Clinical trial NCT04772547
Conditions: Status Epilepticus, Electrographic Coma
Keywords: post-anoxic status epilepticus, cardiac arrest, nonconvulsive status epilepticus, coma, vigabatrin
Sponsor: University of Florida
Start date: 2021-09-22; Completion date: 2024-01-23
Enrollment: 6 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a pilot trial of a single loading dose of vigabatrin in post-anoxic status epilepticus.

Detailed description:
This pilot trial aims to demonstrate the feasibility of enteral administration of a single load of vigabatrin within targeted 48 hours of post-anoxic status epilepticus onset in unconscious survivors of cardiac arrest undergoing targeted temperature management. The load of VGB is in addition to the load of a commonly used intravenous second-line therapy given at the discretion of the treating neurologist. Serial blood tests will be obtained, including vigabatrin levels, taurine levels, neuron specific enolase, light chain neurofilament, and glial fibrillary acidic protein. In survivors that regain consciousness and survive to follow up, 6 months visual field perimetry will be obtained.

Arms: arm 1: 4500 mg of vigabatrin administered enterally
Interventions: intervention 1: Vigabatrin Only Product
Intervention descriptions: intervention 1: enteral medication administration, serial blood draws, and outcome assessment

Protocol documents:
Prot_SAP_000.pdf: 
VIGAB-STAT IIa Protocol 
 
 
 
Cover page for VIGAB-STAT 
 
Sponsor Name 
American Heart Association 
NCT number 
NCT04772547 
Official Title of Study 
A phase IIa feasibility trial of irreversible GABA-transaminase 
inhibition as adjunct treatment of status epilepticus after cardiac 
arrest 
Document date 
11 May 2023 
 
 
 
 
 


VIGAB-STAT IIa Protocol 
 
 
 
Clinical Study Protocol 
 
A phase IIa feasibility trial of irreversible GABA-transaminase 
inhibition as adjunct treatment of status epilepticus after cardiac 
arrest  
 
 
Version 14(11 May 2023) 
 
 


VIGAB-STAT IIa Protocol 
1 
 
 
Clinical Coordinating Center Principal Investigator: 
 
Carolina Maciel, MD, MSCR 
Assistant Professor of Neurology 
Division of Neurocritical Care and Epilepsy 
University of Florida College of Medicine 
Carolina.Maciel@neurology.ufl.edu  
 
Core Directors: 
 
Pharmacokinetics Core 
Charles Peloquin, PharmD 
Professor of Pharmacology; 
Director, Infectious Disease Pharmacokinetics Laboratory 
Department of Pharmacotherapy and Translational Research 
University of Florida College of Pharmacy 
peloquin@cop.ufl.edu  
 
Electroencephalography Core 
Lawrence J. Hirsch, MD 
Chief, Division of Epilepsy and EEG; 
 Co-Director, Yale Comprehensive Epilepsy Center;  
Co-Director, Critical Care EEG Monitoring Program 
Department of Neurology 
Yale School of Medicine 
lawrence.hirsch@yale.edu  
 
 
 
 


VIGAB-STAT IIa Protocol 
 
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Contents 
1. 
List of terms ................................................................................................................................6 
2. 
Trial overview .............................................................................................................................8 
3. 
Background and significance ........................................................................................................8 
Natural history of post-anoxic status epilepticus ...............................................................................8 
Rationale for a therapeutic trial exploring the GABA-ergic pathway ...................................................9 
4. 
Trial hypotheses and outcomes .................................................................................................. 10 
Specific Aims and Hypotheses........................................................................................................ 10 
Primary outcomes......................................................................................................................... 10 
Secondary outcomes..................................................................................................................... 11 
Exploratory outcomes ................................................................................................................... 11 
Rationale for chosen outcomes...................................................................................................... 12 
5. 
Eligibility ................................................................................................................................... 13 
Inclusion criteria ........................................................................................................................... 13 
Exclusion criteria........................................................................................................................... 13 
Note on inclusion and exclusion criteria ......................................................................................... 13 
Note on inclusion window ............................................................................................................. 14 
Exit from the study........................................................................................................................ 14 
6. 
Trial design ............................................................................................................................... 14 
Phases................................................................................................ Error! Bookmark not defined. 
General critical care ...................................................................................................................... 14 
Sedation ................................................................................................................................... 14 
Targeted temperature management .......................................................................................... 15 
Monitoring for seizures.............................................................................................................. 15 
Monitoring for markers of secondary brain injury (NSE)..................... Error! Bookmark not defined. 
Shivering................................................................................................................................... 15 
Screening ..................................................................................................................................... 15 
Blinding ........................................................................................................................................ 15 
Intervention period ....................................................................................................................... 16 
Drug administration .................................................................................................................. 16 
Drug absorption ........................................................................................................................ 16 
After the intervention period......................................................................................................... 16 
Screening for visual adverse events ............................................................................................ 16 


VIGAB-STAT IIa Protocol 
 
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Prognostication ............................................................................................................................ 17 
Clinical examination .................................................................................................................. 17 
EEG .......................................................................................................................................... 17 
Brain CT .................................................................................................................................... 17 
Brain MRI.................................................................................................................................. 17 
NSE........................................................................................................................................... 17 
SSEP ......................................................................................................................................... 17 
VIGAB-STAT criteria for a likely poor neurologic outcome................................................................ 18 
Death ....................................................................................................................................... 18 
WLST ........................................................................................................................................ 18 
Brain death ..................................................................................... Error! Bookmark not defined. 
Recurrent cardiac arrest ............................................................................................................ 18 
Follow up ..................................................................................................................................... 18 
7. 
Co-enrollment ........................................................................................................................... 18 
MOCHA and SPARE ....................................................................................................................... 18 
Stratification ................................................................................... Error! Bookmark not defined. 
Other trials ......................................................................................... Error! Bookmark not defined. 
8. 
Intervention period ......................................................................... Error! Bookmark not defined. 
Vigabatrin........................................................................................... Error! Bookmark not defined. 
Administration ................................................................................ Error! Bookmark not defined. 
Monitoring...................................................................................... Error! Bookmark not defined. 
Adjunct therapy .................................................................................. Error! Bookmark not defined. 
Administration ................................................................................ Error! Bookmark not defined. 
Monitoring...................................................................................... Error! Bookmark not defined. 
9. 
Data Collection.......................................................................................................................... 19 
Baseline data ................................................................................................................................ 22 
Subject characteristics ............................................................................................................... 22 
Pre-hospital data ....................................................................................................................... 22 
Background data ....................................................................................................................... 22 
Data on hospital admission............................................................................................................ 22 
Data on ICU phase ........................................................................................................................ 22 
Data prior to VGB load ............................................................................................................... 22 
Data during the intervention ...................................................................................................... 22 


VIGAB-STAT IIa Protocol 
 
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Daily during the ICU stay ............................................................................................................ 22 
Status epilepticus data............................................................................................................... 23 
At ICU discharge ........................................................................................................................ 23 
At hospital discharge..................................................................................................................... 23 
90 days after intervention ................................................................... Error! Bookmark not defined. 
180 days after intervention ........................................................................................................... 23 
10. 
Ethics and informed consent .................................................................................................. 23 
11. 
Data management ................................................................................................................. 24 
Data handling and record keeping.................................................................................................. 24 
Quality control and quality assurance ............................................................................................ 24 
12. 
Adverse events ...................................................................................................................... 24 
Definitions.................................................................................................................................... 24 
Reporting of serious adverse events............................................................................................... 25 
13. 
Statistical plan and data analysis............................................................................................. 25 
Phase IIa sample size..................................................................................................................... 25 
Analysis methods .......................................................................................................................... 25 
Primary outcome....................................................................................................................... 25 
Secondary outcome................................................................................................................... 26 
Missing data ................................................................................................................................. 26 
Subgroup analysis ......................................................................................................................... 26 
Data safety monitoring committee ...................................................... Error! Bookmark not defined. 
Members of the DSMC .............................................................................................................. 26 
14. 
Publication of data................................................................................................................. 26 
15. 
Insurance .............................................................................................................................. 26 
16. 
Funding................................................................................................................................. 26 
17. 
Timeline ................................................................................................................................ 26 
18. 
Trial participants.................................................................................................................... 27 
Investigators responsibilities ......................................................................................................... 27 
19. 
Appendices ........................................................................................................................... 27 
FOUR score................................................................................................................................... 27 
mRS ............................................................................................................................................. 28 
CPC .............................................................................................................................................. 29 
Epidemiology based Mortality score in Status Epilepticus (EMSE) .................................................... 29 


VIGAB-STAT IIa Protocol 
 
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VIGAB-STAT IIa Protocol 
 
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1. List of terms 
 
ABG – arterial blood gas 
AE — Adverse Event 
AHA — American Heart Association 
ASD – Antiseizure Drug 
BSAS — Bedside Shivering Assessment Scale 
CA — Cardiac Arrest 
CI – Co-investigator 
COSCA – Core Outcome Set for Cardiac Arrest 
CPC — Cerebral Performance Category 
CT — Computed Tomography 
ED – Emergency Department 
DNR — Do Not Resuscitate 
DSMC — Data Safety Monitoring Committee 
DWI – diffusion weighted imaging  
eCRF — electronic Case Report Form 
EEG — Electroencephalography 
EMSE – Epidemiology-based Mortality Score in Status Epilepticus 
EQ5D-5L — Euroqol health Survey 5 Dimensions 5 Level version 
ESICM – European Society of Intensive Care Medicine 
FOUR score — Full Outline of UnResponsiveness score 
GABA — Gamma-AminoButyric Acid 
GABA-t — Gamma-AminoButyric Acid transaminase 
GFAP — glial fibrillary acidic protein 
GOS – Glasgow Outcome Scale 
GOS-E – Glasgow Outcome Scale-Extended 
HRQOL – Health-related quality of life 
ICU — Intensive Care Unit 
IHCA — In-hospital cardiac arrest 
ILCOR — International Liaison Committee on Resuscitation 
IQCODE — Informant Questionnaire on Cognitive Decline in the Elderly 
MoCA — Montreal Cognitive Assessment 
mRS — modified Rankin Scale 
MRI — Magnetic Resonance Imaging 
NfL — Neurofilament Light chain 
NG/OG – nasogastric or orogastric  
NSE — Neuron Specific Enolase 
OHCA — Out-of-hospital Cardiac Arrest 
PASE — Post-Anoxic Status Epilepticus 
PI – Primary Investigator 
PD – Pharmacodynamics 
PK — Pharmacokinetics 
RASS — Richmond Agitation-Sedation Scale 
REMS — Risk Evaluation and Mitigation Strategy  
RN – Registered Nurse 
ROSC — Return of Spontaneous Circulation 
SAE — Serious Adverse Event 
SF-36 – 36-Item Short Form Survey 
SSEP — Somatosensory Evoked Potentials 
TTM — Targeted Temperature Management 
UCH-L1 — ubiquitin C-terminal hydrolase L1 


VIGAB-STAT IIa Protocol 
 
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UF – University of Florida 
VFP – Visual Field Perimetry 
VFQ-25 – Visual Function Questionnaire 25 
VGB – Vigabatrin  
WLST — Withdrawal of Life Supporting Therapies 
WLST-N — Withdrawal of Life Supporting Therapies due to perceived poor neurologic prognosis 
 
 


VIGAB-STAT IIa Protocol 
 
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2. Trial overview 
In 2015, the Institute of Medicine released a call to action for strategies to improve survival following 
cardiac arrest (CA)[1] given the lack of improvement in mortality rates and functional outcomes despite 
advances in resuscitation and the widespread use of targeted temperature management (TTM). By 
confirming the feasibility of using vigabatrin (VGB) as an early adjunct treatment for post-anoxic status 
epilepticus (PASE), while characterizing key pharmacokinetic and pharmacodynamics parameters in the 
post-CA setting, this trial pioneers the study of an innovative therapy for a deadly and frequent 
complication in the post-CA period.  
 
