Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

    • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).

    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    Corticosteroids or clobazam for ESES syndrome: a European, multicenter, randomized, controlled clinical trial

    Summary
    EudraCT number
    		 2013-000531-27
    Trial protocol
    		 NL   FI   ES   BE   DE   GB   FR   DK   IT  
    Global end of trial date
    21 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Apr 2024
    First version publication date
    20 Apr 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    NL43510
    Additional study identifiers
    ISRCTN number
    		 ISRCTN42686094
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Dutch CCMO ABR number: 43510
    Sponsors
    Sponsor organisation name
    University Medical Center Utrecht
    Sponsor organisation address
    Heidelberglaan 100, Utrecht, Netherlands, 3584 CX
    Public contact
    Marleen van Arnhem - Coordinating investigator, University Medical Center Utrecht, 0031 887555555, m.m.l.vanarnhem-3@umcutrecht.nl
    Scientific contact
    Floor Jansen - Principal Investigator, University Medical Center Utrecht, 0031 887555555, F.E.Jansen@umcutrecht.nl
    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
    21 Aug 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Feb 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects on cognition of treatment with either corticosteroids or clobazam in children with ESES syndrome
    Protection of trial subjects
    Yes, by means of proper informed consent forms and a data management plan
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 29
    Country: Number of subjects enrolled
    Spain: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Denmark: 3
    Country: Number of subjects enrolled
    Finland: 5
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 2
    Worldwide total number of subjects
    45
    EEA total number of subjects
    44
    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)
    45
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 The study protocol and amendments were reviewed and approved by independent ethics committees or institutional review boards in agreement with local requirements. All parents or legal representatives of children provided written informed consent before enrolment

    Pre-assignment
    Screening details
    		 Patients fulfilling the eligibility criteria were consecutively selected by paediatric neurologists during admission or visits at the outpatient clinic at the participating centres. In addition, basic characteristics of patients that were not included in the study despite fulfilment of the eligibility criteria were collected

    Period 1
    Period 1 title
    T0
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Participants were randomly assigned (1:1) to treatment with corticosteroids or clobazam. Participants and treating physicians were not masked to the treatment assignment, because of the inherent differences in mode of administration and expected adverse effects between treatment groups. The neuropsychologists and neurophysiologist (EEG readers) who evaluated the outcome were masked to treatment assignment

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Corticosteroids
    Arm description
    		 For participants allocated to corticosteroids, either intravenous pulse methylprednisolone or continuous oral prednisolone was given, according to local experience and the preference of each study centre. In the case of pulse methylprednisolone, the dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months. In the case of oral prednisolone, the dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months

    Investigational medicinal product name
    Oral prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).

    Arm title
    		 Clobazam
    Arm description
    		 For participants allocated to clobazam, the oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations. Treatment was continued for at least 6 months. In both treatment groups, if the child developed intolerable adverse effects or further cognitive regression, addition of or replacement with an alternative intervention, including switching to the other treatment group, could be applied as required in the treating physician’s opinion. After 6 months, treatment could either be continued or the dose tapered according to the treating physician’s preference. Alternative treatment options, thereafter, were allowed
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Clobazam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations

    Number of subjects in period 1
    		Corticosteroids Clobazam
    Started
    22
    23
    Completed
    22
    23
    Period 2
    Period 2 title
    T6
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Corticosteroids
    Arm description
    		 For participants allocated to corticosteroids, either intravenous pulse methylprednisolone or continuous oral prednisolone was given, according to local experience and the preference of each study centre. In the case of pulse methylprednisolone, the dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months. In the case of oral prednisolone, the dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months

    Investigational medicinal product name
    Oral prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).

    Arm title
    		 Clobazam
    Arm description
    		 For participants allocated to clobazam, the oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations. Treatment was continued for at least 6 months. In both treatment groups, if the child developed intolerable adverse effects or further cognitive regression, addition of or replacement with an alternative intervention, including switching to the other treatment group, could be applied as required in the treating physician’s opinion. After 6 months, treatment could either be continued or the dose tapered according to the treating physician’s preference. Alternative treatment options, thereafter, were allowed
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Clobazam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations

    Number of subjects in period 2
    		Corticosteroids Clobazam
    Started
    22
    23
    Completed
    22
    21
    Not completed
    0
    2
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    -
    1
    Period 3
    Period 3 title
    T18
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Corticosteroids
    Arm description
    		 For participants allocated to corticosteroids, either intravenous pulse methylprednisolone or continuous oral prednisolone was given, according to local experience and the preference of each study centre. In the case of pulse methylprednisolone, the dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months. In the case of oral prednisolone, the dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Methylprednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Concentrate for solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    The dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months

    Investigational medicinal product name
    Oral prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard + tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).

