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

Epilepsy Clinical Trial

— EPIK  

Official title:

A Phase 3 Study of Adjunctive XEN496 in Pediatric Subjects With KCNQ2 Developmental and Epileptic Encephalopathy

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT04639310
• Other study ID #: XPF-009-301
• Secondary ID: 2020-002396-35
• Status: Terminated
• Phase: Phase 3
• Start date: March 29, 2021
• Est. completion date: May 16, 2023

Study information

• Verified date: June 2023
• Source: Xenon Pharmaceuticals Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

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

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.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 8
• Est. completion date: May 16, 2023
• Est. primary completion date: May 16, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 6 Years

Eligibility

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.

Related Conditions & MeSH terms

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

Intervention

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.
• 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.

Locations

Country	Name	City	State
Australia	Austin Health	Heidelberg	Victoria
Australia	Children's Health Queensland Hospital and Health Service	South Brisbane	Queensland
Australia	Sydney Children's Hospital	Sydney	New South Wales
Belgium	Universitaire Ziekenhuis Anterpen - Dienst Kinderneurologie	Edegem	Antwerpen
Italy	Istituto Giannina Gaslini - Ospedale Pediatrico	Genova
Italy	U.O. Neurologia Pediatrica Ospedale dei Bambini "Vittore Buzzi"- ASST Fatebenefratelli Sacco	Milan
Italy	UOC Neuropsichiatria Infantile Azienda Ospedaliera Universitaria Integrata Verona Ospedale Donna e Bambino	Verona
Spain	Hospital Sant Joan de Déu	Esplugues de Llobregat	Barcelona
Spain	Hospital Nino Jesus	Madrid
United States	Children's Hospital of Colorado	Aurora	Colorado
United States	Ann & Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	The Cleveland Clinic Foundation	Cleveland	Ohio
United States	Northwest Florida Clinical Research Group	Gulf Breeze	Florida
United States	Columbia University Irving Medical Center	New York	New York
United States	Children's Hospital of Orange County	Orange	California
United States	Children's Hpspital of Philadelphia	Philadelphia	Pennsylvania
United States	Oregon Health and Science University	Portland	Oregon
United States	UCSF Beniof Children's Hospital	San Francisco	California
United States	MultiCare Health System - Mary Bridge Pediatrics - Tacoma	Tacoma	Washington
United States	Children's National Medical Center	Washington	District of Columbia

Sponsors (1)

Lead Sponsor	Collaborator
Xenon Pharmaceuticals Inc.

Countries where clinical trial is conducted

United States,  Australia,  Belgium,  Italy,  Spain, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Assess the safety and tolerability of XEN496 (e.g., adverse events) in pediatric subjects with KCNQ2-DEE	To assess adverse events as criteria for safety and tolerability	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
Primary	Percent change from baseline in monthly (28 day) countable motor seizure frequency during the blinded treatment period	Parent/caregiver seizure diary record will be used to assess frequency, type and duration of seizure activity	From baseline to the end of the double-blind, 12 week treatment period (maintenance)
Secondary	Proportion of subjects with =50 percent reduction in monthly (28 day) seizure frequency	Parent/caregiver seizure diary record will be used to assess frequency, type and duration	From baseline to the end of the double-blind, 12 week treatment period (maintenance)
Secondary	Caregiver Global Impression of Change (CaGI-C) scores for the subject's overall condition and for seizures	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.	Study Days 24, 67, 88 and 109
Secondary	Change from baseline in the Caregiver Global Impression of Severity (CaGI-S) for the subject's overall condition and for seizures	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.	Study Days 1, 24, 67, 88 and 109