Intravenous ganaxolone for the treatment of refractory status epilepticus: Results from an open-label, dose-finding, phase 2 trial

Henrikas Vaitkevicius, R Eugene Ramsay, Christa B Swisher, Aatif M Husain, Alex Aimetti, Maciej Gasior, Henrikas Vaitkevicius, R Eugene Ramsay, Christa B Swisher, Aatif M Husain, Alex Aimetti, Maciej Gasior

Abstract

Objective: Patients with refractory status epilepticus (RSE) have failed treatment with benzodiazepines and ≥1 second-line intravenous (IV) antiseizure medication (ASM). Guidelines recommend IV anesthesia when second-line ASMs have failed, but potential harms can outweigh the benefits. Novel treatments are needed to stop and durably control RSE without escalation to IV anesthetics. Ganaxolone is an investigational neuroactive steroid in development for RSE treatment. This study's objective was to determine the appropriate dosing for IV ganaxolone in RSE and obtain a preliminary assessment of efficacy and safety.

Methods: This was an open-label, phase 2 trial conducted from February 19, 2018 to September 18, 2019, at three sites in the United States. Patients were aged ≥12 years, had convulsive or nonconvulsive SE, and failed to respond to ≥1 second-line IV ASM. Twenty-one patients were screened; 17 were enrolled. Patients received IV ganaxolone added to standard-of-care ASMs. Ganaxolone infusion was initiated as an IV bolus (over 3 min) with continuous infusion of decreasing infusion rates for 48-96 h followed by an 18-h taper. There were three ganaxolone dosing cohorts: low, 500 mg/day; medium, 650 mg/day; and high, 713 mg/day. The primary end point was the number of patients not requiring escalation to IV anesthetic treatment within 24 h of ganaxolone initiation.

Results: Most of the 17 enrolled patients (65%) had nonconvulsive SE, and had failed a median of three prior ASMs, including first-line benzodiazepine and second-line IV ASM therapy. Median time to SE cessation following ganaxolone initiation was 5 min. No patient required escalation to third-line IV anesthetics during the 24-h period following ganaxolone initiation. Two treatment-related serious adverse events (sedation) were reported. Of the three deaths, none was considered related to ganaxolone; all occurred 9-22 days after completing ganaxolone.

Significance: IV ganaxolone achieved rapid and durable seizure control in patients with RSE, and showed acceptable safety and tolerability.

Trial registration: ClinicalTrials.gov NCT03350035.

Keywords: antiseizure medications; clinical trial; critical care; neurosteroids; seizure.

© 2022 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.

Figures

FIGURE 1
FIGURE 1
Trial flow diagram. GNX, ganaxolone; SE, status epilepticus. *Patients who discontinued GNX infusion early were to enter the follow‐up.
FIGURE 2
FIGURE 2
Modeled pharmacokinetic curves for all dose groups. The initial bolus of IV GNX resulted in rapid plasma GNX levels (~900 ng/ml), designed to terminate SE. High‐dose GNX achieves and maintains target plasma levels (≥500 ng/ml) for ~8 h, designed to sustain SE cessation. GNX, ganaxolone; IV, intravenous; SE, status epilepticus.
FIGURE 3
FIGURE 3
Effects of ganaxolone infusion on seizure in patients with RSE. Patients were monitored via continuous EEG during GNX use. SE cessation was determined by trial investigators. (A) Time to cessation of SE following initiation of GNX, as determined by trial‐site investigator assessment. SE cessation occurred rapidly in all dose groups (median, 5 min, dashed line). (B) Percentage change from baseline in seizure burden over time, as determined by central EEG review. Downward arrows indicate time points when GNX dosing targets were

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