    Arm title
    		 Clobazam
    Arm description
    		 For participants allocated to clobazam, the oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations. Treatment was continued for at least 6 months. In both treatment groups, if the child developed intolerable adverse effects or further cognitive regression, addition of or replacement with an alternative intervention, including switching to the other treatment group, could be applied as required in the treating physician’s opinion. After 6 months, treatment could either be continued or the dose tapered according to the treating physician’s preference. Alternative treatment options, thereafter, were allowed
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Clobazam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    The oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations

    Number of subjects in period 3
    		Corticosteroids Clobazam
    Started
    22
    21
    Completed
    21
    21
    Not completed
    1
    0
         Early termination of trial
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Corticosteroids
    Reporting group description
    		 For participants allocated to corticosteroids, either intravenous pulse methylprednisolone or continuous oral prednisolone was given, according to local experience and the preference of each study centre. In the case of pulse methylprednisolone, the dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months. In the case of oral prednisolone, the dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).

    Reporting group title
    Clobazam
    Reporting group description
    		 For participants allocated to clobazam, the oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations. Treatment was continued for at least 6 months. In both treatment groups, if the child developed intolerable adverse effects or further cognitive regression, addition of or replacement with an alternative intervention, including switching to the other treatment group, could be applied as required in the treating physician’s opinion. After 6 months, treatment could either be continued or the dose tapered according to the treating physician’s preference. Alternative treatment options, thereafter, were allowed

    Reporting group values
    		 Corticosteroids Clobazam Total
    Number of subjects
    		 22 23 45
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 7.4 ± 2.5 6.1 ± 1.8 -
    Gender categorical
    Units: Subjects
        Female
    		 7 8 15
        Male
    		 15 15 30
    Complicated perinatal history
    Units: Subjects
        Yes
    		 13 9 22
        No
    		 9 14 23
    Febrile seizures
    Units: Subjects
        Yes
    		 2 5 7
        No
    		 20 18 38
    Afebrile seizures
    Units: Subjects
        Yes
    		 15 20 35
        No
    		 7 3 10
    Seizure type at inclusion
    Units: Subjects
        Generalised
    		 4 5 9
        Focal
    		 11 12 23
        No seizures
    		 7 3 10
        Generalised and focal
    		 0 3 3
    Previously treated with at least one ASM
    Previously treated with at least one antiseizure medications
    Units: Subjects
        Yes
    		 15 18 33
        No
    		 7 5 12
    Aetiology of EE-SWAS
    Units: Subjects
        Unknown
    		 10 9 19
        Established structural or genetic
    		 12 14 26
    MRI abnormalities
    Units: Subjects
        Yes
    		 10 12 22
        No
    		 12 11 23
    Metabolic abnormality
    Units: Subjects
        Yes
    		 0 0 0
        No
    		 22 23 45
    Genetic abnormality
    Units: Subjects
        Yes
    		 1 5 6
        No
    		 21 18 39
    Psychomotor development before EE-SWAS onset
    Units: Subjects
        Normal (EE-SWAS)
    		 9 9 18
        Mildly delayed (developmental EE-SWAS)
    		 8 5 13
        Moderately delayed (developmental EE-SWAS)
    		 3 5 8
        Severely delayed (developmental EE-SWAS)
    		 2 4 6
    Behavioural disorder before EE-SWAS onset
    Units: Subjects
        Yes
    		 6 4 10
        No
    		 16 19 35
    EE-SWAS clinical or EEG semiology
    Units: Subjects
        Typical EE-SWAS
    		 14 18 32
        Atypical EE-SWAS
    		 8 5 13
    Physiological sleep phenomena present at baseline EEG
    Units: Subjects
        Yes
    		 13 16 29
        No
    		 5 6 11
        Unavailable
    		 4 1 5
    Age at onset of seizures
    Units: Years
        arithmetic mean (standard deviation)
    		 5.4 ± 2.8 3.2 ± 2.3 -
    Age at EE-SWAS diagnosis
    Units: Years
        arithmetic mean (standard deviation)
    		 7.2 ± 2.4 5.9 ± 1.8 -
    Sleep spike-wave index percentage at baseline EEG
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    		 87 (82 to 93) 90 (82 to 95) -
    Total IQ at baseline neuropsychological assessment
    Units: IQ points
        arithmetic mean (standard deviation)
    		 76 ± 21 76 ± 21 -
    Cognitive sum score at baseline
    Units: Z-score
        arithmetic mean (standard deviation)
    		 -1.5 ± 1.4 -2.0 ± 1.4 -

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Corticosteroids
    Reporting group description
    		 For participants allocated to corticosteroids, either intravenous pulse methylprednisolone or continuous oral prednisolone was given, according to local experience and the preference of each study centre. In the case of pulse methylprednisolone, the dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months. In the case of oral prednisolone, the dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).

