Early vigabatrin augmenting GABA-ergic pathways in post-anoxic status epilepticus (VIGAB-STAT) phase IIa clinical trial study protocol
Abstract Background 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 functiona...
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| Format: | Article |
| Language: | English |
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BMC
2022-01-01
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| Series: | Neurological Research and Practice |
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| Online Access: | https://doi.org/10.1186/s42466-022-00168-x |
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| author | Carolina B. Maciel Fernanda J. P. Teixeira Katie J. Dickinson Jessica C. Spana Lisa H. Merck Alejandro A. Rabinstein Robert Sergott Guogen Shan Guanhong Miao Charles A. Peloquin Katharina M. Busl Lawrence J. Hirsch |
| author_facet | Carolina B. Maciel Fernanda J. P. Teixeira Katie J. Dickinson Jessica C. Spana Lisa H. Merck Alejandro A. Rabinstein Robert Sergott Guogen Shan Guanhong Miao Charles A. Peloquin Katharina M. Busl Lawrence J. Hirsch |
| author_sort | Carolina B. Maciel |
| collection | DOAJ |
| description | Abstract Background 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. Methods 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. Perspective 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. |
| first_indexed | 2024-12-24T19:08:02Z |
| format | Article |
| id | doaj.art-7278cb4a13c74708827fae6bb045f1b5 |
| institution | Directory Open Access Journal |
| issn | 2524-3489 |
| language | English |
| last_indexed | 2024-12-24T19:08:02Z |
| publishDate | 2022-01-01 |
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| series | Neurological Research and Practice |
| spelling | doaj.art-7278cb4a13c74708827fae6bb045f1b52022-12-21T16:43:04ZengBMCNeurological Research and Practice2524-34892022-01-01411910.1186/s42466-022-00168-xEarly vigabatrin augmenting GABA-ergic pathways in post-anoxic status epilepticus (VIGAB-STAT) phase IIa clinical trial study protocolCarolina B. Maciel0Fernanda J. P. Teixeira1Katie J. Dickinson2Jessica C. Spana3Lisa H. Merck4Alejandro A. Rabinstein5Robert Sergott6Guogen Shan7Guanhong Miao8Charles A. Peloquin9Katharina M. Busl10Lawrence J. Hirsch11Division of Neurocritical Care, Department of Neurology, University of Florida College of MedicineDivision of Neurocritical Care, Department of Neurology, University of Florida College of MedicineDivision of Neurocritical Care, Department of Neurology, University of Florida College of MedicineDivision of Neurocritical Care, Department of Neurology, University of Florida College of MedicineDivision of Neurocritical Care, Department of Neurology, University of Florida College of MedicineDepartment of Neurology, Mayo Clinic College of MedicineDepartment of Ophthalmology, Thomas Jefferson UniversityDepartment of Biostatistics, University of FloridaDepartment of Biostatistics, University of FloridaDepartment of Pharmacotherapy and Translational Research, University of Florida College of PharmacyDivision of Neurocritical Care, Department of Neurology, University of Florida College of MedicineDepartment of Neurology, Yale University School of MedicineAbstract Background 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. Methods 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. Perspective 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.https://doi.org/10.1186/s42466-022-00168-xCardiac arrestHeart arrestPost-anoxic status epilepticusGABAVigabatrinStatus epilepticus |
| spellingShingle | Carolina B. Maciel Fernanda J. P. Teixeira Katie J. Dickinson Jessica C. Spana Lisa H. Merck Alejandro A. Rabinstein Robert Sergott Guogen Shan Guanhong Miao Charles A. Peloquin Katharina M. Busl Lawrence J. Hirsch Early vigabatrin augmenting GABA-ergic pathways in post-anoxic status epilepticus (VIGAB-STAT) phase IIa clinical trial study protocol Neurological Research and Practice Cardiac arrest Heart arrest Post-anoxic status epilepticus GABA Vigabatrin Status epilepticus |
| title | Early vigabatrin augmenting GABA-ergic pathways in post-anoxic status epilepticus (VIGAB-STAT) phase IIa clinical trial study protocol |
| title_full | Early vigabatrin augmenting GABA-ergic pathways in post-anoxic status epilepticus (VIGAB-STAT) phase IIa clinical trial study protocol |
| title_fullStr | Early vigabatrin augmenting GABA-ergic pathways in post-anoxic status epilepticus (VIGAB-STAT) phase IIa clinical trial study protocol |
| title_full_unstemmed | Early vigabatrin augmenting GABA-ergic pathways in post-anoxic status epilepticus (VIGAB-STAT) phase IIa clinical trial study protocol |
| title_short | Early vigabatrin augmenting GABA-ergic pathways in post-anoxic status epilepticus (VIGAB-STAT) phase IIa clinical trial study protocol |
| title_sort | early vigabatrin augmenting gaba ergic pathways in post anoxic status epilepticus vigab stat phase iia clinical trial study protocol |
| topic | Cardiac arrest Heart arrest Post-anoxic status epilepticus GABA Vigabatrin Status epilepticus |
| url | https://doi.org/10.1186/s42466-022-00168-x |
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