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    Clinical Trial Results:
    Randomised factorial design controlled trial comparing carbamazepine, levetiracetam or active monitoring combined with or without sleep behaviour intervention in treatment naive children with rolandic epilepsy

    Summary
    EudraCT number
    		 2018-003893-29
    Trial protocol
    		 GB  
    Global end of trial date
    23 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Apr 2021
    First version publication date
    04 Apr 2021
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CASTLE
    Additional study identifiers
    ISRCTN number
    		 ISRCTN12839803
    US NCT number
    		 NCT04610879
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 ISRCTN Number: ISRCTN12839803, IRAS number: 250324, Funder reference : RP-PG-0615-20007
    Sponsors
    Sponsor organisation name
    Kings College London
    Sponsor organisation address
    5 Cutcombe Road, London, United Kingdom, SE5 9RX
    Public contact
    Professor Deb Pal , Kings College London, Maurice Wohl Clinical Neuroscience Institute , +44 0207 848 5762, deb.pal@kcl.ac.uk
    Scientific contact
    Professor Deb Pal , Kings College London, Maurice Wohl Clinical Neuroscience Institute , +44 0207 848 5762, deb.pal@kcl.ac.uk
    Sponsor organisation name
    King's College Hospital NHS Foundation Trust
    Sponsor organisation address
    Denmark Hill,, London, United Kingdom, SE5 9RS
    Public contact
    Professor Deb Pal, King's College Hospital NHS Foundation Trust, +44 0207 848 5762, deb.pal@kcl.ac.uk
    Scientific contact
    Professor Deb Pal, King's College Hospital NHS Foundation Trust, +44 0207 848 5762, deb.pal@kcl.ac.uk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    12 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    23 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Sep 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of the trial is to test two hypotheses: A) To determine if Carbamazepine or Levetiracetam are superior to no AED (Anti-Epileptic Drug) with respect to time to 6-month seizure remission. B) To determine if a Parent-Based Sleep (PBS) intervention is superior to standard care with respect to 3-month sleep problem frequency measured by Children’s Sleep Habits Questionnaire (CSHQ). The Primary economic objective is: To estimate the cost-utility of Carbamazepine, Levetiracetam and PBS
    Protection of trial subjects
    A trial risk assessment was completed prior to the trial opening. The management of the study was done in line with Ethical, Regulatory and LCTC policies/procedures. Data from the trial will be collected centrally from NHS Digital (or national appropriate) from Hospital Episode Statistics (HES) who operate under a General Data Protection Regulation (GDPR) framework. Both IMPs used in the CASTLE clinical trial (Carbamazepine and Levetiracetam) are licensed for their use to treat epilepsy. The initial prescription of the trial treatment was done so by trained medical professionals in line with routine practice. Those participants who were randomized to standard care were treated as per their local hospital’s routine procedures. All those who oversaw trial activities were trained on the study, which is evidenced by the collection of site training logs and delegation logs. Current CVs and GCP certificates were also obtained for all members of staff who had a delegated duty within the study to ensure the correct level of training had been given for them to complete the delegated task. The consent and assent discussions were undertaken by delegated members of research staff who had experience of obtaining consent in a pediatric population. Children (≥7 years old) who were deemed to have capacity were asked to provide assent to the study. Separate consent and assent forms were sought from participants who wished to take part in the qualitative component of the study. Patient information was collected at site using CRFs specifically designed for the CASTLE trial. Questionnaires used in the study were approved for use in the study by their owners. CANTAB data collected from participants using a pre-configured study iPad was pseudo-anonymised and transferred securely to an online server. All collected information was pseudo-anonymised and transferred to the Liverpool Clinical Trials Centre (LCTC) in an agreed format.
    Background therapy
    		 Carbamazepine is a first-generation AED, is the current NICE standard treatment for Rolandic Epilepsy (RE). Carbamazepine has never been compared against no-treatment in RE, and in view of the Anti-Epileptic Drug (AED’s) known cognitive adverse effects, it is important to know whether any benefit in terms of seizure control offsets its impact on children’s learning. Second-generation AEDs (levetiracetam, lamotrigine, gabapentin, but not topiramate) have fewer cognitive side-effects in healthy adult volunteers than first-generation (carbamazepine, oxcarbazepine, valproate, phenobarbital, phenytoin); and the International League Against Epilepsy judges only levetiracetam, of these second-generation AEDs, to have potential efficacy in RE. A generic version of levetiracetam was released in 2014 with comparable treatment cost to carbamazepine. Although not licensed for monotherapy in children, it is in widespread off-label use and is judged to be efficacious and well-tolerated. Thus levetiracetam would make an ideal and potentially superior comparator and has not been assessed head-to-head with carbamazepine in childhood epilepsy. Despite the frequency of sleep problems in children with epilepsy (and other neurodevelopmental disorders), clinicians in the UK receive little training on the subject. This lack of training, and lack of epilepsy-specific evidence-based interventions, combined with a focus on seizure control means that sleep problems are rarely addressed in routine clinical practice. Even if sleep problems were a management target, the lack of any evidence-based resources for intervention is a barrier to such implementation. The Parent-Based Sleep Intervention (PBS) intervention offers parents education about normal sleep, advice about sleep-promoting practices and targeted strategies parents can employ to help their children to ‘‘learn’’ an appropriate set of sleep behaviors/habits and/or to unlearn inappropriate sleep behaviors.
    Evidence for comparator
    		 The national survey conducted for this study confirmed that UK pediatricians prescribed Carbamazepine as first-line choice (80%), but importantly, the survey revealed that in 40% of cases paediatricians treat RE patients conservatively, i.e. without drugs, as advocated in older textbooks.
    Actual start date of recruitment
    09 Aug 2019
    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
    United Kingdom: 5
    Worldwide total number of subjects
    5
    EEA total number of subjects
    0
    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)
    5
    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
    		 CASTLE received the green light from Liverpool Clinical Trials Center (LCTC) to open on 9/08/2019. The first patient was randomized on 25/11/2019. The last patient was randomized on 09/03/2020. CASTLE recruitment was halted on 23/03/2020 due to COVID-19 and never re-opened due to poor recruitment, resulting in only 5 patients being randomized.

    Pre-assignment
    Screening details
    		 All patients aged ≥5 and <13 years with diagnosis of RE previously untreated with AED were screened at the trial centres to identify potentially eligible participants for the trial. A ‘Screening log’ was maintained of all the patients who undergo screening regardless of whether they are assessed as eligible or decide to participate in the trial.

    Period 1
    Period 1 title
    Main trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 No AED & sleep intervention
    Arm description
    		 No Anti-Epileptic Drug (AED) and sleep behavior intervention
    Arm type
    		 No drug intervention but a sleep intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 CBZ & sleep intervention
    Arm description
    		 Carbamazepine (CBZ) & sleep behavior intervention
    Arm type
    		 Experimental

    Investigational medicinal product name
    Carbamazepine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral carbamazepine prescribed in a formulation and at a dose deemed suitable by the treating physicians and guided by ranges in summary of product characteristics (SmPC).

    Arm title
    		 LEV & sleep intervention
    Arm description
    		 Levetiracetam (LEV) and sleep behavior intervention
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Levetiracetam prescribed in a formulation and at a dose deemed suitable by the treating physicians and guided by ranges in summary of product characteristics (SmPC).

    Arm title
    		 LEV & no sleep intervention
    Arm description
    		 Levetiracetam (LEV) and no sleep behavior intervention (standard care)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Oral levetiracetam prescribed in a formulation and at a dose deemed suitable by the treating physicians and guided by ranges in summary of product characteristics (SmPC).

    Number of subjects in period 1
    		No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Started
    1
    1
    2
    1
    Completed
    1
    1
    1
    1
    Not completed
    0
    0
    1
    0
         Consent withdrawn by subject
    -
    -
    1
    -

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    No AED & sleep intervention
    Reporting group description
    		 No Anti-Epileptic Drug (AED) and sleep behavior intervention

    Reporting group title
    CBZ & sleep intervention
    Reporting group description
    		 Carbamazepine (CBZ) & sleep behavior intervention

    Reporting group title
    LEV & sleep intervention
    Reporting group description
    		 Levetiracetam (LEV) and sleep behavior intervention

    Reporting group title
    LEV & no sleep intervention
    Reporting group description
    		 Levetiracetam (LEV) and no sleep behavior intervention (standard care)

    Reporting group values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention Total
    Number of subjects
    		 1 1 2 1 5
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 1 1 2 1 5
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 11 (11 to 11) 9 (9 to 9) 9 (8 to 10) 7 (7 to 7) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 1 0 1
        Male
    		 1 1 1 1 4
    Did the patient have any seizures in the first month of life?
    Units: Subjects
        Yes
    		 0 0 0 0 0
        No
    		 1 1 2 1 5
        Unknown
    		 0 0 0 0 0
    After the first month of life and before epilepsy, did the patient ever have seizures with fever?
    Full text is "After the first month of life and before developing epilepsy, did the patient ever have seizures or convulsions with fever?".
    Units: Subjects
        Yes
    		 0 0 0 0 0
        No
    		 1 1 2 1 5
        Unknown
    		 0 0 0 0 0
    How many seizures has the patient had in total since onset?
    Units: Subjects
        One
    		 0 0 0 0 0
        Two to Four
    		 0 0 1 0 1
        Five to Ten
    		 0 1 0 0 1
        More than Ten
    		 1 0 1 1 3
        Unknown
    		 0 0 0 0 0
    Has the patient ever had seizures lasting more than 10 minutes or had several seizures in a row?
    Units: Subjects
        Yes
    		 0 0 1 0 1
        No
    		 1 1 1 1 4
        Unknown
    		 0 0 0 0 0
    Has the patient ever had a generalised tonic-clonic seizure or convulsion? (Text continued below)
    Has the patient ever had a generalised tonic-clonic seizure or convulsion since being diagnosed with Childhood Epilepsy with Centrotemporal Spikes aka Benign Rolandic Epilepsy?
    Units: Subjects
        Yes
    		 0 0 1 0 1
        No
    		 1 1 1 1 4
        Unknown
    		 0 0 0 0 0
    Do the patient’s seizures occur at particular times of the day?
    Units: Subjects
        Yes
    		 1 0 1 1 3
        No
    		 0 1 1 0 2
        Unknown
    		 0 0 0 0 0
    Do seizures usually occur soon after going to sleep?
    Units: Subjects
        Yes
    		 1 0 1 1 3
        No
    		 0 1 1 0 2
        Unknown
    		 0 0 0 0 0
    Do seizures usually occur early in the morning?
    Units: Subjects
        Yes
    		 1 0 0 0 1
        No
    		 0 1 2 1 4
        Unknown
    		 0 0 0 0 0
    Do seizures usually occur during a day time nap?
    Units: Subjects
        Yes
    		 0 0 0 0 0
        No
    		 1 1 2 1 5
        Unknown
    		 0 0 0 0 0
    Noticeable features in a typical seizure: Drooping of one side of the face
    Units: Subjects
        Yes
    		 1 0 1 0 2
        No
    		 0 1 1 1 3
        Unknown
    		 0 0 0 0 0
    Noticeable features in a typical seizure: Gurgling noise from the throat
    Units: Subjects
        Yes
    		 0 1 1 0 2
        No
    		 1 0 1 1 3
        Unknown
    		 0 0 0 0 0
    Noticeable features in a typical seizure: Unable to speak
    Units: Subjects
        Yes
    		 1 1 1 1 4
        No
    		 0 0 1 0 1
        Unknown
    		 0 0 0 0 0
    Noticeable features in a typical seizure: Drooling a lot from the mouth
    Units: Subjects
        Yes
    		 1 1 1 0 3
        No
    		 0 0 1 1 2
        Unknown
    		 0 0 0 0 0
    Noticeable features in a typical seizure: Aware during the seizure
    Units: Subjects
        Yes
    		 1 1 1 0 3
        No
    		 0 0 1 1 2
        Unknown
    		 0 0 0 0 0
    Other noticeable features during a seizure: Tingling of tongue and lips
    Units: Subjects
        Yes
    		 1 0 0 0 1
        No
    		 0 0 0 0 0
        Unknown
    		 0 1 2 1 4
    Other noticeable features during a seizure: Vomiting, numb hands, pallor (white face)
    Units: Subjects
        Yes
    		 0 0 1 0 1
        No
    		 0 0 0 0 0
        Unknown
    		 1 1 1 1 4
    Other noticeable features during a seizure: Eye rolling, jerking of both arms
    Units: Subjects
        Yes
    		 0 0 0 1 1
        No
    		 0 0 0 0 0
        Unknown
    		 1 1 2 0 4
    Other noticeable features during a seizure: Facial twitches
    Units: Subjects
        Yes
    		 0 1 0 0 1
        No
    		 0 0 0 0 0
        Unknown
    		 1 0 2 1 4
    Height (cm)
    Patient height in centimetres.
    Units: Centimetres (cm)
        median (full range (min-max))
    		 134.4 (134.4 to 134.4) 130.6 (130.6 to 130.6) 134.5 (125.5 to 143.4) 121 (121 to 121) -
    Weight (kg)
    Patient weight in kilograms.
    Units: Kilograms
        median (full range (min-max))
    		 41.8 (41.8 to 41.8) 23.2 (23.2 to 23.2) 37.9 (25.1 to 50.6) 24.4 (24.4 to 24.4) -
    Days since first seizure
    Difference in days since first seizure from date of randomization.
    Units: Days before randomization
        median (full range (min-max))
    		 1098 (1098 to 1098) 1128.5 (1128.5 to 1128.5) 124 (80 to 168) 105 (105 to 105) -
    Days since first rolandic seizure
    Difference in days since first rolandic seizure from date of randomization. For the Levetiracetam & Sleep Intervention arm, data was only available for 1/2 patients.
    Units: Days before randomization
        median (full range (min-max))
    		 1098 (1098 to 1098) 1128.5 (1128.5 to 1128.5) 168 (168 to 168) 105 (105 to 105) -
    Days since most recent seizure
    Difference in days since most recent seizure from date of randomization.
    Units: Days before randomization
        median (full range (min-max))
    		 7 (7 to 7) 7 (7 to 7) 74 (3 to 145) 4 (4 to 4) -
    Days since rolandic Epilepsy diagnosis
    Difference in days since rolandic Epilepsy diagnosis to date of randomization.
    Units: Days before randomization
        median (full range (min-max))
    		 763 (763 to 763) 0 (0 to 0) 184 (95 to 273) 19 (19 to 19) -
    Subject analysis sets

    Subject analysis set title
    No AED & sleep intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This analysis set includes all patients randomized to No AED & the sleep intervention

    Subject analysis set title
    CBZ & sleep intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This analysis set contains all patients randomized to Carbamazepine & sleep intervention.

    Subject analysis set title
    LEV & sleep intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This analysis set contains all patients randomized to Levetiracetam & sleep intervention.

    Subject analysis set title
    LEV & no sleep intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This analysis set contains all patients randomized to Levetiracetam & no sleep intervention (standard of care).

    Subject analysis sets values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects
    1
    1
    2
    1
    Age categorical
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    1
    1
    2
    1
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    0
    0
    0
    0
        From 65-84 years
    0
    0
    0
    0
        85 years and over
    0
    0
    0
    0
    Age continuous
    Units: years
        median (full range (min-max))
    11 (11 to 11)
    9 (9 to 9)
    9 (8 to 10)
    7 (7 to 7)
    Gender categorical
    Units: Subjects
        Female
    0
    0
    1
    0
        Male
    1
    1
    1
    1
    Did the patient have any seizures in the first month of life?
    Units: Subjects
        Yes
    0
    0
    0
    0
        No
    1
    1
    2
    1
        Unknown
    0
    0
    0
    0
    After the first month of life and before epilepsy, did the patient ever have seizures with fever?
    Full text is "After the first month of life and before developing epilepsy, did the patient ever have seizures or convulsions with fever?".
    Units: Subjects
        Yes
    0
    0
    0
    0
        No
    1
    1
    2
    1
        Unknown
    0
    0
    0
    0
    How many seizures has the patient had in total since onset?
    Units: Subjects
        One
    0
    0
    0
    0
        Two to Four
    0
    0
    1
    0
        Five to Ten
    0
    1
    0
    0
        More than Ten
    1
    0
    1
    1
        Unknown
    0
    0
    0
    0
    Has the patient ever had seizures lasting more than 10 minutes or had several seizures in a row?
    Units: Subjects
        Yes
    0
    0
    1
    0
        No
    1
    1
    1
    1
        Unknown
    0
    0
    0
    0
    Has the patient ever had a generalised tonic-clonic seizure or convulsion? (Text continued below)
    Has the patient ever had a generalised tonic-clonic seizure or convulsion since being diagnosed with Childhood Epilepsy with Centrotemporal Spikes aka Benign Rolandic Epilepsy?
    Units: Subjects
        Yes
    0
    0
    1
    0
        No
    1
    1
    1
    1
        Unknown
    0
    0
    0
    0
    Do the patient’s seizures occur at particular times of the day?
    Units: Subjects
        Yes
    1
    0
    1
    1
        No
    0
    1
    1
    0
        Unknown
    0
    0
    0
    0
    Do seizures usually occur soon after going to sleep?
    Units: Subjects
        Yes
    1
    0
    1
    1
        No
    0
    1
    1
    0
        Unknown
    0
    0
    0
    0
    Do seizures usually occur early in the morning?
    Units: Subjects
        Yes
    1
    0
    0
    0
        No
    0
    1
    2
    1
        Unknown
    0
    0
    0
    0
    Do seizures usually occur during a day time nap?
    Units: Subjects
        Yes
    0
    0
    0
    0
        No
    1
    1
    2
    1
        Unknown
    0
    0
    0
    0
    Noticeable features in a typical seizure: Drooping of one side of the face
    Units: Subjects
        Yes
    1
    0
    1
    0
        No
    0
    1
    1
    1
        Unknown
    0
    0
    0
    0
    Noticeable features in a typical seizure: Gurgling noise from the throat
    Units: Subjects
        Yes
    0
    1
    1
    0
        No
    1
    0
    1
    1
        Unknown
    0
    0
    0
    0
