Brain Diseases, Central Nervous System Diseases, Disease, Epilepsy, Epilepsy in Children, Epilepsy; Seizure, Epileptic Syndromes, Nervous System Diseases
Conditions
Keywords
XEN496, Ezogabine, Retigabine, Encephalopathy, Seizure, KCNQ2
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.
Interventions
DRUGXEN496
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.
DRUGPlacebo
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.
Sponsors
Xenon Pharmaceuticals Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
1 Months to 6 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Monthly (28 Day) Countable Motor Seizure Frequency During the Blinded Treatment Period | 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
| Measure | Time frame | Description |
|---|---|---|
| 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) | Parent/caregiver seizure diary record will be used to assess frequency, type of seizure with a duration of at least 3 seconds. |
| Caregiver Global Impression of Change (CaGI-C) Scores for the Subject's Overall Condition and for Seizures | Study Day 109 | CaGI-C scale is a caregiver-reported assessment of the change from baseline in the subject's overall condition and seizure severity. Responses to the CaGI-C questionnaire are to be rated on a 7-point Likert scale anchored at 1=Very much improved and 7=Very much worse. Subjects at least minimally improved compared to baseline (a score of \<=3) for overall condition or for seizure severity are reported in the analysis population. The primary comparison between treatments will be based on the last visit in the double-blind treatment period (or the early termination visit if the patient discontinued the treatment early). The results at Study Day 109 (end of treatment period) are provided. |
| Change From Baseline in the Caregiver Global Impression of Severity (CaGI-S) for the Subject's Overall Condition and for Seizures | Study Day 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-point Likert scale ranging from none to very severe. The CaGI-S consists of single items relating to each concept and is scored by the caregiver using a 5-point response ranging from 1 to 5, anchored at 1=None and 5=Very Severe. Subjects with improvement of at least 1 level compared to baseline for overall condition or for seizure severity are reported in the analysis population. The results at Study Day 109 (end of treatment period) are provided. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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 | To assess adverse events as criteria for safety and tolerability |
Countries
Australia, Belgium, Italy, Spain, United States
Participant flow
Pre-assignment details
Participants entered a 2 or 4 week baseline period based upon seizure frequency prior to enrollment. Baseline period was extended by an additional 2 weeks to ensure adequate establishment of baseline seizure frequency, at the discretion of the investigator.
Participants by arm
| Arm | Count |
|---|---|
| XEN496 XEN496 capsules: immediate-release, multiparticulate sprinkle capsule formulation of ezogabine administered orally TID for up to approximately 15 weeks (titration and maintenance). | 5 |
| Placebo Placebo capsules: matching XEN496 in appearance containing only inactive ingredients. | 3 |
| Total | 8 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Subject qualified to rollover to open label extension due to meeting disease worsening criteria | 0 | 1 |
Baseline characteristics
| Characteristic | XEN496 | Placebo | Total |
|---|---|---|---|
| Age, Customized age < 2 years Age < 2 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Customized age < 2 years Age >= 2 years | 3 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 3 Participants | 2 Participants | 5 Participants |
| Region of Enrollment Australia | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Belgium | 1 participants | 2 participants | 3 participants |
| Region of Enrollment United States | 3 participants | 1 participants | 4 participants |
| Sex: Female, Male Female | 3 Participants | 2 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 3 |
| other Total, other adverse events | 5 / 5 | 3 / 3 |
| serious Total, serious adverse events | 1 / 5 | 1 / 3 |
Outcome results
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
Time frame: From baseline to the end of the double-blind, 12 week treatment period (maintenance)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| XEN496 | Percent Change From Baseline in Monthly (28 Day) Countable Motor Seizure Frequency During the Blinded Treatment Period | -46.0 percentage change from baseline | Standard Deviation 23.49 |
| Placebo | Percent Change From Baseline in Monthly (28 Day) Countable Motor Seizure Frequency During the Blinded Treatment Period | 25.6 percentage change from baseline | Standard Deviation 46.84 |
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 of the change from baseline in the subject's overall condition and seizure severity. Responses to the CaGI-C questionnaire are to be rated on a 7-point Likert scale anchored at 1=Very much improved and 7=Very much worse. Subjects at least minimally improved compared to baseline (a score of \<=3) for overall condition or for seizure severity are reported in the analysis population. The primary comparison between treatments will be based on the last visit in the double-blind treatment period (or the early termination visit if the patient discontinued the treatment early). The results at Study Day 109 (end of treatment period) are provided.
Time frame: Study Day 109
Population: Subjects at least minimally improved (a score of \<=3) compared to baseline.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| XEN496 | Caregiver Global Impression of Change (CaGI-C) Scores for the Subject's Overall Condition and for Seizures | Seizure Severity | 1 Participants |
| XEN496 | Caregiver Global Impression of Change (CaGI-C) Scores for the Subject's Overall Condition and for Seizures | Overall Condition | 1 Participants |
| Placebo | Caregiver Global Impression of Change (CaGI-C) Scores for the Subject's Overall Condition and for Seizures | Seizure Severity | 1 Participants |
| Placebo | Caregiver Global Impression of Change (CaGI-C) Scores for the Subject's Overall Condition and for Seizures | Overall Condition | 1 Participants |
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-point Likert scale ranging from none to very severe. The CaGI-S consists of single items relating to each concept and is scored by the caregiver using a 5-point response ranging from 1 to 5, anchored at 1=None and 5=Very Severe. Subjects with improvement of at least 1 level compared to baseline for overall condition or for seizure severity are reported in the analysis population. The results at Study Day 109 (end of treatment period) are provided.
Time frame: Study Day 109
Population: Subjects with improvement of at least 1 level compared to baseline
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| XEN496 | Change From Baseline in the Caregiver Global Impression of Severity (CaGI-S) for the Subject's Overall Condition and for Seizures | Overall Condition | 0 Participants |
| XEN496 | Change From Baseline in the Caregiver Global Impression of Severity (CaGI-S) for the Subject's Overall Condition and for Seizures | Seizure Severity | 1 Participants |
| Placebo | Change From Baseline in the Caregiver Global Impression of Severity (CaGI-S) for the Subject's Overall Condition and for Seizures | Overall Condition | 1 Participants |
| Placebo | Change From Baseline in the Caregiver Global Impression of Severity (CaGI-S) for the Subject's Overall Condition and for Seizures | Seizure Severity | 0 Participants |
Secondary
Percentage of Subjects With ≥50 Percent Reduction in Monthly (28 Day) Seizure Frequency
Parent/caregiver seizure diary record will be used to assess frequency, type of seizure with a duration of at least 3 seconds.
Time frame: From baseline to the end of the double-blind, 12 week treatment period (maintenance)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| XEN496 | Percentage of Subjects With ≥50 Percent Reduction in Monthly (28 Day) Seizure Frequency | 2 Participants |
| Placebo | Percentage of Subjects With ≥50 Percent Reduction in Monthly (28 Day) Seizure Frequency | 0 Participants |
Other Pre-specified
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
Time frame: From screening through study completion (Day 109) or Day 151 for those not entering the OLE
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| XEN496 | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE by relationship to study drug | 5 Participants |
| XEN496 | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE | 5 Participants |
| XEN496 | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE of Special Interest | 0 Participants |
| XEN496 | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any Treatment Related TEAE | 1 Participants |
| XEN496 | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any Serious TEAE | 1 Participants |
| XEN496 | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE leading to discontinuation of study drug | 0 Participants |
| XEN496 | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE leading to death | 0 Participants |
| XEN496 | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE leading to dose reduction of treatment interruption | 1 Participants |
| XEN496 | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subject with any AE | 5 Participants |
| XEN496 | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any Severe TEAE | 1 Participants |
| Placebo | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE leading to death | 0 Participants |
| Placebo | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any Severe TEAE | 1 Participants |
| Placebo | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE by relationship to study drug | 3 Participants |
| Placebo | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any Serious TEAE | 1 Participants |
| Placebo | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE of Special Interest | 0 Participants |
| Placebo | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subject with any AE | 3 Participants |
| Placebo | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE | 3 Participants |
| Placebo | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any Treatment Related TEAE | 0 Participants |
| Placebo | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE leading to discontinuation of study drug | 0 Participants |
| Placebo | Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE | No. of Subjects with any TEAE leading to dose reduction of treatment interruption | 0 Participants |