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    Clinical Trial Results:
    Phase 2 Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy, Safety, Tolerability, and Pharmacokinetics of NBI-827104 in Pediatric Subjects with Epileptic Encephalopathy with Continuous Spike-and-Wave During Sleep

    Summary
    EudraCT number
    		 2020-003141-11
    Trial protocol
    		 DK   FR   ES   DE  
    Global end of trial date
    18 Oct 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Apr 2023
    First version publication date
    28 Apr 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NBI-827104-CSWS2010
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04625101
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Neurocrine Biosciences
    Sponsor organisation address
    12780 El Camino Real, San Diego, United States, 92130
    Public contact
    Neurocrine Medical Information, Neurocrine Biosciences, +1 877-641-3461, medinfo@neurocrine.com
    Scientific contact
    Neurocrine Medical Information, Neurocrine Biosciences, +1 877-641-3461, medinfo@neurocrine.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    18 Oct 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Oct 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Oct 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the effect of NBI-827104 on the overnight epileptiform video electroencephalogram (video EEG) activity in pediatric participants with epileptic encephalopathy with continuous spike-wave discharges during sleep (EECSWS).
    Protection of trial subjects
    The study was conducted in full compliance with International Council for Harmonisation (ICH) Technical Requirements for Pharmaceuticals for Human Use GCP guidelines and with the laws and regulations of the country in which the study was conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Apr 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
    Spain: 3
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Switzerland: 2
    Country: Number of subjects enrolled
    United Kingdom: 2
    Country: Number of subjects enrolled
    United States: 14
    Worldwide total number of subjects
    24
    EEA total number of subjects
    6
    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)
    0
    Children (2-11 years)
    21
    Adolescents (12-17 years)
    3
    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
    		 -

    Pre-assignment
    Screening details
    		 Participants were enrolled at 14 clinical sites in the United States and Europe.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NBI-827104
    Arm description
    		 NBI-827104 administered orally daily for up to 13 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NBI-827104
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    NBI-827104 was administered per dose and schedule specified in the arm description.

    Arm title
    		 Placebo
    Arm description
    		 Placebo administered orally daily for up to 13 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo was administered per dose and schedule specified in the arm description.

    Number of subjects in period 1
    		NBI-827104 Placebo
    Started
    16
    8
    Completed
    15
    7
    Not completed
    1
    1
         Protocol deviation
    1
    -
         Withdrawal by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NBI-827104
    Reporting group description
    		 NBI-827104 administered orally daily for up to 13 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered orally daily for up to 13 weeks.

    Reporting group values
    		 NBI-827104 Placebo Total
    Number of subjects
    		 16 8 24
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 14 7 21
        Adolescents (12-17 years)
    		 2 1 3
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 7 3 10
        Male
    		 9 5 14
    Race
    Units: Subjects
        White
    		 15 7 22
        Black or African American
    		 0 1 1
        Other
    		 1 0 1
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 3 0 3
        Not Hispanic or Latino
    		 13 8 21

    End points

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    End points reporting groups
    Reporting group title
    NBI-827104
    Reporting group description
    		 NBI-827104 administered orally daily for up to 13 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered orally daily for up to 13 weeks.

    Primary: Ratio of Spike-Wave Index (SWI) During First Hour of Nonrapid Eye Movement (NREM) Sleep at Week 6

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    End point title
    		 Ratio of Spike-Wave Index (SWI) During First Hour of Nonrapid Eye Movement (NREM) Sleep at Week 6
    End point description
    The ratio of SWI at the end of Week 6 to baseline during the first hour (60 minutes) of NREM sleep based on centralized video-EEG reading, where baseline was defined as the last value measured prior to intake of study treatment on Day 1. Full Analysis Set included all randomized participants who had at least 1 dose of study treatment and at least 1 efficacy video EEG assessment.
    End point type
    Primary
    End point timeframe
    Baseline to Week 6
    End point values
    		 NBI-827104 Placebo
    Number of subjects analysed
    14 [1]
    6 [2]
    Units: Ratio
        least squares mean (standard error)
    -0.02 ± 0.02
    0.01 ± 0.04
    Notes
    [1] - One participant did not have a Week 6 video-EEG and was excluded from the analysis.
    [2] - One participant did not have an evaluable Week 6 video-EEG and was excluded from the analysis.
    Statistical analysis title
    		 Change from Baseline to the end of Week 6
    Comparison groups
    NBI-827104 v Placebo
    Number of subjects included in analysis
    20
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4326
    Method
    		 ANCOVA
    Confidence interval

    Secondary: Ratio of SWI During First Hour of NREM Sleep at Week 12

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    End point title
    		 Ratio of SWI During First Hour of NREM Sleep at Week 12
    End point description
    The ratio of SWI at the end of Week 12 to baseline during the first hour (60 minutes) of NREM sleep based on centralized video-EEG reading, where baseline was defined as the last value measured prior to intake of study treatment on Day 1. Full Analysis Set included all randomized participants who had at least 1 dose of study treatment and at least 1 efficacy video EEG assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 12
    End point values
    		 NBI-827104 Placebo
    Number of subjects analysed
    15
    7
    Units: Ratio
        least squares mean (standard error)
    -0.05 ± 0.02
    0.03 ± 0.03
    No statistical analyses for this end point

