Clinical trial NCT04639310: XEN496 (Ezogabine) in Children With KCNQ2 Developmental and Epileptic Encephalopathy
Official title: A Phase 3 Study of Adjunctive XEN496 in Pediatric Subjects With KCNQ2 Developmental and Epileptic Encephalopathy
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Epilepsy
Epilepsy in Children
Epilepsy; Seizure
Disease
Brain Diseases
Central Nervous System Diseases
Nervous System Diseases
Epileptic Syndromes
Keywords: XEN496
Ezogabine
Retigabine
Encephalopathy
Seizure
KCNQ2
Lead sponsor: Xenon Pharmaceuticals Inc.
Sponsor class: INDUSTRY
First posted: 2020-11-20
Enrollment: 8
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: To investigate the potential antiseizure effects of adjunctive XEN496 (ezogabine) compared with placebo in children with KCNQ2 Developmental and Epileptic Encephalopathy (KCNQ2-DEE).

Detailed description: The EPIK Phase 3 clinical trial is designed as a randomized, double-blind, placebo-controlled, multicenter study targeting to enroll approximately 40 pediatric subjects (aged from 1 month to less than 6 years) with documented genetic evidence consistent with a diagnosis of KCNQ2 Developmental and Epileptic Encephalopathy (KCNQ2-DEE). After screening, subjects will enter a baseline period before being randomized to receive either XEN496 (ezogabine) or placebo, added to their existing antiseizure medications (ASMs), for 12 weeks (maintenance), once a titration period of up to 24 days is complete. At the end of the maintenance phase, eligible subjects will have the opportunity to qualify for and participate in the separate open-label extension (OLE) study and receive XEN496 or, should they choose to exit the study, will undergo a dose taper period of up to 15 days and 4-week follow-up.

Eligibility criteria: Inclusion Criteria:

* Male or female subjects aged from 1 month to less than 6 years, with a body weight of ≥3.0 kg at screening.
* Documented evidence of a genetic test result from an appropriately accredited laboratory, consistent with a diagnosis of KCNQ2-DEE (pathogenic, likely pathogenic, variant of unknown significance, or inconclusive but unlikely to support an alternate diagnosis).
* Seizure onset within 2 weeks after birth and EEG and documented clinical history consistent with KCNQ2-DEE.
* Magnetic resonance imaging has been performed and is without evidence of structural abnormalities, including but not limited to, hypoxia, hypoxia-ischemia, ischemia (arterial or venous), stroke, sinovenous thrombosis, intracranial hemorrhage, or focal or global brain malformation. Brain MRI changes that are described as being associated with the KCNQ2-DEE and presumed to be secondary to the disease itself, will not be exclusionary.
* Must have had focal tonic or other countable motor seizures in the 28 days prior to screening.
* Taking 1 and no more than 4 concomitant antiseizure medications (ASMs). All doses must be stable for at least 1 week prior to screening and expected to be maintained throughout the duration of the study.
* Vagal nerve stimulation (VNS) is allowed and will not be counted as a concomitant ASM. The VNS device must be implanted for at least 6 months before screening, and the device settings must be stable for at least 6 weeks prior to screening and throughout the duration of the study. Use of the VNS device magnet is allowed.
* Ketogenic diet is allowed and will not be counted as a concomitant ASM. Must must be on a stable dietary regimen that produces ketosis for at least 6 weeks prior to screening, and expected to be maintained throughout the study.
* Additional inclusion criteria apply, and will be assessed by the study team.

Exclusion Criteria:

* Presence of a pathogenic or likely pathogenic variant in an additional gene associated with other epilepsy syndromes. (Variants in other epilepsy-associated genes that are not known to be pathogenic or are not likely to be pathogenic based upon adjudication review will not be a basis for exclusion.)
* Presence of a known gain-of-function variant in the KCNQ2 gene, or clinical characteristics consistent with previously reported pathogenic gain-of-function variants in the KCNQ2 gene.
* Seizures secondary to infection, neoplasia, demyelinating disease, degenerative neurological disease, or Central nervous system (CNS) disease deemed progressive, metabolic illness, or progressive degenerative disease.
* Confirmed diagnosis of infantile spasms within the past month prior to screening.
* History or presence of any significant medical or surgical condition or uncontrolled medical illness at screening including, but not limited to, cardiovascular, gastrointestinal, hematologic, hepatic, ocular, pulmonary, renal, or urogenital systems, or other conditions that would not justify the subject's participation in the study, as determined by the investigator's risk benefit assessment.
* QT interval corrected for heart rate by Fridericia's formula (QTcF) of \>440 msec. In addition, subjects with a history of arrhythmia, prolonged QT, heart disease or subjects taking medications known to increase the QT interval.
* History of hyperbilirubinemia, which lasts longer than 1 week will require exclusion of hepatic disease before entering the study.
* History of bilirubin-induced neurological dysfunction.
* Current disturbance of micturition or known urinary obstructions or history of bladder or urinary dysfunction including abnormal post-void residual bladder ultrasound, vesicoureteral reflux, urinary retention, or required urinary catheterization in the preceding 6 months.
* Known to have a terminal illness.
* Any clinically significant laboratory abnormalities or clinically significant abnormalities on pre-study physical examination, vital signs, or ECG that in the judgment of the investigator indicates a medical problem that would preclude study participation.
* Planned to begin a ketogenic or other specialized dietary therapy during the study.
* Caregiver history of chronic noncompliance with their child's prescribed drug regimens that has not been corrected.
* Exposure to any other investigational drug or device within 5 half-lives or 30 days prior to screening, whichever is longer or plans to participate in another drug or device trial at any time during the study.
* Concurrent enrollment in any other type of medical research judged by the investigator not to be scientifically or medically compatible with this study.
* Using felbamate presenting with clinically significant abnormalities and/or hepatic dysfunction during felbamate treatment, and subjects who have taken felbamate for less than 6 months prior to screening.
* Currently taking adrenocorticotropic hormone.
* Did not tolerate ezogabine when taken previously.
* Subjects with a known hypersensitivity to ezogabine or any of the excipients in the study drug.
* Other exclusion criteria apply, and will be assessed by the study team.

Primary outcomes:
measure: Percent Change From Baseline in Monthly (28 Day) Countable Motor Seizure Frequency During the Blinded Treatment Period
timeFrame: From baseline to the end of the double-blind, 12 week treatment period (maintenance)
Secondary outcomes:
measure: Percentage of Subjects With ≥50 Percent Reduction in Monthly (28 Day) Seizure Frequency
timeFrame: From baseline to the end of the double-blind, 12 week treatment period (maintenance)
measure: Caregiver Global Impression of Change (CaGI-C) Scores for the Subject's Overall Condition and for Seizures
timeFrame: Study Day 109
measure: Change From Baseline in the Caregiver Global Impression of Severity (CaGI-S) for the Subject's Overall Condition and for Seizures
timeFrame: Study Day 109
Other outcomes:
measure: Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE
timeFrame: From screening through study completion (Day 109) or Day 151 for those not entering the OLE
Locations:
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center
state: California
city: Aurora
country: United States
facility: Children's Hospital of Colorado
state: Colorado
city: Washington
country: United States
facility: Children's National Health System
state: District of Columbia
city: Gulf Breeze
country: United States
facility: Northwest Florida Clinical Research Group
state: Florida
city: Chicago
country: United States
facility: Anne & Robert H. Lurie Children's Hospital
state: Illinois
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: Cleveland
country: United States
facility: The Cleveland Clinic Foundation
state: Ohio
city: Portland
country: United States
facility: Oregon Health and Science University
state: Oregon
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Tacoma
country: United States
facility: MultiCare Medical Center
state: Washington
city: Sydney
country: Australia
facility: Sydney Children's Hospital
state: New South Wales
city: South Brisbane
country: Australia
facility: Children's Health Queensland Hospital and Health Service
state: Queensland
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Edegem
country: Belgium
facility: Universitaire Ziekenhuis Anterpen - Dienst Kinderneurologie
state: Antwerpen
city: Genova
country: Italy
facility: Istituto Giannina Gaslini
city: Milan
country: Italy
facility: U.O.C. Neurologia Pediatrica Ospedale dei Bambini V. Buzzi
city: Verona
country: Italy
facility: Azienda Ospedaliera Universitaria Integrata di Verona
city: Esplugues de Llobregat
country: Spain
facility: Universitat de Barcelona - Hospital Sant Joan de Déu Barcelona (HSJDB)
state: Barcelona
city: Madrid
country: Spain
facility: Hospital Nino Jesus
Study officials:
affiliation: Xenon Pharmaceuticals Inc.
name: Study Director
role: STUDY_DIRECTOR
References: