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    Clinical Trial Results:
    A randomised controlled trial of the ketogenic diet in the treatment of epilepsy in children under the age of two years

    Summary
    EudraCT number
    		 2013-002195-40
    Trial protocol
    		 GB  
    Global end of trial date
    30 Sep 2021

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

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    13/0656
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02205931
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    UCL
    Sponsor organisation address
    Gower Street, , London, United Kingdom, WC1E 6BT
    Public contact
    Helen Cross, UCL - Institute of Child Health, 0044 2075994105, h.cross@ucl.ac.uk
    Scientific contact
    Helen Cross, UCL - Institute of Child Health, 0044 2075994105, h.cross@ucl.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
    24 Mar 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Sep 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Sep 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To determine the effectiveness on seizure control of the ketogenic diet (KD) compared to further anti-epileptic drug (AED) treatment in children with epilepsy aged 3 months to 2 years who have failed to respond to two or more AEDs. Research question: Are there clear benefits in terms of seizure control in infants with continued seizures, despite two AEDs, treated with a KD as compared to a similar control group who are treated with a further AED?
    Protection of trial subjects
    Common side effects such as constipation, diarrhoea and vomiting, were minimised by manipulation of the diet. Rarely, renal stones occurred. Regular blood evaluation was done to ensure no potential electrolyte imbalance or mineral deficiency. Clinical laboratory assessments for haematology, biochemistry, and ketone assessment in blood and urine were carried out. Metabolic screening was done prior to start of trial to check that there were no contraindications to use of ketogenic diet. The young age of many of the children recruited for this trial had an inpatient admission for initiation (the majority already were inpatients for the management of their epilepsy owing to the frequency of seizures). At each of the centres, the paediatric neurologist worked with the dietetic team using a manualised dietetic care pathway for KD implementation. The risk of blood tests were minimal: • Sometimes a bruise developed where the needle was inserted. This was mitigated by pressing over the site with cotton wool for several minutes with the arm left straight (not bent). • As with any wound, an infection may develop where the needle was inserted; this was very rare and was treated as per standard care. • Rarely, some people feel fainted during a blood test and were treated with standard of care. Some children were withdrawn from the treatment prior to 8 weeks as there was 50% increase in seizure frequency from baseline, or due to some other side effects. Some children were reverted back to standard management when seizure control was not achieved on the KD arm b y 8 weeks. Children on the AED arm were prescribed further AEDs as per standard medical management.
    Background therapy
    		 Children were eligible if they had a a diagnosis of epilepsy and had previously trialled on two anti epileptic medications; they were required to have stable AED doses during the baseline period and the duration of the 8 week primary outcome period
    Evidence for comparator
    		 Anti epileptic medication is standard treatment of epilepsy. Choice of medication will depend on type of seizure/epilepsy. During set up of the study a workshop involving PI representation from all sites was held, to determine consensus on the AEDs that would be utilised in each type of seizure/epilepsy to ensure consistency across sites
    Actual start date of recruitment
    01 Sep 2014
    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: 136
    Worldwide total number of subjects
    136
    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)
    136
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 136 participants recruited from hospital-based paediatric neurology centres implementing the KD. PIC sites were also used to identify participants through patient records. Potential parents/guardians of participants were contacted initially by a member of their direct healthcare team and were sent invitation letter and PIS via post or email.

    Pre-assignment
    Screening details
    		 Potential participants were identified at each site by direct healthcare team. Parents of eligible children were consented. Full history including seizure type, neurological examination, weight, length and head circumference were documented. Children requiring thickeners in their feed for reflux were included as there was no interaction with KD.

    Period 1
    Period 1 title
    Overall Trial period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Trial was open label randomised controlled multicentred.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trial arm 1: Classical ketogenic diet (KD arm)
    Arm description
    		 The experimental intervention will be 8 week trial of KD therapy. A KD Intervention Manual will be created and provided to sites to ensure consistency of the KD implementation across centres. The manual includes basic instructions on how to calculate the classical KD and advice regarding diet implementation, such as supplementation, tube feeding, breastfeeding, weaning and fine-tuning the diet. Children allocated to KD therapy will have their diets individually calculated by a paediatric dietitian with consideration of daily calorie requirements, adequate protein intake for growth and vitamin and mineral supplementation. All diets will be implemented according to a classical KD protocol, i.e. based on a ratio of fat to carbohydrate and protein that will usually be between 2:1 and 4:1. For ketosis meal plans have to accurately calculated for each child. Further adjustments to KD are determined by regular growth monitoring, seizure control and daily home measurement of urine and ketones
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ketogenic diet
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Not assigned
    Routes of administration
    Oral use
    Dosage and administration details
    N/A - Ketogenic diet

    Arm title
    		 Trial Arm 2: Further Anti-epileptic drugs (AED arm)
    Arm description
    		 The control intervention will be drug therapy with most appropriate further AED for a particular child, depending on their presenting seizures and syndrome and previous drugs used. This will be chosen by the expert clinician responsible for management of patient's epilepsy. Paediatric neurologists will meet at an initial workshop to discuss clinical practice with the aim to form the basis of a consensus protocol to ensure the consistency of AED treatments delivered. The Dietetic Assistant will monitor cross-site consistency of IMP prescription according to the protocol. A discussion about diet will be undertaken with families of infants randomised to the AED arm at randomisation visit. If participant already under local dietetic support, then monitoring will continue. If participant does not have local dietetic support but it is deemed necessary by the ketogenic dietitian, an appropriate referral will be made by clinician. Brief discussion about general nutrition will take place.
    Arm type
    		 Control Intervention

    Investigational medicinal product name
    Carbamazepine
    Investigational medicinal product code
    Other name
    Tegratol
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100, 200, 400 mg tablets 100mg/5ml oral suspension

    Investigational medicinal product name
    Clobazam
    Investigational medicinal product code
    Other name
    Frisium
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5mg/5ml and 10mg/5ml oral suspension 10mg tablets

    Investigational medicinal product name
    Clonazepam
    Investigational medicinal product code
    Other name
    Rivotril
    Pharmaceutical forms
    Oral drops, Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    0.5 mg/5ml and 2mg/5ml oral solution 2.5 mg/ml oral drops 500 micrograms, 2 mg tablets

    Investigational medicinal product name
    Ethosuximide
    Investigational medicinal product code
    Other name
    Zarontin
    Pharmaceutical forms
    Capsule, Syrup
    Routes of administration
    Oral use
    Dosage and administration details
    250mg capsules 250mg/5ml syrup

    Investigational medicinal product name
    Lacosmide
    Investigational medicinal product code
    Other name
    Vimpat
    Pharmaceutical forms
    Syrup, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    10mg/ml syrup 50, 100, 150, 250 mg tablets

    Investigational medicinal product name
    Lamotrigine
    Investigational medicinal product code
    Other name
    Lamictal
    Pharmaceutical forms
    Dispersible tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2mg, 5mg, 100 mg dispersible tablets

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    Other name
    Keppra
    Pharmaceutical forms
    Oral solution, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100mg/ml oral solution 250mg, 500mg, 750mg, 1000mg tablets

    Investigational medicinal product name
    Nitrazepam
    Investigational medicinal product code
    Other name
    Mogadon
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2.5mg/5ml oral suspension 5mg tablets

    Investigational medicinal product name
    Phenytoin
    Investigational medicinal product code
    Other name
    Epanutin
    Pharmaceutical forms
    Capsule, Suspension for oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    25, 50, 100mg capsules 50mg infatabs 30mg/5ml suspension

    Investigational medicinal product name
    Rufinamide
    Investigational medicinal product code
    Other name
    Inovelon
    Pharmaceutical forms
    Oral suspension, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    100, 200, 400 mg tablets 40mg/ml oral suspension

    Investigational medicinal product name
    Sodium Valproate
    Investigational medicinal product code
    Other name
    Epilim
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    200mg/5ml

    Investigational medicinal product name
    Stiripentol
    Investigational medicinal product code
    Other name
    Diacomit
    Pharmaceutical forms
    Capsule, Oral powder in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    250mg and 500mg powder (sachets) 250mg and 500mg capsules

    Investigational medicinal product name
    Topiramate
    Investigational medicinal product code
    Other name
    Topamax
    Pharmaceutical forms
    Capsule, Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15mg, 25mg, 50mg sprinkle capsules 25mg, 50mg, 100mg tablets

    Investigational medicinal product name
    Vigabatrin
    Investigational medicinal product code
    Other name
    Sabril
    Pharmaceutical forms
    Oral powder in sachet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg powder (sachets)

    Investigational medicinal product name
    Zonisamide
    Investigational medicinal product code
    Other name
    Zonegran
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    25mg, 50mg, 100mg capsules

    Number of subjects in period 1
    		Trial arm 1: Classical ketogenic diet (KD arm) Trial Arm 2: Further Anti-epileptic drugs (AED arm)
    Started
    78
    58
    Completed
    43
    32
    Not completed
    35
    26
         Wanted KD arm hence not received AED intervention
    -
    4
         Consent withdrawn by subject
    6
    1
         Physician decision
    7
    2
         Withdrawn due to study ending
    11
    10
         Elected for surgery
    -
    2
         Lost to follow-up
    2
    2
         Patient deceased
    3
    -
         Randomised in error
    -
    1
         Protocol deviation
    6
    4

    Baseline characteristics

    		 Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Trial arm 1: Classical ketogenic diet (KD arm)
    Reporting group description
    		 The experimental intervention will be 8 week trial of KD therapy. A KD Intervention Manual will be created and provided to sites to ensure consistency of the KD implementation across centres. The manual includes basic instructions on how to calculate the classical KD and advice regarding diet implementation, such as supplementation, tube feeding, breastfeeding, weaning and fine-tuning the diet. Children allocated to KD therapy will have their diets individually calculated by a paediatric dietitian with consideration of daily calorie requirements, adequate protein intake for growth and vitamin and mineral supplementation. All diets will be implemented according to a classical KD protocol, i.e. based on a ratio of fat to carbohydrate and protein that will usually be between 2:1 and 4:1. For ketosis meal plans have to accurately calculated for each child. Further adjustments to KD are determined by regular growth monitoring, seizure control and daily home measurement of urine and ketones

    Reporting group title
    Trial Arm 2: Further Anti-epileptic drugs (AED arm)
    Reporting group description
    		 The control intervention will be drug therapy with most appropriate further AED for a particular child, depending on their presenting seizures and syndrome and previous drugs used. This will be chosen by the expert clinician responsible for management of patient's epilepsy. Paediatric neurologists will meet at an initial workshop to discuss clinical practice with the aim to form the basis of a consensus protocol to ensure the consistency of AED treatments delivered. The Dietetic Assistant will monitor cross-site consistency of IMP prescription according to the protocol. A discussion about diet will be undertaken with families of infants randomised to the AED arm at randomisation visit. If participant already under local dietetic support, then monitoring will continue. If participant does not have local dietetic support but it is deemed necessary by the ketogenic dietitian, an appropriate referral will be made by clinician. Brief discussion about general nutrition will take place.

    Reporting group values
    		 Trial arm 1: Classical ketogenic diet (KD arm) Trial Arm 2: Further Anti-epileptic drugs (AED arm) Total
    Number of subjects
    		 78 58 136
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    		 78 58 136
    Gender categorical
    Units: Subjects
        Female
    		 39 22 61
        Male
    		 39 36 75
    Subject analysis sets

    Subject analysis set title
    Intention to treat analysis at 8 weeks-KD arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    78 patients started KD intervention. 11 withdrew before 8 weeks. 67 continued KD to 8 weeks. 6 patients not included in 8 week analysis as data missing/incomplete. 61 included in intention-to-treat analysis at 8 weeks.

    Subject analysis set title
    Intention to treat analysis at 12 months-KD arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    24 patients withdrew after 8 weeks before 12 months. 43 patients continued KD to 12 months. 12 patients not included in data analysis at 12 month due to missing/incomplete data. 31 patients included in intention to treat analysis at 12 months.

    Subject analysis set title
    Intention to treat analysis at 8 weeks-AED arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    53 patients started AED intervention. 4 patients withdrew after intervention before 8 weeks. 49 patients continued AED to 8 weeks. 2 patients not included in data analysis at 8 weeks due to missing/incomplete data. 47 included in intention to treat analysis at 8 weeks

    Subject analysis set title
    Intention to treat analysis at 12 months-AED arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    17 patients withdrew after 8 weeks before 12 months. 32 patients continued AED to 12 months. 7 patients not included in analysis due to missing incomplete data. 25 patients included in intention-to-treat analysis at 12 months.

    Subject analysis sets values
    		 Intention to treat analysis at 8 weeks-KD arm Intention to treat analysis at 12 months-KD arm Intention to treat analysis at 8 weeks-AED arm Intention to treat analysis at 12 months-AED arm
    Number of subjects
    61
    31
    47
    25
    Age categorical
    Units: Subjects
        Infants and toddlers (28 days-23 months)
    61
    31
    47
    25
    Age continuous
    Units:
        
    ±
    ±
    ±
    ±
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

    		 Close Top of page
    End points reporting groups
    Reporting group title
    Trial arm 1: Classical ketogenic diet (KD arm)
    Reporting group description
    		 The experimental intervention will be 8 week trial of KD therapy. A KD Intervention Manual will be created and provided to sites to ensure consistency of the KD implementation across centres. The manual includes basic instructions on how to calculate the classical KD and advice regarding diet implementation, such as supplementation, tube feeding, breastfeeding, weaning and fine-tuning the diet. Children allocated to KD therapy will have their diets individually calculated by a paediatric dietitian with consideration of daily calorie requirements, adequate protein intake for growth and vitamin and mineral supplementation. All diets will be implemented according to a classical KD protocol, i.e. based on a ratio of fat to carbohydrate and protein that will usually be between 2:1 and 4:1. For ketosis meal plans have to accurately calculated for each child. Further adjustments to KD are determined by regular growth monitoring, seizure control and daily home measurement of urine and ketones

    Reporting group title
    Trial Arm 2: Further Anti-epileptic drugs (AED arm)
    Reporting group description
    		 The control intervention will be drug therapy with most appropriate further AED for a particular child, depending on their presenting seizures and syndrome and previous drugs used. This will be chosen by the expert clinician responsible for management of patient's epilepsy. Paediatric neurologists will meet at an initial workshop to discuss clinical practice with the aim to form the basis of a consensus protocol to ensure the consistency of AED treatments delivered. The Dietetic Assistant will monitor cross-site consistency of IMP prescription according to the protocol. A discussion about diet will be undertaken with families of infants randomised to the AED arm at randomisation visit. If participant already under local dietetic support, then monitoring will continue. If participant does not have local dietetic support but it is deemed necessary by the ketogenic dietitian, an appropriate referral will be made by clinician. Brief discussion about general nutrition will take place.

    Subject analysis set title
    Intention to treat analysis at 8 weeks-KD arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    78 patients started KD intervention. 11 withdrew before 8 weeks. 67 continued KD to 8 weeks. 6 patients not included in 8 week analysis as data missing/incomplete. 61 included in intention-to-treat analysis at 8 weeks.

    Subject analysis set title
    Intention to treat analysis at 12 months-KD arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    24 patients withdrew after 8 weeks before 12 months. 43 patients continued KD to 12 months. 12 patients not included in data analysis at 12 month due to missing/incomplete data. 31 patients included in intention to treat analysis at 12 months.

    Subject analysis set title
    Intention to treat analysis at 8 weeks-AED arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    53 patients started AED intervention. 4 patients withdrew after intervention before 8 weeks. 49 patients continued AED to 8 weeks. 2 patients not included in data analysis at 8 weeks due to missing/incomplete data. 47 included in intention to treat analysis at 8 weeks

    Subject analysis set title
    Intention to treat analysis at 12 months-AED arm
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    17 patients withdrew after 8 weeks before 12 months. 32 patients continued AED to 12 months. 7 patients not included in analysis due to missing incomplete data. 25 patients included in intention-to-treat analysis at 12 months.

