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    Clinical Trial Results:
    An open-label adaptive study for the assessment of safety, tolerability, pharmacokinetics, and efficacy of multiple doses of radiprodil in subjects with drug-resistant infantile spasms

    Summary
    EudraCT number
    2016-002107-26
    Trial protocol
    GB   BE   DE   BG   FR  
    Global end of trial date
    02 Oct 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    17 Apr 2019
    First version publication date
    17 Apr 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    EP0078
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02829827
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    UCB Biopharma SPRL
    Sponsor organisation address
    Allée de la Recherche 60, Brussels, Belgium, 1070
    Public contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com
    Scientific contact
    Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.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
    10 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Oct 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    Part A: To - Evaluate the safety and tolerability of radiprodil in subjects with drug-resistant infantile spasms - Evaluate the pharmacokinetics of radiprodil in subjects with drug-resistant infantile spasms - Evaluate the efficacy of radiprodil in abolishing clinical spasms in subjects with drug-resistant infantile spasms Part B: To - Evaluate the efficacy of radiprodil in abolishing clinical spasms and achieving the resolution of hypsarrhythmia (or other disordered interictal electroencephalogram (EEG) patterns consistent with the diagnosis) in subjects with drug-resistant infantile spasms - Evaluate the safety and tolerability of radiprodil in subjects with drug-resistant infantile spasms Part C: To - Investigate the safety and tolerability of radiprodil over repeated treatment cycles - Investigate the efficacy of radiprodil in infants who have responded to 2 treatment cycles in Part A but experienced a relapse within 3 days of treatment cessation
    Protection of trial subjects
    During the conduct of the study all subjects were closely monitored.
    Background therapy
    Background therapy as permitted in the protocol.
    Evidence for comparator
    Not applicable.
    Actual start date of recruitment
    04 Dec 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Efficacy, Safety
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    France: 3
    Worldwide total number of subjects
    3
    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)
    0
    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
    The study started to enroll patients in December 2017 and was terminated in October 2018.

    Pre-assignment
    Screening details
    The Participant Flow refers to the Safety Set (SS).

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Radiprodil
    Arm description
    Each subject entered an individualized dose titration schedule. The titration included 3 dose levels of radiprodil: low, medium, high, given bid for 3 days (Day 1L to Day 3L, Day 1M to Day 3M, Day 1H to Day 3H). Titration from L dose to M dose was decided by the investigator: if spasms continued with no safety/tolerability issues, the dose was increased to M, if spasms were absent for 24h, the L dose remained the Maintenance dose. Dose titration from M to H and/or Maintenance of M dose was decided by the investigator, following the same procedure. The Maintenance period occurred over a period of 14 Days (Day14Maint) if spasm continued on Day 3H and there were no safety/tolerability issues, or 28 days (Day28Maint) if spasms were absent for 24h. If spasms were still present at Day14Maint, radiprodil tapering took place: from L dose to L dose 1 per day for 3 days, from M dose to L dose, 3 days bid, from H dose to M dose, 3 days bid.
    Arm type
    Experimental

    Investigational medicinal product name
    Radiprodil
    Investigational medicinal product code
    UCB3491
    Other name
    Pharmaceutical forms
    Granules for oral suspension
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were administered 3 dose levels (low, medium, high) of radiprodil, given bid for 3 days, as follows: low dose from Day1L to Day 3L, with maintenance of low dose if spasms were absent 24h, or titration to middle dose, if spasms continued. Middle dose from Day1M to Day3M, with maintenance of middle dose if spasms were absent 24 hours, or titration to high dose if spasms continued. High dose from Day1H to day3H, with maintenance of high dose if spasms were absent 24h, for 28Days (28Maint), or tapering if spasms were still present over a period of 14 days (Day14Maint). Radiprodil tapering was done from low dose to low dose, once a day for 3 days; middle dose to low dose, 3 days bid and high dose to middle dose, 3 days bid.

    Number of subjects in period 1
    Radiprodil
    Started
    3
    Completed
    0
    Not completed
    3
         Sponsor study termination
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Radiprodil
    Reporting group description
    Each subject entered an individualized dose titration schedule. The titration included 3 dose levels of radiprodil: low, medium, high, given bid for 3 days (Day 1L to Day 3L, Day 1M to Day 3M, Day 1H to Day 3H). Titration from L dose to M dose was decided by the investigator: if spasms continued with no safety/tolerability issues, the dose was increased to M, if spasms were absent for 24h, the L dose remained the Maintenance dose. Dose titration from M to H and/or Maintenance of M dose was decided by the investigator, following the same procedure. The Maintenance period occurred over a period of 14 Days (Day14Maint) if spasm continued on Day 3H and there were no safety/tolerability issues, or 28 days (Day28Maint) if spasms were absent for 24h. If spasms were still present at Day14Maint, radiprodil tapering took place: from L dose to L dose 1 per day for 3 days, from M dose to L dose, 3 days bid, from H dose to M dose, 3 days bid.

    Reporting group values
    Radiprodil Total
    Number of subjects
    3 3
    Age categorical
    Units: Subjects
        <=18 years
    3 3
        Between 18 and 65 years
    0 0
        >=65 years
    0 0
    Age continuous
    Note: Due to low number of subjects (n=3) the Mean and SD could not be calculated, thus 999 is a placeholder value.
    Units: months
        arithmetic mean (standard deviation)
    999 ± 999 -
    Gender categorical
    Units: Subjects
        Male
    2 2
        Female
    1 1
    Subject analysis sets

    Subject analysis set title
    Radiprodil (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Each subject entered an individualized dose titration schedule. The titration included 3 dose levels of radiprodil: low, medium, high, given bid for 3 days (Day 1L to Day 3L, Day 1M to Day 3M, Day 1H to Day 3H). Titration from L dose to M dose was decided by the investigator: if spasms continued with no safety/tolerability issues, the dose was increased to M, if spasms were absent for 24h, the L dose remained the Maintenance dose. Dose titration from M to H and/or Maintenance of M dose was decided by the investigator, following the same procedure. The Maintenance period occurred over a period of 14 Days (Day14Maint) if spasm continued on Day 3H and there were no safety/tolerability issues, or 28 days (Day28Maint) if spasms were absent for 24h. If spasms were still present at Day14Maint, radiprodil tapering took place: from L dose to L dose 1 per day for 3 days, from M dose to L dose, 3 days bid, from H dose to M dose, 3 days bid forming the Safety Set (SS).

    Subject analysis sets values
    Radiprodil (SS)
    Number of subjects
    3
    Age categorical
    Units: Subjects
        <=18 years
    3
        Between 18 and 65 years
    0
        >=65 years
    0
    Age continuous
    Note: Due to low number of subjects (n=3) the Mean and SD could not be calculated, thus 999 is a placeholder value.
    Units: months
        arithmetic mean (standard deviation)
    999 ± 999
    Gender categorical
    Units: Subjects
        Male
    2
        Female
    1

    End points

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    End points reporting groups
    Reporting group title
    Radiprodil
    Reporting group description
    Each subject entered an individualized dose titration schedule. The titration included 3 dose levels of radiprodil: low, medium, high, given bid for 3 days (Day 1L to Day 3L, Day 1M to Day 3M, Day 1H to Day 3H). Titration from L dose to M dose was decided by the investigator: if spasms continued with no safety/tolerability issues, the dose was increased to M, if spasms were absent for 24h, the L dose remained the Maintenance dose. Dose titration from M to H and/or Maintenance of M dose was decided by the investigator, following the same procedure. The Maintenance period occurred over a period of 14 Days (Day14Maint) if spasm continued on Day 3H and there were no safety/tolerability issues, or 28 days (Day28Maint) if spasms were absent for 24h. If spasms were still present at Day14Maint, radiprodil tapering took place: from L dose to L dose 1 per day for 3 days, from M dose to L dose, 3 days bid, from H dose to M dose, 3 days bid.