    Secondary: Number of Participants Considered as Responders as Assessed by the Caregiver Global Impression of Change (CaGI-C) Score

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    End point title
    		 Number of Participants Considered as Responders as Assessed by the Caregiver Global Impression of Change (CaGI-C) Score
    End point description
    The CaGI-C is a 7-point scale that rates the caregiver's assessment of the overall improvement in the participants symptoms since the initiation of study treatment, ranging from 1 (very much improved) to 7 (very much worse). A responder was defined as a participant with a score of 1 (very much improved) or 2 (much improved). Full Analysis Set included all randomized participants who had at least 1 dose of study treatment and at least 1 efficacy video EEG assessment.
    End point type
    Secondary
    End point timeframe
    Week 6 and Week 12
    End point values
    		 NBI-827104 Placebo
    Number of subjects analysed
    15
    7
    Units: Count of Participants
        Week 6
    1
    1
        Week 12
    2
    1
    No statistical analyses for this end point

    Secondary: Number of Participants Considered as Responders as Assessed by the Clinician Global Impression of Change (CGI-C) Score

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    End point title
    		 Number of Participants Considered as Responders as Assessed by the Clinician Global Impression of Change (CGI-C) Score
    End point description
    The CGI-C is a 7-point scale that rates the clinician's assessment of overall improvement in the participant's symptoms since the initiation of study treatment, ranging from 1 (very much improved) to 7 (very much worse). A responder was defined as a participant with a score of 1 (very much improved) or 2 (much improved). Full Analysis Set included all randomized participants who had at least 1 dose of study treatment and at least 1 efficacy video EEG assessment.
    End point type
    Secondary
    End point timeframe
    Week 6 and Week 12
    End point values
    		 NBI-827104 Placebo
    Number of subjects analysed
    15
    7
    Units: Count of Participants
        Week 6
    1
    1
        Week 12
    1
    1
    No statistical analyses for this end point

    Secondary: Number of Participants Considered as Responders as Assessed by the Clinical Global Impression of Severity (CGI-S) Scores

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    End point title
    		 Number of Participants Considered as Responders as Assessed by the Clinical Global Impression of Severity (CGI-S) Scores
    End point description
    The CGI-S is a 7-point scale that rates the clinician's assessment of overall symptom severity, ranging from 1 (normal, not at all ill) to 7 (among the most extremely ill patients). A responder was defined as a participant with at least 1-point improvement in the CGI-S score from baseline. Full Analysis Set included all randomized participants who had at least 1 dose of study treatment and at least 1 efficacy video EEG assessment.
    End point type
    Secondary
    End point timeframe
    Baseline to Week 6 and Baseline to Week 12
    End point values
    		 NBI-827104 Placebo
    Number of subjects analysed
    15
    7
    Units: Count of Participants
        Week 6
    3
    1
        Week 12
    4
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (after dosing) to Week 17
    Adverse event reporting additional description
    Safety analysis set included all randomized participants who had at least 1 dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    NBI-827104
    Reporting group description
    		 NBI-827104 administered orally daily for up to 13 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo administered orally daily for up to 13 weeks.

    Serious adverse events
    		 NBI-827104 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (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: 0%
    Non-serious adverse events
    		 NBI-827104 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 16 (68.75%)
    8 / 8 (100.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 16 (18.75%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    Pyrexia
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Rhinorrhoea
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Affect lability
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Aggression
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Depressed mood
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Irritability
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Restlessness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Suicidal ideation
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Terminal insomnia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    2
    2
    Blood triglycerides increased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Lymphocyte count decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    3
    0
    Protein urine present
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Vitamin D decreased
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Face injury
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Headache
         subjects affected / exposed
    2 / 16 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    Partial seizures
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Somnolence
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Eye disorders
    Eye pain
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal pain lower
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Haematochezia
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Keratosis pilaris
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Pruritus
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    2
    Endocrine disorders
    Precocious puberty
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 16 (12.50%)
    2 / 8 (25.00%)
         occurrences all number
    2
    2
    Infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Nasopharyngitis
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Otitis media
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Rash pustular
         subjects affected / exposed
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    1
    Suspected COVID-19
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    2
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 16 (18.75%)
    1 / 8 (12.50%)
         occurrences all number
    3
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 May 2021
    - A requirement that at least 4 days of baseline seizure diary data should be obtained prior to randomization was added. - Added permitted medications
    05 Aug 2021
    - The option for participants to enroll directly into an open-label extension study after the completion of the Week 12 study visit was added. - Updated inclusion criterion for contraception - Added prohibited medication - Reduced the total blood volume collected during the study - Added additional requirements for study treatment discontinuation

    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.
    None reported
    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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