 
Yulissa Gonzalez 
 
Afsaneh Pirzadeh MD 
University of North Carolina at Chapel Hill  
 
 University of North Carolina at Chapel Hill 
Address: 170 Manning Drive 
 
417 MacNider 
704 2523039 
 
 
 yulissa_gonzalez@neurology.unc.edu  
 
afsaneh_pirzadeh@med.unc.edu  
 
• 
The two PIs and the UNC clinical Resting State fMRI Service manager constitute the Executive committee. It will 
provide project management for the entire project, including oversight of the execution and administrative 
functions. 
• 
The Research Coordinator will assist the communication between care team, research team, ISM and the subject 
LAR. 
• 
ISM will preside the AE meetings between the research team and the care team and will supervise the safety 
monitoring role of the research team. 
• 
The experienced primary coordinators, backup coordinators, and administrative support to assist with 
regulatory compliance, budgets, and quality oversight will be provided by the Neurology Clinical Trials Unit. 
The research coordinator proposed in this trial will be trained by existing expert NCTU staff with expertise 
in onboarding new staff into key roles in clinical research. 
13.6. Safety Oversight 
Safety oversight will be under the direction of an ISM. Who will be independent from the study conduct and free of 
conflict of interest, or measures should be in place to minimize perceived conflict of interest.  The ISM will preside 
over the AE meetings and meet with the Executive Committee at the time of aim 2 analysis and six months from 
enrolling subjects to assess the safety and efficacy of the study. The ISM will provide its input to the Neurology 
Department. 
    
 
13.7. Clinical Monitoring Plan (CMP) 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are protected, that 
the reported trial data are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with 
the currently approved protocol/amendment(s), with International Conference on Harmonization Good Clinical 
Practice (ICH GCP), and with applicable regulatory requirement(s).  
• 
The monitoring will be provided by an ISM with experience in the use of ASM and not linked with the 
research team. This Monitoring will be centralized in UNC health at Chapel Hill and targeted to the patients 
with AE, providing a report for each case. 

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13.8. Quality Assurance and Quality Control  
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC checks that 
will be run on the database will be generated. Any missing data or data anomalies will be discussed between the 
research team for clarification/resolution. 
Following written Standard Operating Procedures (SOPs) from the Neurology Department, the monitor designee 
will verify that the clinical trial is conducted, and data are generated, collected, documented, and reported in 
compliance with the protocol, ICH GCP. 
The investigational site will provide direct access to all trial related sites, source data/documents, and reports for 
the purpose of monitoring and auditing by the Neurology Department, and inspection by local and regulatory 
authorities. 
13.9. Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the participant, 
the investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by the site 
and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations within 
ten days of identification of the protocol deviation, or within ten days of the scheduled protocol-required activity.  
All deviations must be addressed in study source documents, and reported to the Neurology department.  Protocol 
deviations must be sent to the reviewing Institutional Review Board (IRB) per their policies. The site investigator is 
responsible for knowing and adhering to the reviewing IRB requirements.   
  
13.10. Publication and Data Sharing Policy  
Every attempt will be made to publish results in peer-reviewed journals. The PI will serve as first or senior author 
on all publications, with co-authors included according to journal guidelines. Data from this study may be requested 
from other researchers three years after the completion of the primary endpoint by contacting Dr. Varina 
Boerwinkle.  
13.11. Conflict of Interest Policy 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical industry, is 
critical.  Therefore, any actual conflict of interest of persons who have a role in the design, conduct, analysis, 
publication, or any aspect of this trial will be disclosed and managed. Furthermore, persons who have a perceived 
conflict of interest will be required to have such conflicts managed in a way that is appropriate to their participation 
in the design and conduct of this trial.  The study leadership in conjunction with the University of North Carolina 
has established policies and procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest. 
 

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14. Additional Considerations 
 
Not Applicable 
 
15. References 
 
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