VIGABatrin in Post-anoxic STATus Epilepticus - Phase IIa

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.

• Vigabatrin Only Product (Drug), also known as sabril, vigabatrone: enteral medication administration, serial blood draws, and outcome assessment

Primary outcomes

• Primary Pharmacologic Outcome - Absorption [3h]: By analyzing serial vigabatrin levels including baseline, we characterized vigabatrin absorption; the target was to achieve a detectable vigabatrin level in the serum of ≥ 80% of enrolled subjects by 3 hours post-load.
• Primary Feasibility Outcome - Enrollment and Drug Delivery [48 hours]: We looked at the ability to deliver vigabatrin within 48 hours of PASE onset in ≥ 80% of enrolled subjects. Vigabatrin dose was adjusted according to renal functioning (CrCl>50 ml/min: 4500 mg, CrCl 30-50 ml/min: 2250 mg, CrCl<30 ml/min: 1125 mg)
• Primary Feasibility Outcome - Visual Screening (Goldmann Perimetry) [6 months]: We planned to obtain Goldmann perimetry testing in the subjects who could cooperate at the 6 months follow-up. Our goal was to have reliable visual field perimetry in ≥ 80% of survivors who regained consciousness following index hospitalization.
• Primary Feasibility Outcome - Participants With Visual Screening for Taurine Levels [0h, 72h and 168h following vigabatrin administration]: We obtained serial taurine levels during ICU stay at time 0h, 72h and 168h following vigabatrin administration. Our goal was to achieve a 90% completion rate for taurine levels.

Secondary outcomes

• Ultra-early Vigabatrin Administration [0h to 48h after vigabatrin admnistration]: We tracked the proportion of enrolled subjects who received a vigabatrin load within 12 and 24 hours of PASE onset to explore the possibility of ultra-early administration of vigabatrin in subsequent phases.
• Secondary Pharmacologic Outcome: Elimination [72h and 7 days following vigabatrin administration]: By analyzing serial VGB levels, we characterized drug elimination. We anticipated subjects with normal renal function would have undetectable vigabatrin levels by 72 hours, and those with creatinine clearance less than 30 mL/min would have detectable VGB levels at 72 hours. We anticipated undetectable vigabatrin levels in all subjects by 7 days regardless of their renal function.
• PASE Onset Detection [Determined at the time of connection to EEG monitoring]: We tracked the proportion of subjects in whom PASE was present upon connection to EEG (onset misses) to explore alternatives to allow prompt EEG monitoring following the return of spontaneous circulation (ROSC).

Sex: All, ages: 18 Years to 80 Years

Inclusion Criteria:

* age ≥ 18 years
* non-traumatic cardiac arrest (regardless of non-perfusing rhythm, etiology, or location of arrest) in whom the decision to treat unequivocal electrographic status epilepticus (as defined by the American Clinical Neurophysiology Society: 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
* requiring anesthetic infusion for any reason
* have reliable arterial access for frequent blood sampling
* established enteral access within 48h of post-anoxic status epilepticus onset.

Exclusion Criteria:

* prior history of generalized epilepsy
* history of gastrointestinal surgery within the last 21 days
* pregnancy
* status epilepticus onset preceding initiation of electroencephalography monitoring

Participant flow

Outcome results

• Primary Pharmacologic Outcome - Absorption (Primary), Count of participants, Participants: Open Label 6
• Primary Feasibility Outcome - Enrollment and Drug Delivery (Primary), Count of participants, Participants: Open Label 6
• Primary Feasibility Outcome - Visual Screening (Goldmann Perimetry) (Primary)
• Primary Feasibility Outcome - Participants With Visual Screening for Taurine Levels (Primary), Count of participants, Participants: Open Label 6
• Ultra-early Vigabatrin Administration (Secondary), Count of participants, Participants: Open Label 1
• Secondary Pharmacologic Outcome: Elimination (Secondary), Count of participants, Participants: Open Label 2
• PASE Onset Detection (Secondary), Count of participants, Participants: PASE Onset Misses 8

Adverse events

Time frame: As per clinical trial protocol, all subjects were monitored daily for adverse (AE) and serious adverse events (SAE) from the time of enrollment for the duration of their ICU stay. The PI monitored patient safety data within 24 hours of AE's or SAE's. The duration of ICU stay for the subjects was approximately 1 week. Screening for visual AE's was planned at the 6-month follow-up visit. Due to inpatient mortality, none of the enrolled subjects completed the 6-month follow-up.

Limitations and caveats: We could not characterize the exploratory safety outcome in our subjects. We aimed to detect rates of retinopathy on vision loss screening via Goldmann perimetry upon regain of consciousness, ICU discharge, and 6 months, in addition to long-term visual screening at 6 months via Visual Function Questionnaire 25 (VFQ-25). However, all six patients enrolled in the trial did not regain consciousness or survive through the follow-up period. So, the assessments could not be performed.

• Results publication: Maciel CB, Teixeira FJP, Dickinson KJ, Spana JC, Merck LH, Rabinstein AA, Sergott R, Shan G, Miao G, Peloquin CA, Busl KM, Hirsch LJ. Early vigabatrin augmenting GABA-ergic pathways in post-anoxic status epilepticus (VIGAB-STAT) phase IIa clinical trial study protocol. Neurol Res Pract. 2022 Jan 24;4(1):4. doi: 10.1186/s42466-022-00168-x. PMID 35067230

• Study Protocol and Statistical Analysis Plan (PDF, 2023-05-11)
• Informed Consent Form (PDF, 2021-09-08)

• Carolina B Maciel, MD, MSCR, Principal investigator, University of Florida