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    Clinical Trial Results:
    A Phase 3 Study of Adjunctive XEN496 in Pediatric Subjects with KCNQ2 Developmental and Epileptic Encephalopathy

    Summary
    EudraCT number
    		 2020-002396-35
    Trial protocol
    		 BE   ES   FR   IT  
    Global end of trial date
    16 May 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Dec 2023
    First version publication date
    02 Dec 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    XPF-009-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04639310
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Xenon Pharmaceuticals Inc.
    Sponsor organisation address
    200-3650 Gilmore Way, Burnaby, BC, Canada, V5G 4W8
    Public contact
    Medical Affairs, Xenon Pharmaceuticals Inc., +1 604-484-3300, XenonCares@xenon-pharma.com
    Scientific contact
    Medical Affairs, Xenon Pharmaceuticals Inc., +1 604-484-3300, XenonCares@xenon-pharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Jul 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 May 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    16 May 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To investigate the potential antiseizure effects of adjunctive XEN496 (ezogabine) compared with placebo in children with KCNQ2 Developmental and Epileptic Encephalopathy (KCNQ2-DEE).
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles of the “Declaration of Helsinki” and International Council on Harmonisation guideline on Good Clinical Practice (GCP). This clinical trial was reviewed and approved by the appropriate Regulatory Health Agency and Ethics Committee. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects/Legal guardians were required to sign the informed consent form.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Mar 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    United States: 4
    Country: Number of subjects enrolled
    Belgium: 3
    Worldwide total number of subjects
    8
    EEA total number of subjects
    3
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    3
    Children (2-11 years)
    5
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study enrolled 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).

    Pre-assignment
    Screening details
    		 Participants entered a 2 or 4 week baseline period based upon seizure frequency prior to enrollment. At the discretion of the investigator, the baseline period was extended by an additional 2 weeks to ensure adequate establishment of baseline seizure frequency.

    Period 1
    Period 1 title
    Titration & Maintenance (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment
    Arm description
    		 24-day dose titration period to a top dose of 21 mg/kg/day. Subjects continued at the top dose, or the highest tolerated dose up to the top dose, for 12-week maintenance period. If the subject did not immediately enter into the separate open-label extension (OLE) study, the maintenance period was followed by a 15-day taper period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    XEN496
    Investigational medicinal product code
    Other name
    ezogabine, retigabine
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    XEN496 capsules: immediate-release, multi-particulate sprinkle capsule formulation of ezogabine administered orally 3 times a day for up to approximately 15 weeks (titration and maintenance). Parents / caregivers were instructed to sprinkle and mix the contents of the capsules into soft foods or liquids and feed it to the child 3 times a day.

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

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Placebo
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo sprinkle capsules: matching XEN496 in appearance containing only inactive ingredients. Parents / caregivers were instructed to sprinkle and mix the contents of the capsules into soft foods or liquids and feed it to the child three times a day.

    Number of subjects in period 1
    		Treatment Placebo
    Started
    5
    3
    Completed
    5
    2
    Not completed
    0
    1
         Subject qualified to enter OLE early per protocol
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 24-day dose titration period to a top dose of 21 mg/kg/day. Subjects continued at the top dose, or the highest tolerated dose up to the top dose, for 12-week maintenance period. If the subject did not immediately enter into the separate open-label extension (OLE) study, the maintenance period was followed by a 15-day taper period.

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

    Reporting group values
    		 Treatment Placebo Total
    Number of subjects
    		 5 3 8
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 2 1 3
        Children (2-11 years)
    		 3 2 5
    Gender categorical
    Units: Subjects
        Female
    		 3 2 5
        Male
    		 2 1 3
    Race (NIH/OMB)
    Units: Subjects
        Asian
    		 1 0 1
        White
    		 3 2 5
        Unknown or Not Reported
    		 1 1 2
    Region of Enrollment
    Units: Subjects
        Belgium
    		 1 2 3
        Australia
    		 1 0 1
        United States
    		 3 1 4

    End points

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    End points reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 24-day dose titration period to a top dose of 21 mg/kg/day. Subjects continued at the top dose, or the highest tolerated dose up to the top dose, for 12-week maintenance period. If the subject did not immediately enter into the separate open-label extension (OLE) study, the maintenance period was followed by a 15-day taper period.

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

    Primary: Percent Change From Baseline in Monthly (28 Day) Countable Motor Seizure Frequency During the Blinded Treatment Period

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    End point title
    		 Percent Change From Baseline in Monthly (28 Day) Countable Motor Seizure Frequency During the Blinded Treatment Period [1]
    End point description
    Parent/caregiver seizure diary record will be used to assess frequency, type and duration of seizure activity
    End point type
    Primary
    End point timeframe
    From baseline to the end of the double-blind, 12 week treatment period (maintenance)
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Study terminated early with only 8 of 40 participants enrolled.
    End point values
    		 Treatment Placebo
    Number of subjects analysed
    5
    3
    Units: percent
        arithmetic mean (standard deviation)
    -46.0 ( 23.49 )
    25.6 ( 46.84 )
    No statistical analyses for this end point

    Secondary: Proportion of Subjects With ≥50 Percent Reduction in Monthly (28 Day) Seizure Frequency

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    End point title
    		 Proportion of Subjects With ≥50 Percent Reduction in Monthly (28 Day) Seizure Frequency
    End point description
    Parent/caregiver seizure diary record will be used to assess frequency, type of seizure with a duration of at least 3 seconds.
    End point type
    Secondary
    End point timeframe
    From baseline to the end of the double-blind, 12 week treatment period (maintenance)
    End point values
    		 Treatment Placebo
    Number of subjects analysed
    5
    3
    Units: Count of Participants
    2
    0
    No statistical analyses for this end point

    Secondary: Caregiver Global Impression of Change (CaGI-C) Scores for the Subject’s Overall Condition and for Seizures

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    End point title
    		 Caregiver Global Impression of Change (CaGI-C) Scores for the Subject’s Overall Condition and for Seizures
    End point description
    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 point Likert scale ranging from very much improved to very much worse. Only the results for overall condition at Study Day 109 (end of treatment period; subjects with at least minimally improved overall condition [a score of <=3].) are provided.
    End point type
    Secondary
    End point timeframe
    Study Days 24, 67, 88 and 109
    End point values
    		 Treatment Placebo
    Number of subjects analysed
    5
    3
    Units: Count of Participants
    1
    1
    No statistical analyses for this end point

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

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    End point title
    		 Change From Baseline in the Caregiver Global Impression of Severity (CaGI-S) for the Subject’s Overall Condition and for Seizures
    End point description
    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. Only the results for overall condition at Study Day 109 (end of treatment period; responders [>= 1 level improved]) are provided.
    End point type
    Secondary
    End point timeframe
    Study Days 1, 24, 67, 88 and 109
    End point values
    		 Treatment Placebo
    Number of subjects analysed
    5
    3
    Units: Count of Participants
    0
    1
    No statistical analyses for this end point

    Other pre-specified: Assess the Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE

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    End point title
    		 Assess the Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE
    End point description
    To assess adverse events as criteria for safety and tolerability
    End point type
    Other pre-specified
    End point timeframe
    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
    End point values
    		 Treatment Placebo
    Number of subjects analysed
    5
    3
    Units: Count of Participants
        No. of Subject with any AE
    5
    3
        No. of Subjects with any TEAE
    5
    3
        No. of Subjects with any Treatment Related TEAE
    1
    0
        Subj. with any TEAE leading to IMP discontinuation
    0
    0
        Subjects with TEAE leading to dose reduct/interrup
    1
    0
        No. of Subjects with any Severe TEAE
    1
    1
        No. of Subjects with any TEAE- relationship to IMP
    5
    3
        No. of Subjects with any Serious TEAE
    1
    1
        No. of Subjects with any TEAE of Special Interest
    0
    0
        No. of Subjects with any TEAE leading to death
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    15 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Overall - XEN496
    Reporting group description
    		 -

    Reporting group title
    Overall - Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Overall - XEN496 Overall - Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 3 (33.33%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Status epilepticus
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Metapneumovirus pneumonia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia viral
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall - XEN496 Overall - Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 5 (100.00%)
    3 / 3 (100.00%)
    Investigations
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Nervous system disorders
    Lethargy
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Eye disorders
    Conjunctival hyperemia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Diarrhoea
         subjects affected / exposed
    2 / 5 (40.00%)
    1 / 3 (33.33%)
         occurrences all number
    2
    1
    Hemotochemia
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Vomiting
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Teething
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary congestion
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Poor quality sleep
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1
    COVID-19
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 3 (66.67%)
         occurrences all number
    0
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Otitis media
         subjects affected / exposed
    1 / 5 (20.00%)
    0 / 3 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 3 (33.33%)
         occurrences all number
    1
    1
    Viral infection
         subjects affected / exposed
    2 / 5 (40.00%)
    0 / 3 (0.00%)
         occurrences all number
    2
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 3 (33.33%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Jun 2021
    Version 1.0 of the XPF-009-301 clinical study protocol was amended to update laboratory assessments, provide clarifications
    31 Jan 2022
    Version 2.0 of the XPF-009-301 clinical study protocol was amended to incorporate requested updates from applicable Agencies.
    06 May 2022
    Version 3.0 of the XPF-009-301 clinical study protocol was amended confirm dose, inclusion and assessment information.
    10 Nov 2022
    Version 4.0 of the XPF-009-301 clinical study protocol was amended to clarify the inclusion criteria.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    In May 2023, Xenon discontinued the XEN496 program due to significant challenges encountered with enrollment. The program, including this study, was not halted due to safety reasons or for futility (inability to show efficacy).
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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