    Subject analysis set title
    Radiprodil (SS)
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Each subject entered an individualized dose titration schedule. The titration included 3 dose levels of radiprodil: low, medium, high, given bid for 3 days (Day 1L to Day 3L, Day 1M to Day 3M, Day 1H to Day 3H). Titration from L dose to M dose was decided by the investigator: if spasms continued with no safety/tolerability issues, the dose was increased to M, if spasms were absent for 24h, the L dose remained the Maintenance dose. Dose titration from M to H and/or Maintenance of M dose was decided by the investigator, following the same procedure. The Maintenance period occurred over a period of 14 Days (Day14Maint) if spasm continued on Day 3H and there were no safety/tolerability issues, or 28 days (Day28Maint) if spasms were absent for 24h. If spasms were still present at Day14Maint, radiprodil tapering took place: from L dose to L dose 1 per day for 3 days, from M dose to L dose, 3 days bid, from H dose to M dose, 3 days bid forming the Safety Set (SS).

    Primary: Percentage of subjects with clinical response on Day 14 of treatment with the maintenance dose of radiprodil

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    End point title
    Percentage of subjects with clinical response on Day 14 of treatment with the maintenance dose of radiprodil [1]
    End point description
    Clinical response was defined as no spasms on Day 14 of treatment with the maintenance dose of radiprodil. This is the primary efficacy variable for Part A.
    End point type
    Primary
    End point timeframe
    Day 14, counting from the first day of radiprodil at maintenance dose
    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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: percentage of subjects
        number (not applicable)
    33.33
    No statistical analyses for this end point

    Primary: Plasma concentration of radiprodil at Day 1

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    End point title
    Plasma concentration of radiprodil at Day 1 [2]
    End point description
    This is a primary variable for Part A. Radiprodil plasma concentration was expressed in nanograms per millilitre (ng/mL). Concentrations that were Below the lower Limit of Quantification (BLQ) (1ng/mL) were imputed with half of the Lower Limit of Quatification (LLOQ) for the purpose of calculating descriptive statistics. Note: 9999 is a placeholder value as the radiprodil plasma concentration was not analysed for one subject at Day 1.
    End point type
    Primary
    End point timeframe
    PK samples were collected at baseline, any time from Day -14/Day -1 prior dosing and 3h, 4h, 5h, 12h post 1st dose on Day 1 of radiprodil low dose.
    Notes
    [2] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: ng/mL
    number (not applicable)
        Subject 1 - Day 1 - 3h
    9999
        Subject 1 - Day 1 - 4h
    9999
        Subject 1 - Day 1 - 5h
    9999
        Subject 1 - Day 1 - 12h
    9999
        Subject 2 - Day 1 - 3h
    12.3
        Subject 2 - Day 1 - 4h
    10.7
        Subject 2 - Day 1 - 5h
    9.18
        Subject 2 - Day 1 - 12h
    3.58
        Subject 3 - Day 1 - 3h
    13.4
        Subject 3 - Day 1 - 4h
    10.3
        Subject 3 - Day 1 - 5h
    11.7
        Subject 3 - Day 1 - 12h
    4.17
    No statistical analyses for this end point

    Primary: Area Under the concentration time-Curve (AUC) generated from a population - Pharmacokinetic model

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    End point title
    Area Under the concentration time-Curve (AUC) generated from a population - Pharmacokinetic model [3]
    End point description
    This is a primary variable for Part A. Sampling for pharmacokinetic (PK) analyses was done using the Mitra microsampling technique. Note: AUC results are from Day 2 low dose, since not all subjects had usable data from Day 1
    End point type
    Primary
    End point timeframe
    PK samples were collected at baseline, any time from Day -14/Day -1 prior dosing and 3h, 4h, 5h, 12h post 1st dose on Day 1 of radiprodil low dose, mid dose and high dose. Samples were taken at same timepoints after 1st radiprodil low dose on Day 2.
    Notes
    [3] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: ng/ml*h
    number (not applicable)
        Subject 1 - Day 2
    214
        Subject 2 - Day 2
    185
        Subject 3 - Day 2
    198
    No statistical analyses for this end point

    Primary: Maximum plasma concentration (Cmax) generated from a population - Pharmacokinetic model

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    End point title
    Maximum plasma concentration (Cmax) generated from a population - Pharmacokinetic model [4]
    End point description
    This is a primary variable for Part A. Sampling for pharmacokinetic (PK) analyses was done using the Mitra microsampling technique. Note: Cmax results are from Day 2 low dose, since not all subjects had usable data from Day 1.
    End point type
    Primary
    End point timeframe
    PK samples were collected at baseline, any time from Day -14/Day -1 prior dosing and 3h, 4h, 5h, 12h post 1st dose on Day 1 of radiprodil low dose, mid dose and high dose. Samples were taken at same timepoints after 1st radiprodil low dose on Day 2.
    Notes
    [4] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: ng/ml
    number (not applicable)
        Subject 1
    47.1
        Subject 2
    44.3
        Subject 3
    45.8
    No statistical analyses for this end point

    Primary: Apparent terminal half-life (t 1/2) generated from a population - Pharmacokinetic model

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    End point title
    Apparent terminal half-life (t 1/2) generated from a population - Pharmacokinetic model [5]
    End point description
    This is a primary variable for Part A. Sampling for pharmacokinetic (PK) analyses was done using the Mitra microsampling technique. Note: t 1/2 results are from Day 2 low dose, since not all subjects had usable data from Day 1.
    End point type
    Primary
    End point timeframe
    PK samples were collected at baseline, any time from Day -14/Day -1 prior dosing and 3h, 4h, 5h, 12h post 1st dose on Day 1 of radiprodil low dose, mid dose and high dose. Samples were taken at same timepoints after 1st radiprodil low dose on Day 2.
    Notes
    [5] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: Hours
    number (not applicable)
        Subject 1
    6.7
        Subject 2
    5.3
        Subject 3
    5.9
    No statistical analyses for this end point

    Primary: Percentage of subjects with electro-clinical response on Day 14 of treatment with the maintenance dose of radiprodil

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    End point title
    Percentage of subjects with electro-clinical response on Day 14 of treatment with the maintenance dose of radiprodil [6]
    End point description
    Electro-clinical response was defined as no spasms and resolution of hypsarrhythmia on Day 14 of treatment with the maintenance dose of radiprodil. This is the primary efficacy variable for Part B. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Primary
    End point timeframe
    Day 14, counting from the first day of radiprodil at maintenance dose
    Notes
    [6] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    0 [7]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [7] - Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    No statistical analyses for this end point

    Primary: Incidence of Adverse Events (AEs) during the study

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    End point title
    Incidence of Adverse Events (AEs) during the study [8]
    End point description
    An AE is any untoward medical occurrence in a subject or trial subject that is administered a drug or biologic (medicinal product) or that is using a medical device. The event does not necessarily have a causal relationship with that treatment or usage. This is a primary variable for all parts.
    End point type
    Primary
    End point timeframe
    From Baseline (Day -1) to the end of the Post-treatment Period (28 days post last dosing)
    Notes
    [8] - 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: No formal statistical hypothesis testing was planned for this study. Results were summarized as descriptive statistics only.
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: participants
    3
    No statistical analyses for this end point

    Secondary: Percentage of subjects with electro-clinical response on Day 14 of treatment with the maintenance dose of radiprodil Part A

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    End point title
    Percentage of subjects with electro-clinical response on Day 14 of treatment with the maintenance dose of radiprodil Part A
    End point description
    Electro-clinical response was defined as no spasms and resolution of hypsarrhythmia on Day 14 of treatment with the maintenance dose of radiprodil. This is the secondary efficacy variable for Part A.
    End point type
    Secondary
    End point timeframe
    Day 14, counting from the first day of radiprodil at maintenance dose
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: percentage of subjects
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects with clinical response on Day 14 of treatment with the maintenance dose of radiprodil Part B

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    End point title
    Percentage of subjects with clinical response on Day 14 of treatment with the maintenance dose of radiprodil Part B
    End point description
    Clinical response was defined as no spasms on Day 14 of treatment with the maintenance dose of radiprodil. This is the secondary efficacy variable for Part B. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    Day 14, counting from Day 14 of treatment with the maintenance dose of radiprodil
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    0 [9]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [9] - Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    No statistical analyses for this end point

    Secondary: Estimates of exposure generated from a population-Pharmacokinetic model

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    End point title
    Estimates of exposure generated from a population-Pharmacokinetic model
    End point description
    This is a secondary variable for Part B. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    Pharmacokinetic samples were collected on Day 1 of radiprodil low dose, mid dose and high dose. Additionally, blood samples were taken after 1st dose on Day 2 of radiprodil low dose.
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    0 [10]
    Units: ng/ml*h
        number (not applicable)
    Notes
    [10] - Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    No statistical analyses for this end point

    Secondary: Time to cessation of spasms

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    End point title
    Time to cessation of spasms
    End point description
    Time to cessation of spasms for clinical responders on Day 14 of treatment with the maintenance dose of radiprodol. This is a secondary efficacy variable for parts A and B. Note 1: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor. Note 2: If spasms have not stopped by Day 14 Maint, then the time to cessation of spasms was considered to be right-censored at Day 14 Maint.
    End point type
    Secondary
    End point timeframe
    During the first 14 days of treatment with radiprodil
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: days
    number (not applicable)
        Subject 1
    3
        Subject 2
    0
        Subject 3
    0
    No statistical analyses for this end point

    Secondary: Percentage of responders with clinical relapse

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    End point title
    Percentage of responders with clinical relapse
    End point description
    The percentage of clinical responders on Day 14 of treatment with the maintenance dose of radiprodil with clinical relapse within 12 months. This is a secondary efficacy variable for parts A and B. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    12 months, counting from Day 14 of treatment with the maintenance dose of radiprodil
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: percentage of subjects
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Time to clinical relapse from the day of spasm cessation

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    End point title
    Time to clinical relapse from the day of spasm cessation
    End point description
    This is a secondary efficacy variable for parts A and B. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    From day of spasms cessation up to 42 months of age
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3 [11]
    Units: days
        number (not applicable)
    0
    Notes
    [11] - No subjects presented clinical relapse.
    No statistical analyses for this end point

    Secondary: Percentage of electro-clinical responders with electro-clinical relapse

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    End point title
    Percentage of electro-clinical responders with electro-clinical relapse
    End point description
    The percentage of electro-clinical responders on Day 14 of treatment with the maintenance dose of radiprodil with electro-clinical relapse within 12 months. This is a secondary efficacy variable for parts A and B. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    12 months, counting from Day 14 of treatment with the maintenance dose of radiprodil
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: percentage of subjects
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Time to electro-clinical relapse from the day of spasm cessation

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    End point title
    Time to electro-clinical relapse from the day of spasm cessation
    End point description
    This is a secondary efficacy variable for parts A and B. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    From day of spasms cessation up to 42 months of age
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: days
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects with extended electro-clinical response

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    End point title
    Percentage of subjects with extended electro-clinical response
    End point description
    Extended electro-clinical response is defined as no spasms and resolution of hypsarrhythmia for 28 consecutive days from Day 14 of treatment with the maintenance dose of radiprodil. This is a secondary efficacy variable for parts A and B. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    28 days, counting from Day 14 (inclusive) of treatment with the maintenance dose of radiprodil
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    3
    Units: percentage of subjects
        number (not applicable)
    0
    No statistical analyses for this end point

    Secondary: Percentage of subjects with extended clinical response to each additional treatment cycle on Day 14 of treatment with the maintenance dose of radiprodil

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    End point title
    Percentage of subjects with extended clinical response to each additional treatment cycle on Day 14 of treatment with the maintenance dose of radiprodil
    End point description
    Extended clinical response was defined as no spasms for 28 consecutive days from Day 14 of treatment with the maintenance dose of radiprodil. This is a secondary efficacy variable for part C. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    28 days, counting from Day 14 (inclusive) of maintenance dose
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    0 [12]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [12] - Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    No statistical analyses for this end point

    Secondary: Number of treatment cycles per subject

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    End point title
    Number of treatment cycles per subject
    End point description
    This is a secondary variable for Part C. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    During Part C (Day -1 to Day 28 of the Maintenance Period)
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    0 [13]
    Units: treatment cycles
        number (not applicable)
    Notes
    [13] - Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    No statistical analyses for this end point

    Secondary: Percentage of subjects with electro-clinical response to each additional treatment cycle on Day 14 of treatment with the maintenance dose of radiprodil

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    End point title
    Percentage of subjects with electro-clinical response to each additional treatment cycle on Day 14 of treatment with the maintenance dose of radiprodil
    End point description
    Electro-clinical response was defined as no spasms and resolution of hypsarrhythmia on Day 14 of treatment with the maintenance dose of radiprodil. This is a secondary efficacy variable for Part C. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    Day 14, counting from the first day of maintenance dose
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    0 [14]
    Units: percentage of subjects
        number (not applicable)
    Notes
    [14] - Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    No statistical analyses for this end point

    Secondary: Time to clinical relapse from the first day of no witnessed spasms for each treatment cycle

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    End point title
    Time to clinical relapse from the first day of no witnessed spasms for each treatment cycle
    End point description
    This is a secondary efficacy variable for part C. Note: Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    End point type
    Secondary
    End point timeframe
    From the first day of no witnessed spasms up to 42 months of age
    End point values
    Radiprodil (SS)
    Number of subjects analysed
    0 [15]
    Units: days
        number (not applicable)
    Notes
    [15] - Due to insufficient enrollment (n=3), the study was terminated during Part A by the Sponsor.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Baseline (Day -1) to the end of the Post-treatment Period (28 days post last dosing).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Radiprodil (SS)
    Reporting group description
    Each subject entered an individualized dose titration schedule. The titration included 3 dose levels of radiprodil: low, medium, high, given bid for 3 days (Day 1L to Day 3L, Day 1M to Day 3M, Day 1H to Day 3H). Titration from L dose to M dose was decided by the investigator: if spasms continued with no safety/tolerability issues, the dose was increased to M, if spasms were absent for 24h, the L dose remained the Maintenance dose. Dose titration from M to H and/or Maintenance of M dose was decided by the investigator, following the same procedure. The Maintenance period occurred over a period of 14 Days (Day14Maint) if spasm continued on Day 3H and there were no safety/tolerability issues, or 28 days (Day28Maint) if spasms were absent for 24h. If spasms were still present at Day14Maint, radiprodil tapering took place: from L dose to L dose 1 per day for 3 days, from M dose to L dose, 3 days bid, from H dose to M dose, 3 days bid forming the Safety Set (SS).

    Serious adverse events
    Radiprodil (SS)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 3 (66.67%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Lung disorder
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Radiprodil (SS)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 3 (100.00%)
    Congenital, familial and genetic disorders
    Cortical dysplasia
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Lower respiratory tract congestion
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    4
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    2 / 3 (66.67%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Infections and infestations
    Ear infection
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    3
    Conjunctivitis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    2
    Rhinitis
         subjects affected / exposed
    1 / 3 (33.33%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Sep 2016
    Protocol Amendment 1 (16 Sept 2016) was a substantial amendment and included the addition of language to clarify when substantial protocol amendments would be made. In addition, additional dose escalation criteria were added.
    24 Feb 2017
    Protocol Amendment 3 (24 Feb 2017) was a substantial amendment and included clarification of the interpretation of the 4-hour video electroencephalogram (EEG) assessment in Part A and Part B of the study. The protocol was amended to make the independent review of the EEGs in Part A optional, and to clarify the requirement for the primary investigator’s interpretation. Additionally, perampanel was listed as a specific prohibited medication for this study.
    05 Jan 2018
    Protocol Amendment 5 (05 Jan 2018) was a substantial amendment and included amending the inclusion/exclusion criteria so infants could have been enrolled within 6 months of diagnosis in order to increase the ability to recruit with no detrimental effect on the study quality or safety; and removing prior use of non-standard of care (StoC) infantile spasms (IS) treatments as an exclusion criterion but including non-StoC IS treatments as prohibited concomitant medications. The subject referral timeframe for the failure of StoC was modified to allow flexibility, as the previous limit of a maximum of 28 days was considered too restrictive. Additional countries were added for Part A of the study to support recruitment, and additional information was added to clarify a group of subjects in relation to dose titration stopping criteria.
    16 Mar 2018
    Protocol Amendment 6 (16 Mar 2018) was a substantial amendment and allowed individual subjects who had shown a benefit from radiprodil treatment in Part A of the study access to additional treatment cycles by adding study Part C. Access to additional treatment cycles was limited to only those subjects who showed evidence of a direct pharmacological relationship with spasm control in Part A; ie, showed a response, followed by a relapse within 5 half-lives (3 days), and then again a response to a second cycle. Additionally, the subjects must have shown good acute tolerability and safety to both treatment cycles in Part A.

    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.
    After reviewing the feasibility and projected completion date of the study, UCB has made the decision to stop the study.
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