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

NCT04639310 | Terminated Phase 3 Results DMC FDA Drug

• 2 other identifiers: XPF-009-3012020-002396-35
• Study Type: interventional
• Target: 8
• Locations: 5 countries
• Sites: 20

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).

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

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (3)

• Percentage of Subjects With ≥50 Percent Reduction in Monthly (28 Day) Seizure Frequency

  From baseline to the end of the double-blind, 12 week treatment period (maintenance)

• Caregiver Global Impression of Change (CaGI-C) Scores for the Subject's Overall Condition and for Seizures

  Study Day 109

• Change From Baseline in the Caregiver Global Impression of Severity (CaGI-S) for the Subject's Overall Condition and for Seizures

  Study Day 109

Other Outcomes (1)

• Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE

  From screening through study completion (Day 109) or Day 151 for those not entering the OLE

Study Arms (2)

XEN496

EXPERIMENTAL

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

Placebo

PLACEBO COMPARATOR

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

Interventions

XEN496 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.

Also known as: ezogabine, retigabine

XEN496

Placebo 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.

Placebo

Eligibility Criteria

• Age: 1 Month - 6 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.
• 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.

You may not qualify if:

• 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 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.

Sponsors & Collaborators

• Xenon Pharmaceuticals Inc.: lead

Study Sites (20)

Children's Hospital of Orange County

Orange, California, 92868, United States

Location

UCSF Medical Center

San Francisco, California, 94158, United States

Location

Children's Hospital of Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Health System

Washington D.C., District of Columbia, 20010, United States

Location

Northwest Florida Clinical Research Group

Gulf Breeze, Florida, 32561, United States

Location

Anne & Robert H. Lurie Children's Hospital

Chicago, Illinois, 60611, United States

Location

Columbia University Irving Medical Center

New York, New York, 10032, United States

Location

The Cleveland Clinic Foundation

Cleveland, Ohio, 44195, United States

Location

Oregon Health and Science University

Portland, Oregon, 97239, United States

Location

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, 19104-4318, United States

Location

MultiCare Medical Center

Tacoma, Washington, 98405, United States

Location

Sydney Children's Hospital

Sydney, New South Wales, 2031, Australia

Location

Children's Health Queensland Hospital and Health Service

South Brisbane, Queensland, 4101, Australia

Location

Austin Health

Heidelberg, Victoria, 3084, Australia

Location

Universitaire Ziekenhuis Anterpen - Dienst Kinderneurologie

Edegem, Antwerpen, 2650, Belgium

Location

Istituto Giannina Gaslini

Genova, 16147, Italy

Location

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

Milan, 20154, Italy

Location

Azienda Ospedaliera Universitaria Integrata di Verona

Verona, 37126, Italy

Location

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

Esplugues de Llobregat, Barcelona, 08950, Spain

Location

Hospital Nino Jesus

Madrid, 28009, Spain

Location

MeSH Terms

Conditions

Epilepsy; Disease; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes; Seizures

Interventions

ezogabine

Condition Hierarchy (Ancestors)

Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neurologic Manifestations; Signs and Symptoms

Results Point of Contact

• Title: Dr. Noam Butterfield
• Organization: Xenon Pharmaceuticals Inc

nbutterfield@xenon-pharma.com

604 484 3300

Study Officials

• Study Director

  Xenon Pharmaceuticals Inc.

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: November 4, 2020
• First Posted: November 20, 2020
• Study Start: March 29, 2021
• Primary Completion: May 16, 2023
• Study Completion: May 16, 2023
• Last Updated: August 23, 2024
• Results First Posted: August 23, 2024

Record last verified: 2024-08

Locations

AU (3); BE (1); ES (2); IT (3); US (11)