The VIGAB-STAT study is a phase IIa trial exploring the feasibility of using VGB, a Gamma-AminoButyric 
Acid -transaminase (GABAt) inhibitor, as an early adjunct treatment for refractory seizures in CA survivors 
with PASE.  This pilot trial aims to demonstrate the feasibility of enteral administration of a single load of 
VGB within targeted 48 hours of PASE onset in unconscious survivors of CA. The load of VGB is in addition 
to the load of a commonly used intravenous second-line therapy given at the discretion of the treating 
neurologist (e.g., phenytoin, valproic acid, phenobarbital, lacosamide, levetiracetam, etc). The key 
elements collected during phase IIa include: rates of screening, enrollment, and reasons for screen failure; 
ability to deliver VGB enterally within 48h of PASE onset; key pharmacokinetic parameters on absorption 
of VGB in this population and levels of other anti-seizure drugs; and ability to perform vision loss 
surveillance with taurine levels, Goldmann perimetry, and patient-oriented questionnaires.  
 
3. Background and significance 
Natural history of post-anoxic status epilepticus 
Cardiac arrest claims millions of lives annually across the globe. Outcomes depend on resuscitation efforts 
and on the severity of global brain injury resulting from cessation of circulation (primary insult) and 
ongoing injury due to mismatches between cerebral energy supply and demand (secondary brain injury). 
Once return of spontaneous circulation (ROSC) occurs, the treatment relies on mitigating cerebral 
energetic demand.  TTM is one of such treatments, but there is not a widely accepted practice across all 
post-CA patient population. This is because recent evidence questioned its role in affecting neurologic 
outcomes at 6 months compared to targeted normothermia [2] . Seizures, synchronized electrical 
phenomena produced by cortical neurons, are common after CA and lead to a marked increase in the 
cerebral metabolic activity and potential secondary injury. In fact, one in three unconscious CA survivors 
that undergo TTM experience PASE; TTM has not been shown to alter the frequency of post-CA seizures. 
Recent evidence suggests that early and aggressive treatment of PASE may lead to not only improved 
survival, but also functional independence[3-6]. 
 
Historically, PASE has been associated with nearly 100% mortality[4, 7-9]; however, the CA literature is 
confounded by bias due to variability in the provision of aggressive care when a low chance for functional 
recovery is perceived. As a result, this population has been traditionally excluded from observational 
studies and clinical trials of status epilepticus[10-15], and the management of these subjects varies 
widely[16, 17]. Further, non-standardized PASE treatment has failed to improve outcomes[18], leaving 
the Institute of Medicine’s call yet unfulfilled. Despite increasing awareness of the potential positive 
impact of aggressive treatment of PASE with reports of neurologically intact survival[3-6], therapeutic 
interventions remain largely unexplored.  
 


VIGAB-STAT IIa Protocol 
 
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Subjects who develop status epilepticus while in the hospital tend to be refractory to first-line therapy 
(i.e., benzodiazepines) and are less likely to survive and return to a functional state[19]. Outcomes are 
indirectly proportional to status epilepticus duration[20-22] and latency to treatment[23].  Besides 
significant morbidity and mortality, status epilepticus and its treatment are associated with high hospital 
costs and prolonged length-of-stay[24, 25]. Moreover, while less than 50% of all status epilepticus patients 
are treated with anesthetics[26-28], PASE subjects more often receive them for practical reasons—often 
as sedatives to tolerate mechanical ventilation. PASE is also more likely to require aggressive treatment 
to reach seizure control[29]. Midazolam and propofol infusions are the forefront of treatment for 
refractory status epilepticus[11, 30-32] and are also the most commonly used sedatives during TTM. 
Recent pre-clinical studies have demonstrated potential benefits of a combined therapeutic strategy in 
status epilepticus aiming for synergistic mechanisms of action[33, 34], which may reduce duration and 
exposure to anesthetics and mitigate their associated morbidity[27, 35]. By identifying a novel indication 
of a drug with high potential for synergism and virtually devoid of safety concerns during short-term 
therapy, this study is the stepping-stone to filling an important knowledge gap in the care of CA survivors. 
 
Rationale for a therapeutic trial exploring the GABA-ergic pathway 
The GABA pathway is key in seizure initiation and termination[36]. During status epilepticus, there is 
marked alteration of GABA metabolism in this region promoting excitatory pathways; the rate of GABA 
synthesis decreases[37], GABA turnover time increases up to 3-fold[37], and cell surface GABA receptors 
migrate to the intracellular space[38-40].  
 
Emerging evidence suggests that early and aggressive treatment of PASE may lead to good outcomes in 
selected cases[3-6, 41]; however, no standardized treatment has been proven beneficial in this 
population[18], and therapeutic algorithms are largely extrapolated from convulsive status epilepticus 
guidelines. First-line therapy acts by enhancing the GABAA receptor to increase its inhibitory tone. 
Vigabatrin, 4-amino-5-hexenoic acid or gamma-vinyl GABA, is a structural analog of GABA and irreversibly 
inhibits GABA-t—the enzyme responsible for GABA catabolism, thereby increasing brain levels of GABA. 
Vigabatrin may also stimulate GABA release [42]. The overall net effect is a significant elevation in GABA 
levels in nerve terminals, which facilitates GABA-mediated synaptic transmissions and leads to a marked 
and sustained antiseizure effect [43]. Its efficacy as adjunct therapy for intractable epilepsy is well-
established in the literature[44-50]. In addition to its direct anti-seizure effects, VGB may potentiate the 
therapeutic effects of GABAergic anesthetics and antiseizure drugs (ASDs)[51, 52] that are commonly used 
in the post-CA period (e.g., propofol, midazolam, and valproate). Currently, VGB is an FDA-approved 
therapy for infantile spasms and refractory focal-onset seizures in adults. It is also being investigated as a 
neuroprotective therapy in traumatic brain injury[53, 54], though its role as an adjunct therapy in status 
epilepticus is unclear.  
 
Rationale for chosen VGB regimen: A single VGB load is sufficient to achieve a prolonged GABA catabolism 
inhibition[55] and minimizes the risk of vision loss associated with chronic exposure. No toxicity has been 
reported with a single dose of VGB to date. The inhibition of central and peripheral GABA-t has been 
shown to outlast serum VGB elimination[55-57], demonstrating the irreversible nature of GABA 
catabolism inhibition[57, 58]. Vigabatrin has been tested up to 6,000mg daily doses in studies [59], 
including a study comparing placebo, 1,000/day, 3,000/day, and 6,000/day for a total of 12 weeks [60].  
Additionally, 6,000/d dosing led to a similar therapeutic effect on seizure control than 3,000/d [60], but it 
was associated with increase sedation/drowsiness and led to higher proportion of patients discontinuing 
therapy. A dose ceiling effect has been set in initial studies of VGB, in which doses >60mg/kg failed to 
elevate cerebral GABA levels further[61], and prolonged elevations of cerebral GABA levels may reduce 


VIGAB-STAT IIa Protocol 
 
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GABA synthesis [61]. In an individual ~70 kg, 60mg/kg corresponds to 4,200mg. As absorption is expected 
to be lower in the post-cardiac arrest period (due to decreased gastrointestinal motility and gastric 
emptying), a single dose of 4,500mg was selected for patients with normal or mild renal impairment.  
Patients with moderate (CrCl 30-50mL/min) will receive 2,250mg (50% dose reduction), and patients with 
severe renal impairment (CrCl<30cc/min) will receive 1,125mg (75% dose reduction. Thus, to minimize 
toxicity risk, maximize synergistic potential with co-administration of GABA-ergic anesthetics and the 
therapeutic window, we selected a single loading dose of VGB. 
4. Trial hypotheses and outcomes 
Main objective and central hypothesis 
Our overarching goal is to improve outcomes of successfully resuscitated individuals who experience 
refractory seizures following CA. Our central hypothesis is that early inhibition of GABA metabolism 
through VGB is possible in the post-CA period and may be an effective adjunct treatment for PASE. 
Specific aims and hypotheses 
Prove the feasibility of enteral administration of a VGB load within 48 hours of PASE onset in 
resuscitated CA subjects. We hypothesize that administering a single load of VGB within 48 hours of PASE 
onset is feasible. Later study phases will assess the potential therapeutic effects of this intervention.  
Demonstrate the pharmacokinetics (PK) of VGB absorption in the post-CA period. We will follow VGB 
levels serially in the post-CA setting, in which there may be delayed absorption and impaired clearance. 
Delayed absorption is anticipated due to continuous enteral feeding, prevalent delayed gastric emptying 
enteric mobility, and decreased enteric blood flow in the setting of neuromuscular blockade and 
vasopressors. Impaired clearance may occur due to a high prevalence of renal insufficiency and older age. 
We hypothesize that VGB will be detectable in ≥80% and 100% of subjects by 3- and 12h, respectively. We 
expect that peak concentrations will be delayed from 1 to 3h post-VGB in older individuals (≥65-year-old) 
receiving continuous enteral feeding, and that delayed clearance (detectable VGB after 72h) will occur in 
CrCl ≤30cc/min[62-64]. 
 
Primary outcome 
A. Primary feasibility outcome – enrollment and drug delivery 
We will primarily be looking at the ability to deliver VGB in PASE subjects; the target will be 
administering 4,500mg (or dose adjusted in moderate and severe impairment) of VGB enterally 
within 48 hours of PASE onset in ≥ 80% of enrolled subjects. Given the lack of well-established 
alternative treatments in this deadly disease, we anticipate 60-75% enrollment of eligible 
subjects, and will therefore be tracking the ratio between eligible and enrolled subjects, consent 
rates, and reasons for decline in study participation. 
B. Primary feasibility outcome – visual screening 
We will obtain serial taurine levels during ICU stay and Goldmann perimetry testing in the subjects 
are able to cooperate at 6 months follow up. Our goal is to achieve 90% completion rate for 
taurine levels, and have reliable visual field perimetry in ≥ 80% of survivors that regain 
consciousness following index hospitalization.  
C. Primary pharmacologic outcome: PK – absorption 
By analyzing serial VGB levels including baseline, we will validate the drug assay and characterize 
drug absorption; the target will be achieving a detectable VGB level in the serum of ≥ 80% of 


VIGAB-STAT IIa Protocol 
 
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enrolled subjects by 3 hours post-load. We anticipate detectable levels in all subjects by 12 hours. 
We expect peak concentrations to be delayed by one to three hours in older individuals receiving 
continuous enteral tube feedings. 
Secondary outcomes 
A. Secondary feasibility outcome – PASE detection and ultra-early drug delivery 
a. We will track the proportion of subjects in whom PASE was present upon connection to 
EEG (onset misses) to explore alternatives to allow prompt EEG monitoring following 
ROSC.  
b. We will also track the proportion of enrolled subjects who received a VGB load within 12 
and 24 hours of PASE onset to explore the possibility of ultra-early administration of VGB 
in subsequent phases, as the internalization of GABAA receptors (a key mechanism of 
treatment refractoriness) is time-dependent[65]. 
B. Secondary pharmacologic outcome: PK – elimination 
By analyzing serial VGB levels, we will characterize drug elimination. We anticipate undetectable 
VGB levels in all subjects by 7 days regardless of their renal function. Subjects with normal renal 
function will have undetectable VGB levels by 72 hours, and those with creatinine clearance less 
than 30 mL/min will have detectable VGB levels at 72 hours.  
Exploratory outcomes 
A. Exploratory efficacy outcomes 
a. Clinically oriented  
We will track the time from VGB load to resolution of PASE, time from VGB load to start 
of anesthetic wean, total duration of anesthetics for PASE treatment, the overall number 
of ASDs required for status epilepticus resolution, and the changes in neuron specific 
enolase (NSE), glial fibrillary acidic protein (GFAP), neurofilament light chains (NfL), tau 
and ubiquitin C-terminal hydrolase L1 (UCH-L1) over time as a potential indirect metric of 
neuroprotection since higher neuronal injury burden is associated with elevated NSE, 
GFAP and NfL levels. 
b. Physician-reported 
We will record Epidemiology-based Mortality Score in Status Epilepticus (EMSE) during 
index hospitalization to track disease severity. We will record the following outcomes at 
discharge, 6 months: modified Rankin Scale (mRS), Glasgow Outcome Scale- Extended 
(GOS-E), Glasglow- Pittsburgh Cerebral Performance Categories Scale original (CPC) and 
extended (CPC-E) in in person visits. In case subjects cannot attend in person visits, a 
structured questionnaire will be employed for telephone assessments (t-mRS, t-CPC). 
Cognitive function will be assessed by Montreal Cognitive Assessment (MoCA). 
c. Length-of-stay 
We will track total duration of anesthetic infusion for status epilepticus treatment, 
duration of mechanical ventilation, and ICU length-of-stay. 
d. Patient-reported 
We will evaluate self-perceived functional outcomes with the 36-Item Short-Form Health 
Survey (SF-36) according to the Core Outcome Set for Cardiac Arrest (COSCA) initiative 
recommendations on the use of outcome measures of health-related quality of life 
(HRQOL).  


VIGAB-STAT IIa Protocol 
 
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B. Exploratory safety outcomes 
a. Retinopathy 
Concentric visual defects have been reported with chronic use of VGB. As such, we will be 
detecting rates of retinopathy on vision loss screening via Goldmann perimetry upon 
regain of consciousness during index hospitalization (earliest time-point during which 
subject is able to cooperate with testing), ICU discharge and 6 months. In addition, long-
term visual screening at 6 months will include the Visual Function Questionnaire 25 (VFQ-
25). We do not expect to observe visual field restrictions with a single load of VGB as visual 
toxicity correlates with high doses and prolonged therapy. Concentric visual defects with 
chronic use of VGB may be related to a decrease in taurine levels. We will monitor taurine 
levels at baseline, 72 hours, and 7 days post-VGB administration. We anticipate that a 
single load of VGB would not lead to a statistically significant reduction in taurine levels. 
b. MRI brain 
Prolonged VGB therapy has also been associated with reversible MRI changes in the basal 
ganglia, thalamus, cerebellum, and brainstem. Unconscious CA survivors undergo brain 
MRI between 2- and 7-days post-CA for neuroprognostic purposes as a standard of care. 
We will note the proportion of subjects with MRI changes in the VGB cohort. 
C. Exploratory pharmacologic outcomes 
a. Pharmacodynamics (PD) – ASD interactions.  
b. VGB may reduce or increase serum levels of ASDs. We will monitor daily levels of 
antiseizure medications that are co-administered with VGB for 3 days to characterize 
these potential drug-drug interactions and ensure optimal dosing. 
Rationale for chosen outcomes 
The phase IIa study is a feasibility study and is not powered to address efficacy or safety. We will collect 
these metrics and track percent of missing data and the time for completion to inform which clinical 
variables pertaining to efficacy and safety will become primary and secondary clinical outcomes in 
subsequent study phases. 
The explicit purpose of this feasibility study is to deliver the drug within 48 hours of PASE onset and have 
measurable levels by 3-12 hours post-load in addition to completing visual screening. The reported 
bioavailability of VGB is 100%, with a wide volume of distribution, minimal binding to blood proteins and 
elimination mainly through renal clearance[42]. While plasma concentrations of VGB do not correlate with 
its effectiveness[42], they confirm successful absorption of this drug. Renal impairment is common after 
CA[66] and creatinine clearance influences VGB elimination[62]. Further, several other factors may affect 
VGB absorption in the post-CA period. Thus, we will follow serial VGB levels to characterize enteric 
absorption and clearance in this setting. Furthermore, given the potential for drug-drug interactions 
among ASDs, we will be monitoring other ASD levels. For example, up to a 20% reduction in total 
phenytoin plasma levels can be seen with co-administration of VGB[42, 67, 68], while up to a 10% increase 
in carbamazepine levels has been observed with co-administration of VGB[42].  
Most landmark clinical trials with VGB did not include critically ill subjects. However, a recent trial 
evaluating the potential neuroprotective effects of VGB in severe traumatic brain injury demonstrated 
adequate absorption and elevated cerebral GABA levels as determined by microdialysis[53, 54]. Our study 
follows a design used in other studies, measuring serial VGB levels at baseline, 1, 3, and 12 hours following 


VIGAB-STAT IIa Protocol 
 
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VGB administration[53]; the addition of 0-, 0.5-, 1-, 2-, 3-, 6-, 12-, 24-, 48-, 72- and 168-hour (7 days) level 
measurements is aimed at accurately describing absorption, confirming clearance of the drug, and 
confirming the reported lack of correlation of drug levels with a sustained clinical effect. A pre-dose 
sample allows for confirmation that VGB is not already present in the study subjects and no interference 
in the quantification method. 
Variation in anesthetic infusion weaning practices may confound the interpretation of successful wean 
from anesthetics. Further, anesthetics may be given to patients for other reasons than PASE treatment 
such as to maintain tolerability of mechanical ventilation and TTM. Thus, we chose to examine multiple 
secondary outcomes that could more accurately reflect the therapeutic effect of VGB and track the 
indication for maintaining anesthetic infusion rates daily. All the endpoints are objective and will be 
assessed by a blinded investigator to the timing of VGB administration. 
5. Eligibility 
Inclusion criteria 
After Institutional Review Board approval, individuals (and their legally authorized representative) 
meeting the following inclusion criteria will be approached: 1) 18 – 80 years of age, 2) non-traumatic CA 
(regardless of non-perfusing rhythm, etiology, or location of arrest) in whom the decision to treat 
unequivocal electrographic SE (as defined by the American Clinical Neurophysiology Society[69]: having 
generalized spike/sharp-wave discharges ≥ 3Hz or any evolving pattern reaching > 4Hz, lasting ≥ 10 
minutes, or comprising > 50% of any hour of recording) has been made. The inclusion criteria will be 
expanded to include presumed electroclinical status epilepticus defined in this study as ictal-interictal 
continuum patterns of at least 1Hz as long as patient is treated with an antiseizure medication per the 
decision of the clinical treatment team. The time of onset for PASE in this setting will be the time of the 
loading dose of antiseizure medication. 3) requiring anesthetic infusion for any reason, 4) have reliable 
arterial access for frequent blood sampling and 5) established enteral access within 48h of PASE onset. 
The patient’s legal authorized representative (LAR) will be identified with the clinical, research, and social 
work teams. The legal authorized representative will be approached to provide consent for participation 
in the study, during the patient’s acute phase of ICU care after cardiac arrest, while the patient is in coma, 
undergoing continuous seizure monitoring.     In the event COVID related restrictions do not allow for the 
LAR to come to the floor, we will proceed with remote consenting procedures with IRB approved scripts.  
Should the patient regain consciousness at any time during the 6-month study duration, they will 
individually be approached to provide their consent for continued participation in the research protocol. 
Further details on consent process are provided in Section 9.  
Exclusion criteria 
Those with prior history of generalized epilepsy, history of gastrointestinal surgery within the last 21 days, 
and pregnant women will be excluded. In addition, those with PASE onset preceding initiation of EEG 
monitoring will be excluded.  
Note on inclusion and exclusion criteria 
Outcomes following successful resuscitation in CA are multifactorial and depend on both the severity of 
systemic (myocardial, renal, and liver dysfunction) complications and the neurologic post-CA syndrome. 
Post-anoxic status epilepticus may occur following any type of CA, regardless of the location of its 
occurrence (out-of-hospital versus in-hospital) or the type of non-perfusing rhythm. Thus, we will include 


VIGAB-STAT IIa Protocol 
 
14 
 
all non-traumatic types of CA in this study. As with other ASDs, VGB may exacerbate certain types of 
primary epilepsy. Thus, we elect to exclude individuals with a history of primary generalized epilepsy. 
Lastly, as there is no parenteral formulation of VGB, enteral access is a requirement for participation in 
this study. 
Note on inclusion window 
The window from SE onset to drug delivery of 48 hours is very short, particularly when consent from a 
legally authorized representative is pursued in the acute setting and enteral access for drug delivery is 
required. To expedite the process, we will approach the legally authorized representatives of potential 
participants for consent as soon as interictal epileptiform activity is identified on EEG as these subjects 
are at high risk for subsequent PASE[70-72]. 
 
Exit from the study 
Any subject (or legally authorized representative) is free to withdraw consent from the trial at any time. 
Doing so will constitute exit from the study. The reason for withdrawal will be collected and reported, 
including specifics as to which aspects of the trial from which consent and participation are withdrawn 
(e.g., attending follow-up visits, completing diagnostic testing, and allowing for inclusion of their data 
(including survival data) in a database or publication. According to federal requirements for FDA-regulated 
clinical trials, all data collected up to the point of subject withdrawal must be maintained in the database 
and included in subsequent analyses, as appropriate. Legal authorized representative and/or subjects will 
be informed of this requirement.   
Discontinuation of the study intervention by the treating physician due to any adverse events, for 
example, does not constitute subject withdrawal from the study, and therefore, the subject will not exit 
the trial. 
6. Trial design 
Phase IIa: This is a feasibility, single center, open-label pilot, with blinded outcome assessment, of early 
administration a single 4,500mg (or dose adjusted in moderate and severe impairment) VGB in 12 
consecutive PASE subjects.  
 
 
General critical care 
General critical care will be standardized as much as possible for all subjects across various treatment 
sites. Management of fluid homeostasis, hemodynamics, respiration, metabolic disturbances, and 
seizures will be according to local protocols and standard of care.  
 Sedation  
There will not be a specifically-defined protocol for sedation analgesia for the purposes of the study. 
Documentation will be required on the indication for changes in the level of sedation. The bedside nurse 
will notify the study coordinator when titration of sedatives is required and inform clinical reasoning.  
For purposes of data analysis for clinical outcomes, thresholds will be established for anesthetic infusions, 
whereby dosing below the threshold will be considered comfort/sedative dosing only, while dosing above 
the threshold will be considered as anti-seizure treatment, regardless of the indication. The anesthetic 


VIGAB-STAT IIa Protocol 
 
15 
 
thresholds will be as follows: 1) midazolam ≥ 0.1 mg/kg/h, 2) propofol ≥ 50 mcg/kg/min, and 3) ketamine 
≥ 1 mg/kg/hr.  
 Targeted temperature management 
Post-CA practices are evolving with the emergence of highly impactful clinical trials and clinical practices 
of temperature modulation may vary. It is expected that a subset of patients will be treated with TTM, 
with target temperatures ranging from 32-37.5 degrees Celsius. Target temperature selection will be left 
at the discretion of treatment team. Details of TTM phase of care will be collected, whenever applicable. 
 Monitoring for and treatment of seizures 
Continuous EEG monitoring will be connected as soon as possible after CA, with a targeted time from 
ROSC to EEG connection of 6-12 hours post-ROSC. For the phase IIa at the University of Florida, the 
order set for post-CA care includes a STAT order for EEG to be connected, which prompts the EEG 
technician to contact the bedside nurse to coordinate hookup.The clinical management of status 
epilepticus in the post-CA period has been standardized via a treatment algorithm at the University of 
Florida and UF Health Shands Hospital. Diversions from the algorithm will be at the discretion of the 
treating neurocritical physician and will be documented in study records. 
 Monitoring for markers of secondary brain injury (chemical biomarkers) 
We will compare changes on NSE over time between VGB-treated and non-VGB-treated PASE subjects as 
a potential indirect metric of neuroprotection as higher neuronal injury burden is associated with elevated 
NSE [73-75], GFAP and NfL[76].  Biomarkers will be measured serially at five timepoints including at 0h, 
24h, 48h, 72h, and 4d (96h) post vigabatrin administration. 
 
 Shivering 
Shivering will be assessed according to the Bedside Shivering Assessment Scale (BSAS). Goals of treatment 
are to maintain BSAS score 0-1, which will be done for all subjects and tiered prevention and therapeutic 
approach will be implemented according to institutional practices.  
Screening  
Screening will be done according to the inclusion and exclusion criteria and will be performed in multiple 
clinical areas, including the Emergency Department and ICU. The PI and co-investigators will be 
responsible for screening the EEG of eligible subjects for PASE development four times daily.  
We will maintain a screening log to keep track of all eligible subjects, which will inform future decisions 
on inclusion/exclusion criteria in the subsequent study phases. 
Blinding 
The phase IIa feasibility study is open label. However, EEG recordings and Visual Field Perimetry will be 
centrally analyzed at the EEG and Visual Screening cores by an assessor that is blinded to the timing of 
VGB administration and drug levels. De-identified EEG recordings will be exported to Yale University for 
central analyses by Dr. Hirsch, and de-identified Visual Field Perimetry studies will be exported to Dr. 
Sergott at Tomas Jefferson University for central analyses in a blinded fashion. Clinical outcomes will be 
obtained by trained study personnel blinded to the timing of VGB administration and drug levels. 


VIGAB-STAT IIa Protocol 
 
16 
 
Intervention period  
 Drug administration 
University of Florida (UF) Health Shands Hospital is enrolled in the Vigabatrin Risk Evaluation and 
Mitigation Strategy (REMS) program.  The Vigabatrin drug supply for this protocol will be purchased, 
stored, and dispensed through the Investigational Drug Services Pharmacy satellite of the UF Health 
Shands Hospital Pharmacy Department.  The study drug will be segregated from commercial supply 
Vigabatrin.  Investigational supply would be dispensed upon enrollment, consent, and receipt of a valid 
order for investigational supply Vigabatrin by a protocol authorized prescriber.  Prior to dispensing, the 
protocol-trained, REMS-trained pharmacist would verify the authorized prescriber, patient REMS 
enrollment, document the REMS ID numbers and obtain authorization to dispense through the REMS 
program.   
Subjects will receive a one-time loading dose of 4,500 mg of VGB (or dose adjusted in moderate and 
severe impairment) in powder for oral solution formulation (9 packets of 500mg each, each mixed with 
10 ml of water at room temperature, for a total of 90 ml of water and 4,500mg VGB dosing) will be 
administered via enteric tube (naso/orogastric or post-pyloric) within 48 hours of status epilepticus 
onset. For subjects requiring a dose adjustment for renal impairment, the total volume administered will 
be dictated by dose of Vigabatrin (10mL of water for each 500mg packet).. If subjects are receiving the 
study drug through an NG/OG tube that is ordered to be connected to suction, the tube will remain 
clamped for a minimum of 30 minutes. Vigabatrin will not be co-administered with other enteral drugs, 
and no drugs will be given +/- 15 minutes of Vigabatrin administration (when possible per standard of 
care). Subjects will be considered screen failure if VGB is not administered within exact 48 hours from 
electrographic status epilepticus onset. This dose is in conjunction with a loading dose of ASD according 
to local practices and standard of care. This will be done within 48h of PASE onset in successfully 
resuscitated CA subjects. 
 
 Drug absorption 
VGB level will be monitored serially at baseline (prior to load), 0.5h (+/- 5 minutes), 1h (+/- 5 minutes), 2h 
(+/- 15 minutes), 3h (+/- 15 minutes), 6h (+/- 15 minutes), 12h (+/- 15 minutes), 24h (+/- 30 minutes), 48h 
(+/- 30 minutes), 72h (+/- 30 minutes), and 7d (168h) (+/- 30 minutes) post-VGB administration along with 
daily levels of concurrent ASD. All PK samples will be collected from an arterial line. If sufficient arterial 
access is not available at the scheduled time, peripheral venipuncture will be the preferred second 
method of blood collection, and will be noted in source documentation. The study team will provide 
support to clinical nursing staff in order to ensure prioritization and timeliness of study-specific activities. 
After the intervention period  
 Screening for visual adverse events 
The main adverse effect associated with VGB is visual loss from retinopathy[77, 78], which may lead to 
concentric visual field defects that may be related to taurine deficiency. Therefore, vision loss surveillance 
comprised of  serial taurine levels and Goldmann perimetry (to assess visual changes/visual loss should 
the patient regain of consciousness), during their  6 month follow-up visit; Goldmann perimetry is a 
validated method to monitor for and quantify potential effects of VGB treatment[79-83]. In addition, a 
VFQ-25 will be administered at 6-month follow up visit.  


VIGAB-STAT IIa Protocol 
 
17 
 
Other anticipated adverse events 
The risks of drawing blood from a vein include discomfort at the site of puncture; possible bruising and 
swelling around the puncture site; rarely an infection. As arterial and central line catheters are used for 
several days in the post-cardiac arrest period, these risks associated with the blood draws are less likely 
to occur when blood sampling is not via puncture.  
The adverse events commonly seen with continued use of VGB (such as fatigue, somnolence, dizziness 
and imbalance, abnormal eye movement, tremor, memory impairment, weight gain, joint pain, and 
confusion) are less expected to be evident in this patient population, as coma precludes the assessment 
of pain, fatigue, and cognitive symptoms.   
 
Prognostication 
 Clinical examination 
Per standard of care, a daily sedated neurological exam will be completed on each subject. Attention will 
be paid to presence of myoclonus post-CA and its semiology, the presence of any clinical correlate to 
electrographic PASE, and the coma exam. We will also collect pupillometry measurements during daily 
neurological exams and at 1h post VGB load. We subscribe to the AHA and ESICM guidelines, which highly 
encourage the use of a multimodal approach to neuroprognostication. Current guidelines recommend a 
minimum of 72 hours post-complete rewarming before neuroprognostication to give every effort to avoid 
premature WLST in subjects with a chance of neurological recovery. 
 EEG  
A minimum monitoring of 72hours post-ROSC is standard of care at University of Florida. The presence of 
epileptiform discharges, continuity, and reactivity of background to a standardized protocol of escalating 
external stimulation will be noted.   
Brain CT 
In accordance with local practices, a noncontrast CT of head is strongly recommended in cases of unclear 
CA etiology. The presence of early hypoxic-ischemic brain injury such as gray-white differentiation and 
diffuse cerebral edema will be noted. In subjects that do not regain consciousness within 48 hours of 
ROSC, a repeat noncontrast CT is recommended for prognostication. 
 Brain MRI 
MRI brain without gadolinium will be obtained in post-CA unconscious subjects within 2-7 days of ROSC, 
if deemed safe according to the treatment team according to local prognostication practices. The 
presence of hypoxic-ischemic brain injury, and the pattern of DWI restriction will be noted.  
 NSE 
Serial NSE (daily for 5 days) is obtained according to local prognostication practices. The presence of 
hemolysis and the type of assay used, as well as titers will be recorded.  
 SSEP 
Somatosensory evoked potentials are a reliable prognosticator after 48hours of ROSC. The presence or 
absence of N20 peaks will be noted.  


VIGAB-STAT IIa Protocol 
 
18 
 
VIGAB-STAT criteria for a likely poor neurologic outcome 
 Death 
The time and mode of death (related to WLST or care limitation, recurrent and refractory CA, brain 
death) will be noted. Brain death will be determined by institutional protocol and if organ support is 
maintained for reasons other than the purpose of the study, study data will continue to be obtained 
with patient LAR approval. 
 WLST 
Goals of care and decision making related to end of life will be led by treatment teams. EEG monitoring 
will continue as long as the subject remains in PASE until the decision of withdrawal of life sustaining 
therapies and transition to comfort measures only is made.  
Recurrent cardiac arrest 
With recurrent episodes of CA, subjects will remain eligible following ROSC as long as the decision to 
maintain aggressive care is in place.  
Follow up 
Formal follow-up appointments will be conducted at 6 months (+/- 1 month) post-CA, whether the subject 
remains hospitalized or discharged. A voucher of $25.00 will be provided upon discharge to assist with 
transportation for the 6 months visit. Follow-up appointments will be conducted by blinded assessors and 
focusing on cognitive function, quality-of-life, and recurrence of seizures. The assessor may be any 
qualified provider including physician, research nurse, or extended provider. The assessment will consist 
of a structured telephone interview for those that are unable to participate in in person visits. Epilepsy 
assessment will consist of a brief questionnaire asking about recurrent seizures and number of ASD 
required for maintenance therapy.  
7. Co-enrollment 
MOCHA and SPARE 
When meeting inclusion criteria, participating centers also involved in the MOCHA and/or SPARE trials will 
obtain consent and co-enrollment in the appropriate trial(s). The MOCHA trial is an observational trial, 
and co-enrollment with other studies (registries or interventional trials such as VIGAB-STAT) is permitted 
as long as the other study protocols do not call for premature neuroprognostic assessments earlier than 
72 hours post-CA. Therefore, each subject’s co-enrollment eligibility will be reviewed on a case-by-case 
basis. If enrolling sites are in agreement, and the studies under consideration at a given site are approved 
by the Steering Committee, the subject may be co-enrolled in MOCHA, SPARE, or other studies.  
 


VIGAB-STAT IIa Protocol 
19 
 
8. Data Collection 
Test/Lab 
Baseline 
D0 
D1 
D2 
PASE 
VGB 
Administered 
(0h) 
0.5h 
1h 
2h 
3h 
6h 
12h 
24h 
48h 
72h 
96h 
120h 
168h 
D14/ICU 
Discharge 
Hospital 
Discharge 
D180 
Review of 
Eligibility: 
Inclusion/Exclusion 
Criteria 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac-specific 
Treatments and 
Assessments 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
Assessments 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pupillometry 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
FOUR 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medications 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
mRS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
GOS-E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
CPC-E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


VIGAB-STAT IIa Protocol 
 
20 
 
MoCA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
EMSE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
VGB level 
 
 
 
 
 
Xc 
Xe 
Xe 
Xf 
Xf 
Xf 
Xf 
Xg 
Xg 
Xg 
 
 
Xg 
 
 
 
Standard Anti-
seizure drug level 
 
 
 
 
 
Xc 
 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
 
 
 
Routine complete 
blood cell count, 
complete 
metabolic panel, 
ABG, lactic acid 
x 
x 
x 
x 
x 
 
 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
Biomarkers: NSE, 
GFAP, NfL, UCH-L1, 
tau 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Taurine level 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
cEEG 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
Goldmann 
perimetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
VFQ-25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Events 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Discharge 
Summary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
a 
Time in days (D) refers to time from CA, while time in hours (h) refers to time from VGB load, unless otherwise specified. 


VIGAB-STAT IIa Protocol 
 
21 
 
 
c 
Baseline testing will be done prior to administration of VGB load. 
d 
Baseline testing will be done as soon as the patient is able to cooperate. 
e 
Acceptable window for collection is +/- 5 minutes. 
f 
Acceptable window for collection is +/- 15 minutes. 
g 
Acceptable window for collection is +/- 30 minutes. 
 
 
 
 
 


VIGAB-STAT IIa Protocol 
22 
 
Baseline data 
 Subject characteristics 
• 
Inclusion/exclusion criteria 
• 
National identification number 
• 
Demographics 
 Pre-hospital data 
• 
Drugs administered 
 Background data 
• 
Medical history 
• 
Home medications 
• 
Factors predisposing to seizure (e.g., prior traumatic brain injury or other structural injury, 
history of epilepsy, congenital malformations) 
• 
Routine blood work (standard of care): complete blood count, complete metabolic panel, ABG, 
Lactic Acid 
Data on hospital admission 
• 
FOUR-score 
• 
Neurological assessments 
• 
Signs of PASE prior to EEG monitoring 
Data on ICU phase 
 Data prior to VGB load 
• 
VGB level 
• 
ASD level 
• 
Taurine level 
• 
Brain injury biomarkers panel: NSE, tau, GFAP, UCH-L1, NfL 
• 
Pupillometry measurements 
Data during the intervention 
• 
FOUR-score 
• 
Pupillometry (1h post VGB load) 
• 
Levels and labs as in chart, including all daily blood work obtained as standard of care 
• 
Brain injury biomarkers panel: NSE, tau, GFAP, UCH-L1, NfL for 5 days following VGB 
 
 Daily during the ICU stay 
• 
FOUR-score 
• 
Neurological assessments and pupillometry 
• 
Serious adverse events (SAEs) 
• 
If active intensive care is withdrawn, specify reason 
• 
Levels and labs as in chart, including all daily blood work obtained as standard of care 
• 
Code status, changes in code status, and level of medical intervention 


VIGAB-STAT IIa Protocol 
 
23 
 
 Status epilepticus data 
• 
Time from VGB load to resolution of PASE 
• 
Time from VGB load to start of anesthetic wean 
• 
Total duration of anesthetic infusion for SE treatment 
• 
Overall number of anti-seizure drugs required for PASE resolution 
• 
EMSE 
 At ICU discharge 
• 
FOUR-score 
• 
Time when obeying verbal commands (awake – FOUR-score M4) 
• 
Duration of mechanical ventilation 
• 
ICU length of stay 
• 
CPC, mRS, GOS-E 
At hospital discharge 
• 
FOUR-score 
• 
Discharge status (e.g., good, fair, stable, poor, critical, dead) 
• 
CPC, mRS, GOS-E, first portion of CPC-E 
• 
Discharge destination  
180 days after intervention 
• 
Survival status 
• 
CPC, mRS, GOS-E, second portion of CPC-E 
• 
MoCA 
• 
Goldmann perimetry 
• 
VFQ-25 
• 
SF-36 
9. Ethics and informed consent 
Informed consent from a legal authorized representative, including counseling and enrollment required 
in accordance with Risk Evaluation and Mitigation Strategies (REMS) program by a certified REMS 
physician, will be obtained for all patients prior to VGB administration.  The consent form must also be 
signed by the investigator seeking the consent.  In the event of COVID related restrictions preventing the 
LAR from coming to the floor,  the research staff will email the informed consent to the LAR and schedule 
a time for the PI and the LAR to discuss the trial.  This will be documented according to Good Clinical 
Practice standards.  The study will be explained described to the legal authorized representative in an 
appropriately considerate manner by the principal investigator or certified REMS physician co-
investigator, and the legal authorized representative will have opportunity to ask additional clarifying 
questions.  
The social worker assigned to the case (either in the ED or the ICU) will assist with the timely and accurate 
identification of legal authorized representative (LAR). The LAR will consent on behalf of the subject per 
regulatory requirements, until such time that the subject is able to consent for themselves. This is deemed 
to be consistent with the Declaration of Helsinki article 30 available from the World Medical Association. 


VIGAB-STAT IIa Protocol 
 
24 
 
Subjects regaining consciousness will be assessed for capacity by the treating neurologist, and if deemed 
to have capacity to participate in the informed consent process, will be asked for written consent as soon 
as they are able to make an informed decision. Assessment for capacity will be completed on an as-needed 
basis. The consenter will be provided with written and oral information on this trial to make an informed 
decision about participation in the trial. LARs will be counseled that decisions on research participation 
should be made in accordance with the subject’s values and wishes. If these are unknown, the LAR will be 
counseled to make such decisions in the best interest of the subject. Potential subjects and their LARs will 
only be approached after the attending physician responsible for care of the patient has discussed the 
potential subject’s prognosis (including the possibility of terminal illness or disability) with the potential 
subject and LAR. The investigator will coordinate directly with the attending physician to ensure this 
discussion has occurred prior to informed consent. The consent form must be signed by the participant 
or legally acceptable surrogate and by the investigator seeking the consent.  
10. 
Data management 
Data handling and record keeping 
Individual subject data will be handled according to HIPAA and individual institutional policy. All subject 
data will be made anonymous when translated to study database. Raw EEG recordings will be de-
identified, assigned a study ID, and exported in EDF format to Yale University via secure cloud system. 
Visual Field Perimetry will be de-identified, assigned a study ID, and exported to Tomas Jefferson 
University for central analyses via secure cloud system.  
Quality control and quality assurance 
This trial will be monitored independent of the institution by a hired service. The frequency of on-site 
monitoring will depend on compliance with the protocol, number of enrolled subjects and data handling. 
At a minimum, there will be a pre-study visit, one during the study, and one post-study. All participating 
sites will abide by the same quality control protocol, CRF, inclusion/exclusion criteria, registration 
instructions, randomization protocol, and specific medical treatment protocols. 
11. 
Adverse events 
Definitions 
Defining adverse events and distinguishing between these and sentinel events will be the sole 
responsibility of the primary and each local investigator. Documentation and reporting of events will 
depend on institutional policy and the local investigator.  
An adverse event (AE) is any untoward medical occurrence in a clinical trial subject. These are expected 
in all subjects with ROSC from CA, and therefore, AEs that may be related to study intervention will be 
reported. 


VIGAB-STAT IIa Protocol 
 
25 
 
Safety monitoring plan 
The principal investigator will monitor the patient safety data for each AE and serious AE within 24 hours 
of occurrence. Several serious adverse events are expected to occur given the severity of the condition 
being studied. Each adverse event will be adjudicated to determine if it is possibly related to the study 
drug or unrelated. If the principal investigator feels there is possible harm to subject safety or the 
possibility of, any harm due to something new that was learned during the study, she will activate the 
multi-disciplinary Data Safety Monitoring Committee for this trial. The Data Safety Monitoring Committee 
is comprised of a Neuro-Ophthalmologist (Dr Bryce Buchowicz), 2 Neuro-intensivist (Dr. Katharina Busl 
and Dr. Michael Pizzi), 1 Medical Intensivist (TBD). The committee will meet to discuss and review any 
referred event.  
 
Additionally, this study will have a designated Data Safety Monitoring Board comprised of 5 members 
without ties to the current study or any conflicts of interest:  1 Emergency Medicine and Critical Care 
specialist (Dr. Casey Carr), 1 general neurologist with expertise in clinical trials (Dr. -Matthew Burns), 2 
epileptologists (Dr. Giridhar Kalamangalam and Dr. Maria Bruzzone), 1 cardiologist (Dr. Alexander Parker), 
and 1 Pulmonary Critical Care specialist (Dr. Ali Khawaja). The DSMB will be charged with the duty of 
meeting every 6 months to discuss all the adverse events for the study, and generate a written report 
which will be submitted to the IRB.  The DSMB will be informed of all serious adverse events and all mild 
adverse events which are potentially study-related in the opinion of the investigator. The PI will designate 
each adverse event as mild or severe; determine relatedness to intervention; and indicate anticipated or 
unanticipated. The DSMB may employ a stopping rule for greater than 1 drug related death.  
 
Reporting of serious adverse events 
A serious adverse event (SAE) is defined as any event that: 
• 
Results in death 
• 
Is life-threatening 
• 
Requires hospitalization or increased length of stay 
• 
Results in persistent or significant disability or incapacity 
12. 
Statistical plan and data analyses 
Phase IIa sample size 
12 subjects from the University of Florida 
Analysis methods 
This feasibility pilot is not intended to detect therapeutic effects. Thus, we have omitted power 
calculations. 
 Primary outcome 
Descriptive statistics with rates and proportions will be obtained regarding feasibility outcomes. 
Regarding the PK outcome, we will use the noncompartmental method for pharmacokinetic analyses. The 
key pharmacokinetic parameters, maximum concentration in plasma (Cmax) and the time to reach 


VIGAB-STAT IIa Protocol 
 
26 
 
maximum concentration (Tmax) will be determined directly from the plasma concentration-time profile of 
each participant. The area under the VGB concentration-time curve in plasma from zero to the time of the 
last quantifiable concentration (AUC0-tlqc) will be calculated using the linear trapezoidal methods, and the 
AUC will be extrapolated to infinity for the evaluation of AUC0-inf. 
 Secondary outcome 
For exploratory aim 1, we will calculate the rate of retinopathy and the proportion of subjects with MRI 
changes. For exploratory aim 2, standard summary statistics will be provided for the post-VGB time to 
resolution of PASE, post-VGB time to start of anesthetic wean, overall number of anti-seizure drugs 
required for PASE resolution, total duration of anesthetic infusion for PASE treatment, duration of 
mechanical ventilation, intensive care unit length-of-stay, and cerebral performance category scale at 
hospital discharge and at 6 months.  
 
Missing data 
Missing data will be reported.  
Subgroup analysis 
Subgroups that will be analyzed during subsequent phases of the trial include: 
• 
GFR 
• 
Need for and mode of renal replacement therapy 
• 
Type of feedings 
• 
Elderly vs non-elderly 
• 
Neuromuscular blockade 
• 
Vasopressor use  
 
13. 
Publication of data 
The trial will be analyzed by an independent statistician, and the results interpreted by the steering group. 
All individual data will remain confidential. The final manuscript will be submitted to a peer-reviewed 
international journal. Authorship will be granted using the Vancouver definitions and depending on 
personal involvement. The author list will include the steering group members, national investigators, and 
additional names in alphabetical order.  
14. 
Insurance 
15. 
Funding 
American Heart Association Innovative Project Award 20IPA35380013 
 
16. 
Timeline 
Project Start Date: April 10th, 2021 
 


VIGAB-STAT IIa Protocol 
 
27 
 
 
17. 
Trial participants 
 
Steering Committee: 
 
Carolina Maciel, MD  
 
PI, Neurocritical Care, University of Florida 
Lawrence J. Hirsch, MD 
 
EEG Core, Chief of Epilepsy, Yale University 
Charles Peloquin, PharmD 
 
PK Core, University of Florida 
Robert Sergott, MD 
 
 
VS Core, Chief of Neuro-Ophthalmology, Wills Eye Hospital 
David M. Greer MD, MA 
 
CI, Neurology, Boston University 
Alejandro Rabinstein, MD 
 
CI, Neurology, Mayo Clinic 
Ramani Balu, MD, PhD 
 
CI, Neurology, University of Pennsylvania 
Eugene Ramsay, MD  
 
CI, Director of Ochsner Comprehensive Epilepsy Center 
Monica Dhakar, MD  
 
CI, Neurology, Emory University 
Kent A. Owusu, PharmD 
 
CI, Yale-New Haven Health 
Stephan Eisenschenk, MD 
 
CI, University of Florida 
 
 
Investigators responsibilities 
 
18. 
Appendices 
FOUR score 
A 
The FOUR Score 
Eye response 
Eyelids open and tracking, or blinking on command 
 
 
 
4 
Eyelids open but not tracking 
 
 
 
 
 
 
3 
Eyelids closed but open to loud voice 
 
 
 
 
 
2 
Eyelids closed but open to pain  
 
 
 
 
 
1 
Eyelids closed with pain 
 
 
 
 
 
 
0 
 
Motor response 
Makes sign (thumbs-up, fist, other) 
 
 
 
 
 
4 
Localizing to pain 
 
 
 
 
 
 
 
3 
Flexion response to pain 
 
 
 
 
 
 
2 


VIGAB-STAT IIa Protocol 
 
28 
 
Extension response to pain  
 
 
 
 
 
 
1 
No response to pain 
 
 
 
 
 
 
 
0 
Generalized myoclonic status  
 
 
 
 
 
0 
 
Brainstem response 
Pupil reflexes present, corneal reflexes present, and cough present 
 
4 
One pupil wide and fixed, corneal reflexes present, and cough present  
3 
Pupil reflexes absent, corneal reflexes present  
 
 
 
2 
Pupil reflexes present, corneal reflexes absent  
 
 
 
2 
Pupil reflexes absent, corneal reflexes absent, cough present 
 
 
1 
Pupil reflexes absent, corneal reflexes absent, cough absent 
 
 
0 
 
Breathing 
Not intubated with regular breathing 
 
 
 
 
 
4 
Not intubated with Cheyne-Stokes type of breathing 
 
 
 
3 
Not intubated with irregular breathing  
 
 
 
 
2 
Not intubated with apnea 
 
 
 
 
 
 
0 
Intubated with breathing above ventilator rate  
 
 
 
1 
Intubated with breathing at ventilator rate 
 
 
 
 
0 
 
mRS 
B 
Modified Rankin Scale 
0 
No symptoms 
1 
No significant disability, despite symptoms; able to perform all usual duties and activities. 
2 
Slight disability; unable to perform all pervious activities but able to look after own affairs 
without assistance. 
3 
Moderate disability; requires some help, but able to walk without assistance. 
4 
Moderately severe disability; unable to walk without assistance and unable to attend to own 
bodily needs without assistance. 
5 
Severe disability; bedridden, incontinent, and requires constant nursing care and attention. 


VIGAB-STAT IIa Protocol 
 
29 
 
6 
Dead 
 
CPC 
C 
Cerebral Performance Category (CPC) score scale 
CPC1 
Good cerebral performance: conscious, alert, able to work, might have mild neurologic or 
psychologic deficit. 
CPC2 
Moderate cerebral disability: conscious, sufficient cerebral function for independent activities of 
daily life. Able to work in sheltered environment. 
CPC3 
Severe cerebral disability: conscious, dependent on other for daily support because of impaired 
brain function. Ranges from ambulatory state to severe dementia or paralysis. 
CPC4 
Coma or vegetative state: any degree of coma without the presence of all brain death criteria. 
Unawareness, even if appears awake (vegetative state) without interaction with environment; 
may have spontaneous eye opening and sleep/awake cycles. Cerebral unresponsiveness. 
CPC5 
Brain death: apnea, areflexia, EEG silence, etc. 
Glasgow Outcome Scale – Extended 
 
1 
Death 
2 
vegetative state 
3 
lower severe disability 
4 
upper severe disability 
5 
lower moderate disability 
6 
upper moderate disability 
7 
lower good recovery 
8 
upper good recovery 
 
 
Epidemiology based Mortality score in Status Epilepticus (EMSE) 
D 
EMSE Scoring 


VIGAB-STAT IIa Protocol 
 
30 
 
 
Version history 
 
 
 
References 
 
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Medicine Io (2015) Strategies to Improve Cardiac Arrest Survival: A Time to Act. In: Editor 
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854 
 

ICF_001.pdf: 
IRB Project #: 202003076 
Page 1 of 16 
IRB Version: 10/01/2018 
PI Version: 09/08/2021 
Cover page for VIGAB-STAT 
 
Sponsor Name 
American Heart Association 
NCT number 
NCT04772547 
Official Title of Study 
A phase IIa feasibility trial of irreversible GABA-transaminase inhibition 
as adjunct treatment of status epilepticus after cardiac arrest 
Document date 
8 September 2021 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


IRB Project #: 202003076 
Page 2 of 16 
IRB Version: 10/01/2018 
PI Version: 09/08/2021 
 
INFORMED CONSENT FORM 
to Participate in Research, and 
AUTHORIZATION  
to Collect, Use, and Disclose Protected Health Information (PHI) 
 
INTRODUCTION 
 
 
If you are the legally authorized representative for the subject, as you read the information 
in this Consent Form, you should put yourself in the subject’s place to decide whether or 
not to allow us to collect research information about the subject and to allow the subject to 
take part in this study.  Therefore, for the rest of this form, the word “you” refers to the 
subject (adult participant). 
 
If you are an adult participant reading this form, the word "you" refers to you. 
 
Name of person seeking your consent: 
 
 
Place of employment & position:  
 
 
 
GENERAL INFORMATION ABOUT THIS STUDY 
 
1. Name of Participant ("Study Subject") 
 
___________________________________________________________________  
 
2. What is the Title of this research study (this “Research Study”)? 
VIGAB-STAT IIa:  Vigabatrin in post-anoxic status epilepticus – Phase IIa 
 
3. Whom do you call if you have questions about this Research Study (the “Study 
Team”)? 
 
Principal Investigator: Carolina B. Maciel, MD, MSCR  (352) 273-5550 
 
Other research staff:  Study Coordinator at (352) 273-5554 
 
4.   Who is paying for this Research Study? 
  
The sponsor of this study is American Heart Association. 


IRB Project #: 202003076 
Page 3 of 16 
IRB Version: 10/01/2018 
PI Version: 09/08/2021 
5. In general, what do you need to know about this Research Study? 
Agreeing to become involved in any research is always voluntary.  By signing this 
form, you are not waiving any of your legal rights.  If you decide not to participate in 
this research, you will not be penalized in any way and you will not lose any benefits 
to which you are entitled. If you have questions about your rights as a research 
subject, please call the University of Florida Institutional Review Board (IRB) office at 
(352) 273-9600.     
a) In general, what is the purpose of the research, how long will you be involved?  
Cardiac arrest claims millions of lives annually, and even after the heart is restarted 
patients have a high risk for death and disability due to brain damage. Up to one in 
three unconscious patients that survives a cardiac arrest may experience 
uncontrollable seizures (or status epilepticus); nearly 100% of these patients 
ultimately die from the degree of brain injury associated with these seizures. Recent 
studies showed that early and aggressive treatment of these uncontrollable seizures  
could vastly improve survival and the degree of disability. These seizures may 
appear with convulsions such as body jerk or without any obvious outward sign, 
therefore, continuous monitoring of the electrical activity of the brain to detect 
uncontrollable seizures and monitor response to treatment is used as standard of 
care.  
This study aims to understand the possibility of using a medication called vigabatrin 
as an early treatment for uncontrollable seizures after cardiac arrest. This 
medication is FDA approved as an add-on medication therapy for patients with 
refractory epilepsy, a condition that renders patients at risk for recurrent seizures 
over their lifetime, but has never been studied in uncontrollable seizures after 
cardiac arrest. This study will look at the ability to provide the drug within a specific 
time period and learn how the drug is absorbed into and eliminated from the body in 
patients that have survived a cardiac arrest. Your involvement will last 6 months, 
during your ICU stay until discharge, and a brief visit 6 months after discharge. 
b) What is involved with your participation, and what are the procedures to be followed 
in the research? While undergoing standard general clinical care for uncontrollable 
seizures: you will receive a one-time dose of 4,500 mg of vigabatrin in addition to 
a dose of an antiseizure drug chosen by your treating physician. This dose will be 
adjusted downward if your kidney function is significantly impaired. Blood levels of 
vigabatrin will be monitored before giving you the drug and at the following intervals 
after drug administration: 0.5h, 1h, 2h, 3h, 6h, 12h, 24h, 48h, 72h, and 7d (168h) 
We will also measure daily levels of any other antiseizure drugs you might be 
taking when applicable.  In addition, blood work will be obtained once daily for 5 
days to check for evidence of damage to the brain cells potentially caused by 
seizure activity. As soon as you are conscious and able, some tests will be given 
to you. You will also have follow-up appointments at which time you will be given 
more tests at 6 months after you leave the ICU. 
c) What are the likely risks or discomforts to you? All of the usual risks and discomforts 
of a stay in the ICU after a cardiac arrest will remain present.  


IRB Project #: 202003076 
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IRB Version: 10/01/2018 
PI Version: 09/08/2021 
The drug will be administered via a feeding tube, which you will already have in 
place as means for providing nutrition during your ICU stay. Visual loss has been 
reported with chronic use of vigabatrin and may be permanent. This is why all 
patients that use vigabatrin must be part of a mandatory registry that is required 
by the FDA, regardless of participating in a study. As such, we will be using a 
specific eye exam called the Goldmann perimetry exam to monitor any potential 
changes to your vision after you get discharged from the hospital at the six-month 
follow-up visit. Further description of this specific exam is explained later in the 
document. Prolonged vigabatrin therapy has also been associated with bright 
spots in some areas of the brain seen on the MRI scan; these changes usually go 
away with time and are unlikely to represent a risk for damage to the brain long-
term. The risk of developing visual loss and these changes in the brain on imaging 
after one dose of vigabatrin is unknown as there have been no cases reporting 
these complications after a single dose. Any antiseizure medication can cause 
confusion, dizziness, somnolence, fatigue during its use, and these side effects 
have also been reported with vigabatrin.  The risks of drawing blood from a vein 
include discomfort at the site of puncture; possible bruising and swelling around the 
puncture site; rarely an infection; and, uncommonly, faintness from the procedure. 
Vigabatrin also has a number of potential side effects and these are detailed under 
Question 12 of this form 
d) What are the likely benefits to you or to others from this research;  
The participation study may provide benefit to you: as vigabatrin is a strong 
antiseizure medication, it may help control your seizures even after just one dose. 
Controlling seizures after a cardiac arrest is important as it may prevent brain cells 
from dying. This study could provide a helpful treatment for patients suffering from 
uncontrollable seizures in the future. The Principal Investigator may benefit from 
publications based on results from this study. 
e) What are the appropriate alternative procedures or courses of treatment, if any, 
that might be helpful to you?  
If you choose not to participate you will still receive the standard treatment options 
for cardiac arrest and uncontrollable seizures during your stay in the ICU. 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law.  This website will not include information that can identify 
you.  At most, the Web site will include a summary of the results. You can search this 
Web site at any time.  
Additional and more detailed information is provided within the remainder of 
this Informed Consent form, please read before deciding if you wish to 
participate in this study 
 
 


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WHAT CAN YOU EXPECT IF YOU PARTICIPATE IN THIS STUDY? 
 
6. What will be done as part of your normal clinical care (even if you did not 
participate in this Research Study)?  
 
General critical care, support of your vital organs such as blood pressure and breathing, 
artificial nutrition and hydration, and management of abnormal blood work results, and 
treatment for seizures will be according to local protocols and standard of care, whether 
or not you participate in the study. You may require special devices to be inserted while 
you are in the ICU, such as an arterial line (a special type of catheter that allows the 
medical team to monitor your blood pressure and draw blood), a central line (a special 
type of IV that travels to your heart), or a feeding tube placed through your nose or 
mouth. You will receive treatment for your cardiac arrest in the standard way. 
 
Standard of care procedures such as blood work, brain imaging with CT or MRI, and 
monitoring for hidden seizures (those without jerking) with continuous brain wave 
monitoring (EEG) will be performed and data from these procedures will become part 
of this study. 
 
7.  What will be done only because you are in this Research Study?  
 
As part of this study, you will receive a one-time dose of 4,500 mg of vigabatrin (or lower 
depending on your kidney function). The study drug will be given by itself, and when 
allowed by your normal clinical care, no other drugs will be given within 15 minutes of 
administration. Drug level will be monitored before giving vigabatrin and afterward at, 
0.5h, 1h, 2h, 3h, 6h, 12h, 24h, 48h, 72h, and 7d (168h) along with daily levels of 
antiseizure drugs you may be taking, each of these blood draws will consist of 1cc of 
blood. In addition, blood work for tests that suggest damage to brain cells will be 
collected once a day for 5 days after receiving the drug, collectively these blood draws 
will consist of 1-2 teaspoonfuls of blood per day. The study team will collect these blood 
samples from your arterial line that was placed as part of your normal clinical care 
whenever possible. If for any reason the study team cannot collect blood from your 
arterial line, we will collect blood through venipuncture. 
 
The study team will perform neurological assessments daily while you are in the ICU. 
As part of the neurological assessments, the study team will take measurements of the 
size of your pupils and how quickly they react to light, called pupillometry. Pupillometry 
is performed with a special device called a pupillometer. It uses a camera to take a 
video of each of your eyes and to calculate your pupil size and how quickly your pupils 
react to light. This test takes 1-2 minutes and does not hurt. As soon as you recover 
from the coma and are able, some tests will be given to you that include questionnaires 
summarizing your level of disability and visual assessment to screen for potential visual 
loss. You will also have formal follow-up appointments at which you will be given more 
tests at 6 months after you leave the ICU. 
A table of scheduled events is included at the end of this form.  
 


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The following tests will be administered and data gathered at the following timepoints. 
 
Baseline 
The following subject characteristics and medical information will be collected 
• Criteria for entry into the study 
 • Demographics  
• Drugs administered 
• Medical history  
• Home medications  
• Factors leading to seizure (e.g., prior traumatic brain injury or other structural 
injury, history of epilepsy, congenital defects)  
•  Results of FOUR-score assessment during admission.  This assessment 
assesses the severity of coma. 
• Neurological assessments  
• Signs of uncontrollable seizures prior to EEG monitoring  
• vigabatrin levels in your blood 
• antiseizure drug levels 
• Results of blood tests done upon admission 
 
Data that will be collected during drug administration: 
• FOUR-score – data will be collected on the severity of your coma 
• Neurological assessments 
• Pupillometry 
• Drug levels and results of monitoring labs  
 
Data collected daily during your stay in the intensive care unit  
• FOUR-score  
• Neurological assessments 
• Pupillometry  
• Serious adverse events (SAEs)  
• Levels and results of labs 
• Data will be collected on details of uncontrollable seizures and the times 
associated with the administration of vigabatrin 
• EMSE – epidemiology based mortality score – this will be used to track severity of 
seizures 
 
Data to be collected at ICU discharge  
• FOUR-score  
• You will be asked to obey verbal commands  
• Data will be collected on the amount of time on mechanical ventilation  
• ICU length of stay  
• Neurological assessments  
 
Data to be collected at hospital discharge  
• FOUR-score  
• Discharge status (e.g., good, fair, stable, poor, critical, dead)  


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• Neurological assessments  
• Discharge destination  
 
Data to be collected on Day180  
You will return to the Neuromedicine Hospital and the following data will be collected 
and assessments performed 
• Survival status  
• Neurological Assessments  
• MoCA – this is a cognitive assessment which will ask you 9 questions to test your 
memory, math calculations, orientation to date and time and concentration 
• Goldmann perimetry– you will be scheduled at the Neuro-Ophthalmology Clinic at 
the Oaks Mall.  This is a visual test to determine your range of peripheral vision and 
may take 5-15 minutes to complete 
• VFQ-25 – you will be asked 25 questions about your eyesight and may take 5-10 
minutes to complete 
• SF-36 – you will be asked questions about your quality of life and general health 
and may take 5-10 minutes to complete 


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Test/Lab 
Baseline 
D0 
D1 
D2 
PAS
E 
VGB 
Administered 
(0h) 
0.
5
h 
1h 
2h 
3h 
6h 
12
h 
24
h 
48
h 
72
h 
96
h 
120
h 
168
h 
D14/ICU 
Discharge 
Hospital 
Discharge 
D1
80 
Review of 
Eligibility: 
Inclusion/Exclusio
n Criteriab 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vitals 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac-specific 
Treatments and 
Assessments 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
Assessments 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pupillometry 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
FOUR 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medications 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
mRS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
GOS-E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
CPC-E 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 


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MoCA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
EMSE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
VGB level 
 
 
 
 
 
Xc 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
Standard Anti-
seizure drug level 
 
 
 
 
 
Xc 
 
X 
 
X 
 
X 
X 
 
X 
 
 
X 
 
 
 
Routine complete 
blood cell count, 
complete 
metabolic panel, 
ABG, lactic acid 
x 
x 
x 
x 
x 
 
 
 
 
 
x 
 
x 
x 
x 
x 
x 
x 
 
 
 
Biomarkers: NSE, 
GFAP, NfL 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
X 
X 
X 
 
 
 
 
 
Taurine level 
 
 
 
 
 
Xc 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
cEEG 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRI Window 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 
 
 
Goldmann 
perimetry 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
VFQ-25 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Clinical Events 
 
X 
X 
X 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Discharge 
Summary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 


 
 
 
 
 
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Once this research study is completed, any information that could identify you might be 
removed from any identifiable private information or identifiable biospecimens collected 
and that, after such removal, the information or biospecimens could be used for future 
research studies or distributed to another investigator for future research studies without 
additional informed consent from you or your legally authorized representative 
 
If you have any questions now or at any time during this Research Study, please contact 
one of the Research Team members listed in question 3 of this form. 
 
8. What identifiable health information will be collected about you and how will it be 
used? 
 
 
The Research Team will collect medical record data, EEG and MRI data, lab tests, 
demographic information, questionnaires related to the study and all standard 
hospital, diagnostic, and treatment related information.  
 
The Research Team may collect this information from other healthcare providers, 
such as laboratories, which are a part of this research, as well as healthcare providers 
that are not part of this research (other doctors, hospitals or clinics). Other 
professionals at the University of Florida or Shands Hospital who provide study-related 
care, and the University of Florida Institutional Review Board (IRB), may also collect 
your health information.  
 
The Research Team listed in question 3 above will use or share your health information 
as described below to carry out this research study. The results of your EEG and visual 
testing (Goldmann perimetry) will be de-identified and no personal information will be 
shared with co-investigators at other institutions (Yale University and Tomas Jefferson 
University, respectively) who are analyzing the data.  
 
 
9.  With whom will this health information be shared? 
 
This health information may be shared with: 
 
• 
the study sponsor (listed in Question 4 of this form); 
• 
United States governmental agencies which are responsible for overseeing 
research, such as the Food and Drug Administration, the Department of Health 
and Human Services, and the Office of Human Research Protections;  
• 
Government agencies which are responsible for overseeing public health 
concerns such as the Centers for Disease Control and federal, state and local 
health departments. 
• 
Your insurance company for purposes of obtaining payment 


 
 
 
 
 
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• 
The IRB that reviewed this Research Study and ensures your rights as a Study 
Subject are protected  
 
Otherwise, your identifiable health information will not be shared without your 
permission unless required by law or a court order. Once your health information is 
shared with those listed above, it is possible that they could share it without your 
permission because it would no longer be protected by the federal privacy law.  
  
10. How long will you be in this Research Study? 
 
Your participation will last approximately six months consisting of: the length of your 
ICU stay and treatment, and at 6 month follow up visit after discharge from the ICU.   
 
This Authorization to use and share your health information expires at the end of the 
study, unless you revoke it (take it back) sooner. 
 
11. How many people are expected to take part in this Research Study? 
 
12 status epilepticus subjects who suffered a cardiac arrest will take part in this phase 
of this study. 
 
WHAT ARE THE RISKS AND BENEFITS OF THIS STUDY AND  
WHAT ARE YOUR OPTIONS? 
 
12. What are the possible discomforts and risks from taking part in this Research 
Study? 
 
There are risks and discomforts during the admission in the ICU after a cardiac arrest 
and those will be discussed with you. Damage to your vision (from blurriness to visual 
loss) have been reported with chronic use of vigabatrin and may be permanent. As 
such, we will be performing eye exams and assessments upon your regaining of 
consciousness. We will also perform pupillometry during your ICU admission. There 
are no risks associated with these tests.  
As is commonly seen with any antiseizure medication, the use of vigabatrin may cause 
fatigue, somnolence, dizziness and imbalance, abnormal eye movement, tremor, 
memory impairment, weight gain, joint pain, and confusion, all of which go away after 
discontinuation of use. Using vigabatrin for long periods has also been associated with 
bright spots in some areas of the brain seen on MRI scan, which go away when 
vigabatrin treatment is stopped and may not cause any known long-term sequelae.  
The drug may have risks unknown at this time.  


 
 
 
 
 
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Additionally, the risks of drawing blood from a vein include discomfort at the site of puncture; 
possible bruising and swelling around the puncture site; rarely an infection; and, 
uncommonly, faintness from the procedure. When possible, the study team will collect 
blood samples from your arterial  line, which you will already have as part of your normal 
clinical care. Collecting blood from an arterial line does not hurt and there are no additional 
risks. 
 
This Research Study may also include risks that are unknown at this time. 
 
Please note, participating in more than one research study or project may further 
increase the risks to you.  If you are already enrolled in a research study, please inform 
one of the Research Team members listed in question 3 of this form or the person 
reviewing this consent with you before enrolling in this or any other research study or 
project. 
 
During the study, the Research Team will notify you of new information that may 
become available and might affect your decision to remain in the study.  
 
The University of Florida is required by law to protect your health information. Your 
health information will be stored in locked filing cabinets or on computer servers with 
secure passwords, or encrypted electronic storage devices, as required by University 
policy. However, there is a slight risk that information about you could be released 
inappropriately or accidentally. Depending on the type of information, a release could 
upset or embarrass you, or possibly affect your ability to get insurance or a job.  
 
If you wish to discuss the information above or any discomforts you may experience, 
please ask questions now or call one of the Research Team members listed in question 
3 in this form. 
 
13a. What are the potential benefits to you for taking part in this Research Study? 
 
 
The vigabatrin treatment may help control your seizures and protect your brain cells 
from dying.    
 
13b. How could others possibly benefit from this Research Study? 
 
 
This study could lead to a treatment that could improve the outcomes for patients 
suffering from uncontrollable seizures after cardiac arrest. 
 


 
 
 
 
 
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13c. How could the Research Team members benefit from this Research Study? 
 
In general, presenting research results helps the career of a researcher. Therefore, the 
Research Team listed in question 3 of this form may benefit if the results of this 
Research Study are presented at scientific meetings or in scientific journals. 
 
 
14. What other choices do you have if you do not want to be in this study?  
 
If you choose not to participate in this study you will receive the standard treatment 
options for uncontrollable seizures (status epilepticus) and post-cardiac arrest recovery. 
 
You may also refuse to authorize the use of your health information, but if you refuse, 
you may not be allowed to be in this research study or receive any research-related 
treatment that is only available in this research study. However, your decision not to 
sign this Authorization will not affect any other treatment you may be eligible to receive. 
 
15a. Can you withdraw from this study? 
 
You may withdraw your consent and stop participating in this Research Study at any 
time.  If you do withdraw your consent, there will be no penalty to you, and you will not 
lose any benefits to which you are otherwise entitled. If you decide to withdraw your 
consent to participate in this Research Study for any reason, please contact the 
Research Team listed in question 3 of this form. They will tell you how to safely stop 
your participation. 
 
You can also change your mind and take back this Authorization at any time by sending 
a written notice to the Research Team listed in question 3 of this form to let them know 
your decision. If you take back this Authorization, the Research Team may only use and 
disclose your health information already collected for this research study. No additional 
health information about you will be collected or disclosed to the Research Team. 
However, if you take back this Authorization, you may not be able to continue in this 
study. Please discuss this with a member of the Research Team listed in question #3. 
 
15b. Can the Principal Investigator withdraw you from this Research Study?  
 
You may be withdrawn from this Research Study without your consent for the following 
reasons: 
 
• The principal investigator believes the study is not in your best interest. 
• You are no longer eligible to participate in the study. 
• The study ends early. 
 


 
 
 
 
 
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WHAT ARE THE FINANCIAL ISSUES IF YOU PARTICIPATE? 
 
16. If you choose to take part in this Research Study, will it cost you anything? 
 
No, there will be no additional costs to you or your health plan as a result of your 
participation in this study. The sponsor will pay for all health care costs related to your 
participation, including all required study items, services and procedures described in 
this consent form. However, if you feel you have received a bill related to this study, 
please contact the Principal Investigator. 
 
If you receive any healthcare at UF Health that is not related to this study, this care will 
be billed as usual. 
 
17. Will you be paid for taking part in this Research Study? 
 
You will be paid a $25 stipend to cover travel expenses for your return to the research 
clinic for the Day 180 visit.  You must complete this visit in order to receive the stipend.   
 
 Your payment for participation in this research study is handled through the University 
of Florida’s Human Subject Payment (HSP) Program.  Your information which will 
include your name, address, date of birth, and SSN (depending on amount of money 
you are paid) is protected.  Access to the (HSP) Program site is limited to certain staff 
with the assigned security role.  You will be randomly assigned a specific identification 
(ID) number to protect your identity. 
If you have any problems regarding your payment contact the study coordinator. 
  
 
18. What if you are injured while in this Research Study? 
  
If you are injured as a direct result of your participation in this study, only the professional 
services that you receive from any University of Florida Health Science Center 
healthcare provider will be provided without charge.  These healthcare providers include 
physicians, physician assistants, nurse practitioners, dentists or psychologists. Any 
other expenses, including Shands hospital expenses, will be billed to you or your 
insurance provider.  
You will be responsible for any deductible, co-insurance, or co-payments. Some 
insurance companies may not cover costs associated with research studies or 
research-related injuries. Please contact your insurance company for additional 
information.  


 
 
 
 
 
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The Principal Investigator will determine whether your injury is related to your 
participation in this study.  
No additional compensation is routinely offered. The Principal Investigator and others 
involved in this study may be University of Florida employees. As employees of the 
University, they are protected under state law, which limits financial recovery for 
negligence. 
 
Please contact one of the Research Team members listed in question 3 of this form if 
you experience an injury or have questions about any discomforts that you experience 
while participating in this Research Study. 
 
 


 
 
 
 
 
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SIGNATURES 
As an investigator or the investigator’s representative, I have explained to the participant 
the purpose, the procedures, the possible benefits, and the risks of this research study; 
the alternative to being in the study; and how the participant’s protected health 
information will be collected, used, and shared with others:  
 
___________________________________________________________________ 
Signature of Person Obtaining Consent & Authorization   
Date 
 
Consenting Adults.  You have been informed about this study’s purpose, procedures, 
possible benefits, and risks; the alternatives to being in the study; and how your protected 
health information will be collected, used and shared with others.  You have received a 
copy of this Form.  You have been given the opportunity to ask questions before you sign, 
and you have been told that you can ask other questions at any time.   
 
Adult Consenting for Self.  By signing this form, you voluntarily agree to participate in 
this study. You hereby authorize the collection, use and sharing of your protected health 
information as described above.  By signing this form, you are not waiving any of your 
legal rights. 
 
___________________________________________________________________ 
Signature of Adult Consenting & Authorizing for Self  
Date 
 
Parent/Adult Legally Representing the Subject.  By signing this form, you voluntarily 
give your permission for the person named below to participate in this study.  You hereby 
authorize the collection, use and sharing of protected health information for the person 
named below as described above.  You are not waiving any legal rights for yourself or the 
person you are legally representing.  After your signature, please print your name and 
your relationship to the subject. 
 
___________________________________________________________________ 
Consent & Authorization Signature  
 
 
 
Date 
of Legal Representative 
 
 
 
 
____________________________________ ___________________________________ 
Print:  Name of Legal Representative  
 
 
Print:  Relationship to Participant:   
 
______________________________________________ 
Print:  Name of Subject:   
 
______________________________________________ 
Print:  Name of Subject: