A Randomized, Double-Blind, Placebo-Controlled Phase 3 Study to Evaluate the Safety and Efficacy of XEN1101 as an Adjunctive Therapy in the Treatment of Primary Generalized Tonic-Clonic Seizures
Antonio Gil-Nagel1, David Vossler2, Elinor Ben-Menachem3, W. LaFrance4, Cynthia Harden5, Jenny Qian5, Gregory Beatch5, Christopher Kenney5
1Hospital Ruber Internacional, Madrid, Spain, 2University of Washington, Seattle and UW Medicine/Valley Medical Center, Renton, WA, USA, 3Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden, 4Rhode Island Hospital, Brown University, and VA Providence Health Care System, Providence, RI, USA, 5Xenon Pharmaceuticals Inc., Burnaby BC, Canada
Objective:
Describe the rationale and study design of X-ACKT, a randomized, double-blind, placebo-controlled Phase 3 study to evaluate the safety and efficacy of XEN1101 as an adjunctive therapy in the treatment of primary generalized tonic-clonic seizures (PGTCS).
Background:
XEN1101 is a novel, potent, selective Kv7.2/7.3 potassium channel opener which shows broad spectrum seizure suppression in preclinical models. In epilepsy patients with photosensitivity, ICA-105665, a Kv7 potassium channel opener no longer in development, suppressed paroxysmal EEG activity (Kasteleijn-Nolst Trenité et al, Epilepsia. 2013;54(8)). These data support the broad-spectrum anti-seizure potential of XEN1101 and provide the rationale for a PGTCS trial.
Design/Methods:
X-ACKT is a Phase 3, multicenter, randomized, double-blind, placebo-controlled study to evaluate the PK, safety and efficacy of XEN1101 in the fed state in adults aged 18-75 years with a seizure frequency of ≥3 PGTCS over an 8-week baseline, taking 1-3 anti-seizure medications (ASMs). Approximately 160 subjects will be randomized at 1:1 (25mg:placebo) to a 12-week double-blind period (DBP) following an 8-week baseline period to assess seizure frequency. Subjects completing the DBP may be eligible for an open-label extension (OLE) trial under a separate protocol.
Results:
The primary efficacy endpoint is median percent change in monthly PGTCS frequency from baseline. The key secondary outcomes are the proportion of subjects experiencing ≥50% reduction in monthly PGTCS frequency from baseline (RR50), seizure freedom and the Patient Global Impression of Change compared to baseline. Safety will be evaluated by severity and frequency of treatment emergent adverse events (AEs) and serious AEs; clinically significant changes in clinical laboratory findings, physical, neurologic and ophthalmologic exams, ECGs, vital signs, and urinary symptoms will also be evaluated.
Conclusions:
X-ACKT will provide insight into the safety, tolerability, and efficacy of XEN1101 as adjunctive therapy in the treatment of PGTCS and is designed to support registration of XEN1101 for the treatment of PGTCS.