    Reporting group title
    Clobazam
    Reporting group description
    		 For participants allocated to clobazam, the oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations. Treatment was continued for at least 6 months. In both treatment groups, if the child developed intolerable adverse effects or further cognitive regression, addition of or replacement with an alternative intervention, including switching to the other treatment group, could be applied as required in the treating physician’s opinion. After 6 months, treatment could either be continued or the dose tapered according to the treating physician’s preference. Alternative treatment options, thereafter, were allowed
    Reporting group title
    Corticosteroids
    Reporting group description
    		 For participants allocated to corticosteroids, either intravenous pulse methylprednisolone or continuous oral prednisolone was given, according to local experience and the preference of each study centre. In the case of pulse methylprednisolone, the dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months. In the case of oral prednisolone, the dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).

    Reporting group title
    Clobazam
    Reporting group description
    		 For participants allocated to clobazam, the oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations. Treatment was continued for at least 6 months. In both treatment groups, if the child developed intolerable adverse effects or further cognitive regression, addition of or replacement with an alternative intervention, including switching to the other treatment group, could be applied as required in the treating physician’s opinion. After 6 months, treatment could either be continued or the dose tapered according to the treating physician’s preference. Alternative treatment options, thereafter, were allowed
    Reporting group title
    Corticosteroids
    Reporting group description
    		 For participants allocated to corticosteroids, either intravenous pulse methylprednisolone or continuous oral prednisolone was given, according to local experience and the preference of each study centre. In the case of pulse methylprednisolone, the dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months. In the case of oral prednisolone, the dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).

    Reporting group title
    Clobazam
    Reporting group description
    		 For participants allocated to clobazam, the oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations. Treatment was continued for at least 6 months. In both treatment groups, if the child developed intolerable adverse effects or further cognitive regression, addition of or replacement with an alternative intervention, including switching to the other treatment group, could be applied as required in the treating physician’s opinion. After 6 months, treatment could either be continued or the dose tapered according to the treating physician’s preference. Alternative treatment options, thereafter, were allowed

    Primary: IQ responder T6

    		 Close Top of page
    End point title
    		 IQ responder T6
    End point description
    End point type
    Primary
    End point timeframe
    T6
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    20
    18
    Units: Percentage
        Yes
    5
    0
        No
    15
    18
    Statistical analysis title
    		 RR ratio
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.025
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    10
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.2
         upper limit
    		 1310.4

    Primary: Cognitive sum score responder rate T6

    		 Close Top of page
    End point title
    		 Cognitive sum score responder rate T6
    End point description
    End point type
    Primary
    End point timeframe
    T6
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    22
    21
    Units: Percentag
        Yes
    1
    1
        No
    21
    20
    Statistical analysis title
    		 RR ratio
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.97
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 11.7

    Secondary: Delta IQ T6

    		 Close Top of page
    End point title
    		 Delta IQ T6
    End point description
    End point type
    Secondary
    End point timeframe
    T6
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    20
    18
    Units: IQ points
        arithmetic mean (standard deviation)
    4.9 ± 9.3
    -0.7 ± 6.2
    Statistical analysis title
    		 Linear regression
    Comparison groups
    Clobazam v Corticosteroids
    Number of subjects included in analysis
    38
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.039
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    5.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 10.8

    Secondary: Delta cognitive sum score T6

    		 Close Top of page
    End point title
    		 Delta cognitive sum score T6
    End point description
    End point type
    Secondary
    End point timeframe
    T6
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    22
    21
    Units: Z-score
        arithmetic mean (standard deviation)
    0.3 ± 0.41
    0.1 ± 0.43
    Statistical analysis title
    		 Linear regression
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.1
         upper limit
    		 0.4

    Secondary: Delta SWI (%) T6

    		 Close Top of page
    End point title
    		 Delta SWI (%) T6
    End point description
    End point type
    Secondary
    End point timeframe
    T6
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    22
    21
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    -5 (-55 to 7)
    0 (-12 to 4)
    Statistical analysis title
    		 Wilcoxon rank-sum test
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.72
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Global daily functioning (VAS score) T6

