XEN496 (Ezogabine) in Children With KCNQ2 Developmental and Epileptic Encephalopathy

NCT ID: NCT04639310

Last Updated: 2024-08-23

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE3
• Total Enrollment: 8 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-03-29
• Study Completion Date: 2023-05-16

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.

Conditions

Epilepsy; Epilepsy in Children; Epilepsy; Seizure; Disease; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: QUADRUPLE

Study Groups

XEN496

24-day dose titration period to a top dose of 21 mg/kg/day. Subjects continue at the top dose, or the highest tolerated dose up to the top dose, for 12-week maintenance period. If the subject does not immediately enter into the separate open-label extension (OLE) study, the maintenance period will be followed by a 15-day taper period.

Group Type: EXPERIMENTAL

XEN496

Intervention Type: DRUG

XEN496 sprinkle capsules. Parents / caregivers will be instructed to sprinkle and mix the contents of the capsules into soft foods or liquids and feed it to the child TID.

Placebo

To maintain the blinded aspect of the study, subjects will be titrated on placebo over the 24-day period and remain at this dose for the 12-week maintenance period. If the subject does not immediately enter into the separate OLE study, the maintenance period will be followed by a 15-day taper period.

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Placebo sprinkle capsules. Parents / caregivers will be instructed to sprinkle and mix the contents of the capsules into soft foods or liquids and feed it to the child TID.

Interventions

XEN496

XEN496 sprinkle capsules. Parents / caregivers will be instructed to sprinkle and mix the contents of the capsules into soft foods or liquids and feed it to the child TID.

Intervention Type: DRUG

Placebo

Placebo sprinkle capsules. Parents / caregivers will be instructed to sprinkle and mix the contents of the capsules into soft foods or liquids and feed it to the child TID.

Intervention Type: DRUG

Other Intervention Names

ezogabine; retigabine

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.

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.

• Minimum Eligible Age: 1 Month
• Maximum Eligible Age: 6 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Xenon Pharmaceuticals Inc.

INDUSTRY

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Study Director

Role: STUDY_DIRECTOR

Xenon Pharmaceuticals Inc.

Locations

Children's Hospital of Orange County

Orange, California, United States

UCSF Medical Center

San Francisco, California, United States

Children's Hospital of Colorado

Aurora, Colorado, United States

Children's National Health System

Washington D.C., District of Columbia, United States

Northwest Florida Clinical Research Group

Gulf Breeze, Florida, United States

Anne & Robert H. Lurie Children's Hospital

Chicago, Illinois, United States

Columbia University Irving Medical Center

New York, New York, United States

The Cleveland Clinic Foundation

Cleveland, Ohio, United States

Oregon Health and Science University

Portland, Oregon, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

MultiCare Medical Center

Tacoma, Washington, United States

Sydney Children's Hospital

Sydney, New South Wales, Australia

Children's Health Queensland Hospital and Health Service

South Brisbane, Queensland, Australia

Austin Health

Heidelberg, Victoria, Australia

Universitaire Ziekenhuis Anterpen - Dienst Kinderneurologie

Edegem, Antwerpen, Belgium

Istituto Giannina Gaslini

Genova, , Italy

U.O.C. Neurologia Pediatrica Ospedale dei Bambini V. Buzzi

Milan, , Italy

Azienda Ospedaliera Universitaria Integrata di Verona

Verona, , Italy

Universitat de Barcelona - Hospital Sant Joan de Déu Barcelona (HSJDB)

Esplugues de Llobregat, Barcelona, Spain

Hospital Nino Jesus

Madrid, , Spain

Countries

United States; Australia; Belgium; Italy; Spain

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

2020-002396-35

Identifier Type: EUDRACT_NUMBER

Identifier Source: secondary_id

XPF-009-301

Identifier Type: -

Identifier Source: org_study_id