    Noticeable features in a typical seizure: Unable to speak
    Units: Subjects
        Yes
    1
    1
    1
    1
        No
    0
    0
    1
    0
        Unknown
    0
    0
    0
    0
    Noticeable features in a typical seizure: Drooling a lot from the mouth
    Units: Subjects
        Yes
    1
    1
    1
    0
        No
    0
    0
    1
    1
        Unknown
    0
    0
    0
    0
    Noticeable features in a typical seizure: Aware during the seizure
    Units: Subjects
        Yes
    1
    1
    1
    0
        No
    0
    0
    1
    1
        Unknown
    0
    0
    0
    0
    Other noticeable features during a seizure: Tingling of tongue and lips
    Units: Subjects
        Yes
    1
    0
    0
    0
        No
    0
    0
    0
    0
        Unknown
    0
    1
    2
    1
    Other noticeable features during a seizure: Vomiting, numb hands, pallor (white face)
    Units: Subjects
        Yes
    0
    0
    1
    0
        No
    0
    0
    0
    0
        Unknown
    1
    1
    1
    1
    Other noticeable features during a seizure: Eye rolling, jerking of both arms
    Units: Subjects
        Yes
    0
    0
    0
    1
        No
    0
    0
    0
    0
        Unknown
    1
    1
    2
    0
    Other noticeable features during a seizure: Facial twitches
    Units: Subjects
        Yes
    0
    1
    0
    0
        No
    0
    0
    0
    0
        Unknown
    1
    0
    2
    1
    Height (cm)
    Patient height in centimetres.
    Units: Centimetres (cm)
        median (full range (min-max))
    134.4 (134.4 to 134.4)
    130.6 (130.6 to 130.6)
    134.5 (125.5 to 143.4)
    121 (121 to 121)
    Weight (kg)
    Patient weight in kilograms.
    Units: Kilograms
        median (full range (min-max))
    41.8 (41.8 to 41.8)
    23.2 (23.2 to 23.2)
    37.9 (25.1 to 50.6)
    24.4 (24.4 to 24.4)
    Days since first seizure
    Difference in days since first seizure from date of randomization.
    Units: Days before randomization
        median (full range (min-max))
    1098 (1098 to 1098)
    1128.5 (1128.5 to 1128.5)
    124 (80 to 168)
    105 (105 to 105)
    Days since first rolandic seizure
    Difference in days since first rolandic seizure from date of randomization. For the Levetiracetam & Sleep Intervention arm, data was only available for 1/2 patients.
    Units: Days before randomization
        median (full range (min-max))
    1098 (1098 to 1098)
    1128.5 (1128.5 to 1128.5)
    168 (168 to 168)
    105 (105 to 105)
    Days since most recent seizure
    Difference in days since most recent seizure from date of randomization.
    Units: Days before randomization
        median (full range (min-max))
    7 (7 to 7)
    7 (7 to 7)
    74 (3 to 145)
    4 (4 to 4)
    Days since rolandic Epilepsy diagnosis
    Difference in days since rolandic Epilepsy diagnosis to date of randomization.
    Units: Days before randomization
        median (full range (min-max))
    763 (763 to 763)
    0 (0 to 0)
    184 (95 to 273)
    19 (19 to 19)

    End points

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    End points reporting groups
    Reporting group title
    No AED & sleep intervention
    Reporting group description
    		 No Anti-Epileptic Drug (AED) and sleep behavior intervention

    Reporting group title
    CBZ & sleep intervention
    Reporting group description
    		 Carbamazepine (CBZ) & sleep behavior intervention

    Reporting group title
    LEV & sleep intervention
    Reporting group description
    		 Levetiracetam (LEV) and sleep behavior intervention

    Reporting group title
    LEV & no sleep intervention
    Reporting group description
    		 Levetiracetam (LEV) and no sleep behavior intervention (standard care)

    Subject analysis set title
    No AED & sleep intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This analysis set includes all patients randomized to No AED & the sleep intervention

    Subject analysis set title
    CBZ & sleep intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This analysis set contains all patients randomized to Carbamazepine & sleep intervention.

    Subject analysis set title
    LEV & sleep intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This analysis set contains all patients randomized to Levetiracetam & sleep intervention.

    Subject analysis set title
    LEV & no sleep intervention
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    This analysis set contains all patients randomized to Levetiracetam & no sleep intervention (standard of care).

    Primary: Primary outcome 1: Time to 6-month seizure remission

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    End point title
    		 Primary outcome 1: Time to 6-month seizure remission [1]
    End point description
    This endpoint was not reached for all 5 participants and no analysis could be performed.
    End point type
    Primary
    End point timeframe
    Anytime from days since randomization until date of last follow-up.
    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: Due to only 5 participants being recruited for the trial, no statistical analysis could be performed only summary statistics could be provided.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    1
    1
    2
    1
    Units: Days since randomization
        median (full range (min-max))
    187.0 (187.0 to 187.0)
    112.0 (112.0 to 112.0)
    128.5 (86.0 to 171.0)
    192.0 (192.0 to 192.0)
    No statistical analyses for this end point

    Primary: Primary outcome 2: Total sleep problem scores as measured by the CSHQ (at 3 months)

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    End point title
    		 Primary outcome 2: Total sleep problem scores as measured by the CSHQ (at 3 months) [2]
    End point description
    This outcome is looking at scores and completion rates from the Child Sleep Habit Questionnaire (CSHQ). A score of 0 represents the questionnaire not being filled in.
    End point type
    Primary
    End point timeframe
    The sleep score questionnaire is completed at baseline and 3 month study visit.
    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: Due to only 5 participants being recruited for the trial, no statistical analysis could be performed only summary statistics could be provided.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    1
    1 [3]
    2 [4]
    1
    Units: Sleep scores
    median (full range (min-max))
        CSHQ Score at Baseline
    90 (90 to 90)
    45 (45 to 45)
    78.5 (78 to 79)
    49 (49 to 49)
        CSHQ Score at 3 Months
    90 (90 to 90)
    0 (0 to 0)
    83 (83 to 83)
    53 (53 to 53)
    Notes
    [3] - The 3 month score was not completed for this patient.
    [4] - This data is present for both patients at baseline, but only 1 at the 3 month time point.
    No statistical analyses for this end point

    Secondary: Secondary outcome 1: Time to treatment failure due to inadequate seizure control or unacceptable adverse reactions

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    End point title
    		 Secondary outcome 1: Time to treatment failure due to inadequate seizure control or unacceptable adverse reactions
    End point description
    This endpoint was not reached for any of the 5 patients on the trial, meaning no analysis could be performed and only the median(min-max) time of last patient follow-up in days is presented.
    End point type
    Secondary
    End point timeframe
    Anytime from randomization until date of last patient follow-up.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    1
    1
    2
    1
    Units: Days since randomization
        median (full range (min-max))
    187.0 (187.0 to 187.0)
    112.0 (112.0 to 112.0)
    128.5 (86.0 to 171.0)
    192.0 (192.0 to 192.0)
    No statistical analyses for this end point

    Secondary: Secondary outcome 2: Time to treatment failure due to inadequate seizure control

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    End point title
    		 Secondary outcome 2: Time to treatment failure due to inadequate seizure control
    End point description
    This endpoint was not reached for any of the 5 patients on the trial, meaning no analysis could be performed so only median (min-max) time to last patient follow-up is presented for this outcome.
    End point type
    Secondary
    End point timeframe
    Anytime from randomization until date of last patient follow-up.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    1
    1
    2
    1
    Units: Days since randomization
        median (full range (min-max))
    187.0 (187.0 to 187.0)
    112.0 (112.0 to 112.0)
    128.5 (86.0 to 171.1)
    192.0 (192.0 to 192.0)
    No statistical analyses for this end point

    Secondary: Secondary outcome 3: Time to treatment failure due to unacceptable adverse reactions

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    End point title
    		 Secondary outcome 3: Time to treatment failure due to unacceptable adverse reactions
    End point description
    This endpoint was not reached for any of the 5 patients on the trial, meaning no analysis could be performed so only the median (min-max) time to last patient follow-up is presented in days for this outcome.
    End point type
    Secondary
    End point timeframe
    Anytime from randomization until date of last patient follow-up.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    1
    1
    2
    1
    Units: Days since randomization
        median (full range (min-max))
    187.0 (187.0 to 187.0)
    112.0 (112.0 to 112.0)
    128.5 (86.0 to 171.0)
    192.0 (192.0 to 192.0)
    No statistical analyses for this end point

    Secondary: Secondary outcome 4: Time to first seizure

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    End point title
    		 Secondary outcome 4: Time to first seizure
    End point description
    This endpoint is the time in days until the patient has their first seizure since randomization. Only 3 patients reported seizures after randomization.
    End point type
    Secondary
    End point timeframe
    Anytime from randomization until last patient follow-up date.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    1
    1
    0 [5]
    1
    Units: Days since randomization
        median (full range (min-max))
    17.0 (17.0 to 17.0)
    35.0 (35.0 to 35.0)
    ( to )
    80.0 (80.0 to 80.0)
    Notes
    [5] - None of the patients in this arm had a seizure after randomization.
    No statistical analyses for this end point

    Secondary: Secondary outcome 5: Time to 12-month remission from seizures

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    End point title
    		 Secondary outcome 5: Time to 12-month remission from seizures
    End point description
    None of the patients had 12 month seizure remission so this endpoint could not be analysed, only the median (min-max) time in days to last patient follow-up is presented.
    End point type
    Secondary
    End point timeframe
    Anytime from randomization until last patient follow-up.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    1
    1
    2
    1
    Units: Days since randomization
        median (full range (min-max))
    187.0 (187.0 to 187.0)
    112.0 (112.0 to 112.0)
    128.5 (86.0 to 171.0)
    192.0 (192.0 to 192.0)
    No statistical analyses for this end point

    Secondary: Secondary outcome 6: Total sleep problem score on CSHQ at 12 months since randomization

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    End point title
    		 Secondary outcome 6: Total sleep problem score on CSHQ at 12 months since randomization
    End point description
    No patients on the study met the 12-month time point before the trial was closed prematurely so this endpoint could not be analysed.
    End point type
    Secondary
    End point timeframe
    Captured at 12 months from randomization.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    0 [6]
    0 [7]
    0 [8]
    0 [9]
    Units: Sleep scores
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [6] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    [7] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    [8] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    [9] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    No statistical analyses for this end point

    Secondary: Secondary outcome 7: Cognition (CANTAB)

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    End point title
    		 Secondary outcome 7: Cognition (CANTAB)
    End point description
    CANTAB total scores are provided in three chosen assessments delivered by CANTAB iPad Neuropsychological battery. CANTAB was only completed at the 3 month visit for 1 patient, and only the Motor Screening Task (MOT) scores were provided. This was only a warm up screen test.
    End point type
    Secondary
    End point timeframe
    This outcome is measured at baseline, 3 and 12 months post randomization.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention
    Number of subjects analysed
    0 [10]
    0 [11]
    1 [12]
    Units: CANTAB Score
    median (full range (min-max))
        MOTML score at 3 months
    ( to )
    ( to )
    696.1 (696.1 to 696.1)
        MOTSDL score at 3 months
    ( to )
    ( to )
    112.2 (112.2 to 112.2)
        MOTTC score at 3 months
    ( to )
    ( to )
    10 (10 to 10)
        MOTTE score at 3 months
    ( to )
    ( to )
    0 (0 to 0)
    Notes
    [10] - No CANTAB data was collected for this patient at 3 months.
    [11] - No CANTAB data was collected for this patient at 3 months.
    [12] - CANTAB data was only collected for one of the two patients in this arm at 3 months.
    No statistical analyses for this end point

    Secondary: Secondary outcome 8: Health related quality of life

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    End point title
    		 Secondary outcome 8: Health related quality of life
    End point description
    The CHEQOL score is derived by totaling the scores provided on the Child Health-related Quality of Life CRF at each time point. None of the patients reached the 12-month time point on the trial before it closed prematurely, so this endpoint could not be analysed.
    End point type
    Secondary
    End point timeframe
    This is completed at baseline and 12 months post randomization.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    0 [13]
    0 [14]
    0 [15]
    0 [16]
    Units: CHEQOL score totals
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [13] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    [14] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    [15] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    [16] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    No statistical analyses for this end point

    Secondary: Secondary outcome 9: To compare measures of children’s behaviour across the different treatment groups

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    End point title
    		 Secondary outcome 9: To compare measures of children’s behaviour across the different treatment groups
    End point description
    Scores from the Strengths and Difficulties Questionnaire (SDQ). The 12-month time point was not reached for any of the patients on the trial prior to the trial closing prematurely, so no analysis could be performed for this outcome.
    End point type
    Secondary
    End point timeframe
    Completed at baseline and 12 months post randomization.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    0 [17]
    0 [18]
    0 [19]
    0 [20]
    Units: Strengths and Difficulties score
        median (full range (min-max))
    ( to )
    ( to )
    ( to )
    ( to )
    Notes
    [17] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    [18] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    [19] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    [20] - No patients reached the 12-month time point in the trial prior to it being closed prematurely.
    No statistical analyses for this end point

    Secondary: Secondary outcome 10: To identify any adverse reactions

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    End point title
    		 Secondary outcome 10: To identify any adverse reactions
    End point description
    This is a descriptive analysis and details of adverse reactions can also be found under the "Adverse Events" section. Only adverse reactions were reported for this study., but all serious adverse events were reported also, however there were no serious adverse events on the trial.
    End point type
    Secondary
    End point timeframe
    Anytime from randomization until last patient follow-up date.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    0 [21]
    0 [22]
    1 [23]
    0 [24]
    Units: Number of adverse reactions
    number (not applicable)
        Number of adverse reactions
    5
    Notes
    [21] - There are no adverse reactions reported for this patient.
    [22] - There are no adverse reactions reported for this patient.
    [23] - Only one patient in this arm reported adverse reactions.
    [24] - There are no adverse reactions reported for this patient.
    No statistical analyses for this end point

    Secondary: Secondary outcome 11: Sickness related school absences

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    End point title
    		 Secondary outcome 11: Sickness related school absences
    End point description
    This outcome reports the total number of reported sickness related school absences (days).
    End point type
    Secondary
    End point timeframe
    Anytime from randomization until date of last patient follow-up.
    End point values
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Number of subjects analysed
    1
    1 [25]
    2 [26]
    1 [27]
    Units: Number of reported sickness days
    number (not applicable)
        Number of reported sick days at 3 months
    0
    0
    0
    0
        Number of reported sick days at 6 months
    0
    0
    0
    0
        Number of sick days missing at 3 months
    0
    1
    1
    1
        Number of sick days missing at 6 months
    0
    0
    0
    0
    Notes
    [25] - This patient withdrew after 3 months.
    [26] - One patient in this arm withdrew after 3 months, the second only reported this data at 6 months.
    [27] - The data for this participant at 3 months was missing, only the 6 month time point is provided.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Anytime from randomization until date of last patient follow-up.
    Adverse event reporting additional description
    All serious adverse events were reported for CASTLE, and only adverse events related to participant’s treatment with one of the CASTLE IMPs (carbamazepine or levetiracetam) were reported, assessed by PI. Collection method for all AEs was at each visit and the participant would be asked about adverse events and medical notes would also be reviewed.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    No AED & sleep intervention
    Reporting group description
    		 Patients randomized to no anti-epileptic drug and the sleep intervention.

    Reporting group title
    CBZ & sleep intervention
    Reporting group description
    		 Patients randomized to Carbamazepine and the sleep intervention.

    Reporting group title
    LEV & sleep intervention
    Reporting group description
    		 Patients who were randomized to Levetiracetam and the sleep intervention.

    Reporting group title
    LEV & no sleep intervention
    Reporting group description
    		 Patients randomized to Levetiracetam and no sleep intervention (standard care).

    Serious adverse events
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    0 / 2 (0.00%)
    0 / 1 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 No AED & sleep intervention CBZ & sleep intervention LEV & sleep intervention LEV & no sleep intervention
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Moody
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    worsening behaviour
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Cold
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    0 / 1 (0.00%)
    0 / 1 (0.00%)
    1 / 2 (50.00%)
    0 / 1 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Apr 2019
    Protocol version 2.0. This amendment to the protocol contained the addition of some new primary and secondary outcomes and the re-wording of some existing outcomes. The data collection processes were updated, in line with the amended outcomes. There were also updates to other study processes included in the document, such as safety/death reporting and retention/storage of data at the end of the trial. Clarification around obtaining consent and the actigraphy and qualitative interview activities was added to the protocol as part of this amendment.
    18 Aug 2020
    Protocol Version 3.0 (finalized on 18/08/2020). This amendment to the protocol detailed the processes in the event of an early trial termination, including reduced length of follow up and procedure for EEG review. There was also an update to the SmPC information included in the document, namely the update of the Carbamazepine SmPC name, following the discontinuation of the original IMP brand, and the inclusion of liquid/syrup formulations.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    23 Mar 2020
    The trial was halted due to the COVID-19 outbreak and all sites were closed for recruitment. The trial was never re-opened due to poor recruitment, with the global trial end date being 23/09/2020.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Early termination of the trial meant there were only 5 patients recruited into this trial, so many of the powered analyses specified in the protocol could not go ahead.
    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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