    		 Close Top of page
    End point title
    		 Global daily functioning (VAS score) T6
    End point description
    End point type
    Secondary
    End point timeframe
    T6
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    17
    16
    Units: VAS score
        arithmetic mean (standard deviation)
    1.3 ± 1.3
    1.3 ± 1.0
    Statistical analysis title
    		 Linear regression
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.96
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.8
         upper limit
    		 0.8

    Secondary: EEG responder T6

    		 Close Top of page
    End point title
    		 EEG responder T6
    End point description
    End point type
    Secondary
    End point timeframe
    T6
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    22
    21
    Units: Percentage
        Yes
    7
    4
        No
    15
    17
    Statistical analysis title
    		 RR ratio
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    43
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 3.5

    Secondary: Sleep SWI <50% T6

    		 Close Top of page
    End point title
    		 Sleep SWI <50% T6
    End point description
    End point type
    Secondary
    End point timeframe
    T6
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    22
    21
    Units: Percentage
        Yes
    7
    3
        No
    15
    18
    Statistical analysis title
    		 RR ratio
    Comparison groups
    Clobazam v Corticosteroids
    Number of subjects included in analysis
    43
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.18
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 1.1

    Secondary: Occurrence of seizures T6

    		 Close Top of page
    End point title
    		 Occurrence of seizures T6
    End point description
    End point type
    Secondary
    End point timeframe
    T6
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    22
    21
    Units: Percentage
        Yes
    8
    9
        No
    14
    12
    Statistical analysis title
    		 RR ratio
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    43
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 1.5

    Secondary: IQ responder rate T18

    		 Close Top of page
    End point title
    		 IQ responder rate T18
    End point description
    End point type
    Secondary
    End point timeframe
    T18
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    17
    14
    Units: Percentage
        Yes
    2
    3
        No
    15
    11
    Statistical analysis title
    		 RR ratio
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.47
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.1
         upper limit
    		 2.3

    Secondary: Cognitive sum score responder rate T18

    		 Close Top of page
    End point title
    		 Cognitive sum score responder rate T18
    End point description
    End point type
    Secondary
    End point timeframe
    T18
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    20
    20
    Units: Percentage
        Yes
    3
    2
        No
    17
    18
    Statistical analysis title
    		 RR ratio
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.3
         upper limit
    		 5.9

    Secondary: Delta IQ T18

    		 Close Top of page
    End point title
    		 Delta IQ T18
    End point description
    End point type
    Secondary
    End point timeframe
    T18
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    17
    14
    Units: IQ points
        arithmetic mean (standard deviation)
    1.2 ± 10.2
    -0.1 ± 12.0
    Statistical analysis title
    		 Linear regression
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    31
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.76
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.9
         upper limit
    		 9.4

    Secondary: Delta cognitive sum scoreT18

    		 Close Top of page
    End point title
    		 Delta cognitive sum scoreT18
    End point description
    End point type
    Secondary
    End point timeframe
    T18
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    20
    20
    Units: Z-score
        arithmetic mean (standard deviation)
    0.2 ± 0.5
    0.1 ± 0.9
    Statistical analysis title
    		 Linear regression
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.6
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.3
         upper limit
    		 0.6

    Secondary: Delta SWI (%) T18

    		 Close Top of page
    End point title
    		 Delta SWI (%) T18
    End point description
    End point type
    Secondary
    End point timeframe
    T18
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    21
    21
    Units: Percentage
        median (inter-quartile range (Q1-Q3))
    -10 (-39 to 2)
    -3 (-55 to 4)
    Statistical analysis title
    		 Wilcoxon rank-sum test
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.86
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Global daily functioning (VAS score) T18

    		 Close Top of page
    End point title
    		 Global daily functioning (VAS score) T18
    End point description
    End point type
    Secondary
    End point timeframe
    T18
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    14
    14
    Units: VAS score
        arithmetic mean (standard deviation)
    1.8 ± 1.4
    2.0 ± 1.8
    Statistical analysis title
    		 Linear regression
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    28
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.73
    Method
    		 Regression, Linear
    Parameter type
    		 Median difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.5
         upper limit
    		 1.1

    Secondary: EEG responder T18

    		 Close Top of page
    End point title
    		 EEG responder T18
    End point description
    End point type
    Secondary
    End point timeframe
    T18
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    21
    21
    Units: Percentage
        Yes
    9
    6
        No
    12
    15
    Statistical analysis title
    		 RR ratio
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.34
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 2.6

    Secondary: Sleep SWI <50% T18

    		 Close Top of page
    End point title
    		 Sleep SWI <50% T18
    End point description
    End point type
    Secondary
    End point timeframe
    T18
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    21
    21
    Units: Percentage
        Yes
    7
    6
        No
    14
    15
    Statistical analysis title
    		 RR ratio
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    42
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.74
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 1.2

    Secondary: Occurrence of seizures T18

    		 Close Top of page
    End point title
    		 Occurrence of seizures T18
    End point description
    End point type
    Secondary
    End point timeframe
    T18
    End point values
    		 Corticosteroids Clobazam
    Number of subjects analysed
    21
    21
    Units: Percentage
        Yes
    8
    8
        No
    13
    13
    Statistical analysis title
    		 RR ratio
    Comparison groups
    Corticosteroids v Clobazam
    Number of subjects included in analysis
    42
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 > 0.99
    Method
    		 Regression, Logistic
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.4
         upper limit
    		 1.8

    Adverse events

    		 Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Reported at T6
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Research Online
    Dictionary version
    2
    Reporting groups
    Reporting group title
    Corticosteroids
    Reporting group description
    		 For participants allocated to corticosteroids, either intravenous pulse methylprednisolone or continuous oral prednisolone was given, according to local experience and the preference of each study centre. In the case of pulse methylprednisolone, the dose was 20 mg/kg given over 30 min once daily for 3 consecutive days then at 4-week intervals for 6 months. In the case of oral prednisolone, the dose was initially 2 mg/kg per day, to a maximum of 60 mg per day, for 1 month followed by 1–2 mg/kg per day (maximum 60 mg per day) for the next 5 months (dose decided by the treating physician).

    Reporting group title
    Clobazam
    Reporting group description
    		 For participants allocated to clobazam, the oral dose was titrated to 0·5 mg/kg per day within 2 weeks. If well tolerated, the dose was increased to a maximum of 1·2 mg/kg, once daily. If the clobazam dose exceeded 20 mg per day, it could be divided in two daily oral administrations. Treatment was continued for at least 6 months. In both treatment groups, if the child developed intolerable adverse effects or further cognitive regression, addition of or replacement with an alternative intervention, including switching to the other treatment group, could be applied as required in the treating physician’s opinion. After 6 months, treatment could either be continued or the dose tapered according to the treating physician’s preference. Alternative treatment options, thereafter, were allowed

    Serious adverse events
    		 Corticosteroids Clobazam
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Seizure aggrevation
    Additional description: hospitalisation due to seizure aggravation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory tract infection
    Additional description: Hospitalisation due to respiratory tract infection
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngitis
    Additional description: Hospitalisation due to laryngitis
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (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: 1%
    Non-serious adverse events
    		 Corticosteroids Clobazam
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 22 (45.45%)
    11 / 21 (52.38%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 22 (9.09%)
    2 / 21 (9.52%)
         occurrences all number
    2
    2
    Confusion
         subjects affected / exposed
    2 / 22 (9.09%)
    0 / 21 (0.00%)
         occurrences all number
    2
    0
    Gait unsteadiness
         subjects affected / exposed
    0 / 22 (0.00%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    General disorders and administration site conditions
    Fatique
         subjects affected / exposed
    2 / 22 (9.09%)
    5 / 21 (23.81%)
         occurrences all number
    2
    5
    Gastrointestinal disorders
    Loss of appetite
         subjects affected / exposed
    1 / 22 (4.55%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Abdominal pain
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Constipation
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Emotionally unstable
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Behavioural disturbances
         subjects affected / exposed
    2 / 22 (9.09%)
    4 / 21 (19.05%)
         occurrences all number
    2
    4
    Apathy
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Bed wetting
         subjects affected / exposed
    0 / 22 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Endocrine disorders
    Weight gain
         subjects affected / exposed
    3 / 22 (13.64%)
    2 / 21 (9.52%)
         occurrences all number
    3
    2
    Glycosuria
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Intermittent back pain
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Infections and infestations
    Respiratory infection
         subjects affected / exposed
    1 / 22 (4.55%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Otitis media
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Wound infection
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Fever
         subjects affected / exposed
    1 / 22 (4.55%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0

    More information

    		 Close Top of page

    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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.
    We did not reach the targeted sample size, which affects the robustness of the conclusions that can be drawn from the analysis of primary and secondary outcome measures

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33228736
    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.

    European Medicines Agency © 1995-Sat May 04 07:05:13 CEST 2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA