Early vigabatrin augmenting GABA-ergic pathways in post-anoxic status epilepticus (VIGAB-STAT) phase IIa clinical trial study protocol

Neurological Research and Practice - Tập 4 - Trang 1-9 - 2022
Carolina B. Maciel1,2,3,4, Fernanda J. P. Teixeira1, Katie J. Dickinson1, Jessica C. Spana1, Lisa H. Merck1,5, Alejandro A. Rabinstein6, Robert Sergott7, Guogen Shan8, Guanhong Miao8, Charles A. Peloquin9, Katharina M. Busl1, Lawrence J. Hirsch2
1Division of Neurocritical Care, Department of Neurology, University of Florida College of Medicine, Gainesville, USA
2Department of Neurology, Yale University School of Medicine, New Haven, USA
3Department of Neurology, University of Utah, Salt Lake City, USA
4Department of Neurology, University of Florida, Gainesville, USA
5Department of Emergency Medicine, University of Florida College of Medicine, Gainesville, USA
6Department of Neurology, Mayo Clinic College of Medicine, Rochester, USA
7Department of Ophthalmology, Thomas Jefferson University, Philadelphia, USA
8Department of Biostatistics, University of Florida, Gainesville, USA
9Department of Pharmacotherapy and Translational Research, University of Florida College of Pharmacy, Gainesville, USA

Tóm tắt

Nearly one in three unconscious cardiac arrest survivors experience post-anoxic status epilepticus (PASE). Historically, PASE has been deemed untreatable resulting in its exclusion from status epilepticus clinical trials. However, emerging reports of survivors achieving functional independence following early and aggressive treatment of PASE challenged this widespread therapeutic nihilism. In the absence of proven therapies specific to PASE, standard of care treatment leans on general management strategies for status epilepticus. Vigabatrin—an approved therapy for refractory focal-onset seizures in adults—inhibits the enzyme responsible for GABA catabolism, increases brain GABA levels and may act synergistically with anesthetic agents to abort seizures. Our central hypothesis is that early inhibition of GABA breakdown is possible in the post-cardiac arrest period and may be an effective adjunctive treatment in PASE. This is a phase IIa, single-center, open-label, pilot clinical trial with blinded outcome assessment, of a single dose of vigabatrin in 12 consecutive PASE subjects. Subjects will receive a single loading dose of 4500 mg of vigabatrin (or dose adjusted in moderate and severe renal impairment) via enteric tube within 48 h of PASE onset. Vigabatrin levels will be monitored at 0- (baseline), 0.5-, 1-, 2-, 3-, 6-, 12-, 24-, 48-, 72- and 168-h (7 days) post-vigabatrin. Serum biomarkers of neuronal injury will be measured at 0-, 24-, 48-, 72- and 96-h post-vigabatrin. The primary feasibility endpoint is the proportion of enrolled subjects among identified eligible subjects receiving vigabatrin within 48 h of PASE onset. The primary pharmacokinetic endpoint is the measured vigabatrin level at 3 h post-administration. Descriptive statistics with rates and proportions will be obtained regarding feasibility outcomes, along with the noncompartmental method for pharmacokinetic analyses. The area under the vigabatrin concentration-time curve in plasma from zero to the time of the last quantifiable concentration (AUC0-tlqc) will be calculated to estimate dose-linear pharmacokinetics. Vigabatrin demonstrates high potential for synergism with current standard of care therapies. Demonstration of the feasibility of vigabatrin administration and preliminary safety in PASE will pave the way for future efficacy and safety trials of this pharmacotherapeutic. Trial Registration NCT04772547.

Tài liệu tham khảo

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