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

• ClinicalTrials.gov Identifier: NCT04639310
• Recruitment Status: Recruiting
• First Posted: November 20, 2020
• Last Update Posted: October 25, 2021
• Sponsor: Xenon Pharmaceuticals Inc.
• Information provided by (Responsible Party): Xenon Pharmaceuticals Inc.

Study Description

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).

Condition or disease	Intervention/treatment	Phase
Epilepsy; Epilepsy in Children; Epilepsy; Seizure; Disease; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes	Drug: XEN496; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Phase 3 Study of Adjunctive XEN496 in Pediatric Subjects With KCNQ2 Developmental and Epileptic Encephalopathy
• Actual Study Start Date: March 29, 2021
• Estimated Primary Completion Date: November 2022
• Estimated Study Completion Date: December 2022

Arms and Interventions

Arm	Intervention/treatment
Experimental: 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.	Drug: 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.; Other Names: ezogabine; retigabine
Placebo Comparator: 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.	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.

Outcome Measures

Primary Outcome Measures :

1. Percent change from baseline in monthly (28 day) countable motor seizure frequency during the blinded treatment period [ Time Frame: From baseline to the end of the double-blind, 12 week treatment period (maintenance) ]
   Parent/caregiver seizure diary record will be used to assess frequency, type and duration of seizure activity

Secondary Outcome Measures :

1. Proportion of subjects with ≥50 percent reduction in monthly (28 day) seizure frequency [ Time Frame: From baseline to the end of the double-blind, 12 week treatment period (maintenance) ]
   Parent/caregiver seizure diary record will be used to assess frequency, type and duration
2. Caregiver Global Impression of Change (CaGI-C) scores for the subject's overall condition and for seizures [ Time Frame: Study Days 24, 67, 88 and 109 ]
   CaGI-C scale is a caregiver-reported assessment for the subject's overall condition and for seizures. Responses to the CaGI-C questionnaire are to be rated on a 7 item Likert scale ranging from very much improved to very much worse.
3. Change from baseline in the Caregiver Global Impression of Severity (CaGI-S) for the subject's overall condition and for seizures [ Time Frame: Study Days 1, 24, 67, 88 and 109 ]
   CaGI-S scale is Caregiver-reported assessment of the severity of the subject's seizures and overall condition over the previous 7 days. Responses to the CaGI-S questionnaire are to be rated on a 5 item Likert scale ranging from none to very severe.

Other Outcome Measures:

1. Assess the safety and tolerability of XEN496 (e.g., adverse events) in pediatric subjects with KCNQ2-DEE [ Time Frame: From screening through to the end of the study (maintenance phase for those continuing into the OLE) or Day 151 for those exiting the study ]
   To assess adverse events as criteria for safety and tolerability

Eligibility Criteria

• Ages Eligible for Study: 1 Month to 6 Years (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.
• 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.
• 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.
• Other exclusion criteria apply, and will be assessed by the study team.

Contacts and Locations

Contacts

Contact: Xenon Pharmaceuticals Inc.; 1-604-484-3300; XenonCares@xenon-pharma.com

Locations

United States, Colorado

Children's Hospital of Colorado; Recruiting

Aurora, Colorado, United States, 80045

United States, Florida

Northwest Florida Clinical Research Group; Recruiting

Gulf Breeze, Florida, United States, 32561

United States, Illinois

Ann & Robert H. Lurie Children's Hospital of Chicago; Recruiting

Chicago, Illinois, United States, 60611

United States, New York

Columbia University Irving Medical Center; Recruiting

New York, New York, United States, 10032

United States, Ohio

The Cleveland Clinic Foundation; Recruiting

Cleveland, Ohio, United States, 44195

United States, Oregon

Oregon Health and Science University; Recruiting

Portland, Oregon, United States, 97239

United States, Washington

MultiCare Health System - Mary Bridge Pediatrics - Tacoma; Recruiting

Tacoma, Washington, United States, 98405

Australia, New South Wales

Sydney Children's Hospital; Recruiting

Sydney, New South Wales, Australia, 2031

Australia, Queensland

Children's Health Queensland Hospital and Health Service; Recruiting

South Brisbane, Queensland, Australia, 4101

Australia, Victoria

Austin Health; Recruiting

Heidelberg, Victoria, Australia, 3084

Sponsors and Collaborators

Xenon Pharmaceuticals Inc.

Investigators

• Study Director: Study Director; Xenon Pharmaceuticals Inc.

More Information

• Responsible Party: Xenon Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT04639310
• Other Study ID Numbers: XPF-009-301; 2020-002396-35 ( EudraCT Number )
• First Posted: November 20, 2020
• Last Update Posted: October 25, 2021
• Last Verified: October 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Xenon Pharmaceuticals Inc.:

XEN496; Ezogabine; Retigabine; Encephalopathy; Seizure; KCNQ2

Additional relevant MeSH terms:

Epilepsy; Seizures; Brain Diseases; Nervous System Diseases; Central Nervous System Diseases; Epileptic Syndromes; Neurologic Manifestations; Ezogabine; Anticonvulsants; Membrane Transport Modulators; Molecular Mechanisms of Pharmacological Action