    Primary: no of seizures

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    End point title
    		 no of seizures
    End point description
    seizure count in weeks 6 to 8 of the intervention period and in the baseline assessment period.
    End point type
    Primary
    End point timeframe
    after 8 weeks treatment
    End point values
    		 Trial arm 1: Classical ketogenic diet (KD arm) Trial Arm 2: Further Anti-epileptic drugs (AED arm) Intention to treat analysis at 8 weeks-KD arm Intention to treat analysis at 8 weeks-AED arm
    Number of subjects analysed
    61
    47
    61
    47
    Units: number
        median (inter-quartile range (Q1-Q3))
    3 (2 to 11)
    5 (1 to 16)
    3 (2 to 11)
    5 (1 to 16)
    Statistical analysis title
    		 Poisson mixed model
    Comparison groups
    Intention to treat analysis at 8 weeks-KD arm v Intention to treat analysis at 8 weeks-AED arm
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 incident rate ratio
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 2.11

    Secondary: Seizure freedom

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    End point title
    		 Seizure freedom
    End point description
    % those anaysed free of seizures for weeks 6-8.
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 Intention to treat analysis at 8 weeks-KD arm Intention to treat analysis at 8 weeks-AED arm
    Number of subjects analysed
    61
    47
    Units: number
    7
    6
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Intention to treat analysis at 8 weeks-KD arm v Intention to treat analysis at 8 weeks-AED arm
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.88
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.27
         upper limit
    		 2.8

    Secondary: Responder rate

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    End point title
    		 Responder rate
    End point description
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 Intention to treat analysis at 8 weeks-KD arm Intention to treat analysis at 12 months-KD arm
    Number of subjects analysed
    61
    47
    Units: number
    28
    19
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Intention to treat analysis at 8 weeks-KD arm v Intention to treat analysis at 12 months-KD arm
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.55
         upper limit
    		 2.65

    Secondary: Tolerability

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    End point title
    		 Tolerability
    End point description
    End point type
    Secondary
    End point timeframe
    8 weeks
    End point values
    		 Intention to treat analysis at 8 weeks-KD arm Intention to treat analysis at 8 weeks-AED arm
    Number of subjects analysed
    61
    47
    Units: Side effect score
        median (inter-quartile range (Q1-Q3))
    40 (38 to 42)
    41 (39 to 44)
    No statistical analyses for this end point

    Secondary: Quality of life

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    End point title
    		 Quality of life
    End point description
    Child overall health score
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intention to treat analysis at 12 months-KD arm Intention to treat analysis at 12 months-AED arm
    Number of subjects analysed
    30
    25
    Units: Score
        median (inter-quartile range (Q1-Q3))
    60 (30 to 60)
    30 (30 to 60)
    Statistical analysis title
    		 Mixed linear regression
    Comparison groups
    Intention to treat analysis at 12 months-KD arm v Intention to treat analysis at 12 months-AED arm
    Number of subjects included in analysis
    55
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 coefficient
    Point estimate
    1.23
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.7
         upper limit
    		 15.17

    Secondary: Vineland neurodevelopmental score

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    End point title
    		 Vineland neurodevelopmental score
    End point description
    End point type
    Secondary
    End point timeframe
    12 months
    End point values
    		 Intention to treat analysis at 12 months-KD arm Intention to treat analysis at 12 months-AED arm
    Number of subjects analysed
    15
    11
    Units: Score
        median (inter-quartile range (Q1-Q3))
    41 (39 to 43)
    40 (39 to 41)
    Statistical analysis title
    		 linear regression
    Comparison groups
    Intention to treat analysis at 12 months-KD arm v Intention to treat analysis at 12 months-AED arm
    Number of subjects included in analysis
    26
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 coefficient
    Point estimate
    0.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.34
         upper limit
    		 5.67

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    2.1
    Reporting groups
    Reporting group title
    Trial arm 1: Classical ketogenic diet (KD arm)
    Reporting group description
    		 The experimental intervention will be 8 week trial of KD therapy. A KD Intervention Manual will be created and provided to sites to ensure consistency of the KD implementation across centres. The manual includes basic instructions on how to calculate the classical KD and advice regarding diet implementation, such as supplementation, tube feeding, breastfeeding, weaning and fine-tuning the diet. Children allocated to KD therapy will have their diets individually calculated by a paediatric dietitian with consideration of daily calorie requirements, adequate protein intake for growth and vitamin and mineral supplementation. All diets will be implemented according to a classical KD protocol, i.e. based on a ratio of fat to carbohydrate and protein that will usually be between 2:1 and 4:1. For ketosis meal plans have to accurately calculated for each child. Further adjustments to KD are determined by regular growth monitoring, seizure control and daily home measurement of urine and ketones

    Reporting group title
    Trial Arm 2: Further Anti-epileptic drugs (AED arm)
    Reporting group description
    		 The control intervention will be drug therapy with most appropriate further AED for a particular child, depending on their presenting seizures and syndrome and previous drugs used. This will be chosen by the expert clinician responsible for management of patient's epilepsy. Paediatric neurologists will meet at an initial workshop to discuss clinical practice with the aim to form the basis of a consensus protocol to ensure the consistency of AED treatments delivered. The Dietetic Assistant will monitor cross-site consistency of IMP prescription according to the protocol. A discussion about diet will be undertaken with families of infants randomised to the AED arm at randomisation visit. If participant already under local dietetic support, then monitoring will continue. If participant does not have local dietetic support but it is deemed necessary by the ketogenic dietitian, an appropriate referral will be made by clinician. Brief discussion about general nutrition will take place.

    Serious adverse events
    		 Trial arm 1: Classical ketogenic diet (KD arm) Trial Arm 2: Further Anti-epileptic drugs (AED arm)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    78 / 78 (100.00%)
    58 / 58 (100.00%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    0
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Shunt malfunction
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Surgical and medical procedures
    Adenotonsillectomy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrostomy
         subjects affected / exposed
    1 / 78 (1.28%)
    4 / 58 (6.90%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Oesophagogastric fundoplasty
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ventriculo-peritoneal shunt
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Nervous system disorders
    Epilepsy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infantile spasms
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lethargy
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    15 / 78 (19.23%)
    10 / 58 (17.24%)
         occurrences causally related to treatment / all
    0 / 46
    0 / 28
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Status epilepticus
         subjects affected / exposed
    4 / 78 (5.13%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 8
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypotonia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest discomfort
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 58 (3.45%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Somnolence
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Dermatitis allergic
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    coffee ground vomiting
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Melaena
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varices oesophageal
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Aspiration
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cough
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Croup infectious
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiration abnormal
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory arrest
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Respiratory depression
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory disorder
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 78 (1.28%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wheezing
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Adenoiditis
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchiolitis
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    11 / 78 (14.10%)
    6 / 58 (10.34%)
         occurrences causally related to treatment / all
    0 / 22
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Parainfluenzae virus infection
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    6 / 78 (7.69%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory tract infection
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinitis
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhinovirus infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Varicella
         subjects affected / exposed
    3 / 78 (3.85%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral infection
         subjects affected / exposed
    4 / 78 (5.13%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 5
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Viral tonsillitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tonsillitis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Blood ketone body
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Feeding disorder
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ketosis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Malnutrition
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Weight gain poor
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    2 / 78 (2.56%)
    0 / 58 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Trial arm 1: Classical ketogenic diet (KD arm) Trial Arm 2: Further Anti-epileptic drugs (AED arm)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    72 / 78 (92.31%)
    54 / 58 (93.10%)
    Nervous system disorders
    Seizure cluster
         subjects affected / exposed
    2 / 78 (2.56%)
    3 / 58 (5.17%)
         occurrences all number
    2
    3
    Seizure
         subjects affected / exposed
    9 / 78 (11.54%)
    10 / 58 (17.24%)
         occurrences all number
    12
    13
    Somnolence
         subjects affected / exposed
    3 / 78 (3.85%)
    3 / 58 (5.17%)
         occurrences all number
    3
    3
    General disorders and administration site conditions
    Lethargy
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 58 (1.72%)
         occurrences all number
    0
    3
    Pyrexia
         subjects affected / exposed
    7 / 78 (8.97%)
    10 / 58 (17.24%)
         occurrences all number
    9
    15
    Feeling abnormal
         subjects affected / exposed
    0 / 78 (0.00%)
    4 / 58 (6.90%)
         occurrences all number
    0
    7
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    12 / 78 (15.38%)
    4 / 58 (6.90%)
         occurrences all number
    13
    5
    Diarrhoea
         subjects affected / exposed
    7 / 78 (8.97%)
    4 / 58 (6.90%)
         occurrences all number
    8
    8
    Abdominal pain
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 58 (1.72%)
         occurrences all number
    4
    1
    Teething
         subjects affected / exposed
    10 / 78 (12.82%)
    4 / 58 (6.90%)
         occurrences all number
    16
    51
    Vomiting
         subjects affected / exposed
    11 / 78 (14.10%)
    11 / 58 (18.97%)
         occurrences all number
    13
    16
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    8 / 78 (10.26%)
    5 / 58 (8.62%)
         occurrences all number
    9
    7
    Nasopharyngitis
         subjects affected / exposed
    6 / 78 (7.69%)
    7 / 58 (12.07%)
         occurrences all number
    9
    9
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 78 (5.13%)
    4 / 58 (6.90%)
         occurrences all number
    4
    6
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 78 (5.13%)
    6 / 58 (10.34%)
         occurrences all number
    4
    6
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    10 / 78 (12.82%)
    11 / 58 (18.97%)
         occurrences all number
    11
    17
    Tonsillitis
         subjects affected / exposed
    3 / 78 (3.85%)
    1 / 58 (1.72%)
         occurrences all number
    4
    4
    Urinary tract infection
         subjects affected / exposed
    2 / 78 (2.56%)
    3 / 58 (5.17%)
         occurrences all number
    3
    3
    Viral infection
         subjects affected / exposed
    4 / 78 (5.13%)
    3 / 58 (5.17%)
         occurrences all number
    4
    3
    Metabolism and nutrition disorders
    Hyperketosis
         subjects affected / exposed
    7 / 78 (8.97%)
    1 / 58 (1.72%)
         occurrences all number
    7
    2

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2014
    Response to grounds of non-acceptance (dated 11th Aug 2014) from the MHRA. Changes to Protocol to reflect information in line with the above request- exclusion criteria
    08 May 2015
    1. Ketones are to be recorded for both groups of infants. 2. KIWE Side Effects, Seizure Diary and Food Diary updated.
    07 Sep 2015
    1. The addition of P.I.C sites: Dr Andrea Whitney, University Hospital Southampton NHS Foundation Trust and Dr Archana Desurkar, Sheffield Teaching Hospitals NHS Foundation Trust 2. Update of contact details for CI and TM; Schematic trial design flowchart to include seizure recording frequency (Protocol v4.0 and Research site PIS v2.0) 3. Clarification of procedures within the main text and flowchart of assessments within the protocol.
    12 Nov 2015
    1. Protocol - Reducing seizure frequency to greater than or equal to 4 seizures/week; If the child is prone to particularly frequent seizures in excess of 2/day then minimum one week baseline would be considered to suffice instead of 2 weeks; +/5 days deviation window allowed at randomisation, 4 weeks and 8 weeks 2. Removal of “β hydroxybutyrate and acetoacetate” as not required as part of haematology. 3. Minor changes to the schematic of trial design, study procedures and schedule of assessments and flowchart of study assessments to reflect the trial procedures more accurately. 4. MHRA amendment - There has been updated reference safety information for the following SPC's: SmPC Vigabatrin (ROT June 2014), SmPC Sodium Valporate (ROT March 2015), SmPC Phenytoin infatabs (ROT August 2015), SmPC levetiracetam (ROT August 2015), SmPC Lamotrigine (ROT July 2015), SmPC lacosamide (ROT October 2014), SmPC ethosuximide syrup (ROT July 2014), SmPC ethosuximide caps (ROT May 2015)
    07 Nov 2016
    1. Reducing the inclusion age from 3 months – 24 months to 1 month – 24 months. 2. Removing the Month 3 visit, and thus after the Week 8 visit, the patients will be followed up at 6, 9, and 12 months only. 3. Optionally, the week 4 visit can be conducted over the telephone. 4. Special assay to be taken at baseline rather than at randomisation for patients on both arms, to avoid getting bled twice. 5. Widening the visit windows for months 6, 9, and 12 to +/- 2 weeks. 6. Adding new sites to the protocol including St Georges Hospital, Sheffield Teaching Hospitals, The Newcastle upon Tyne Hospitals, Lancashire Teach Hospitals, University Hospital Southampton and Leicester Royal Infirmary 7. Changing the addresses for the CI, Trial Manager and Dietetic Assistant. 8. Clarifying the routine blood tests to be taken 9. Amending the seizure diary to include medication changes and weight recordings (optional) 10. Adding emergency contact information on the patient information sheet
    16 May 2017
    1. Change of PI at Leicester and Bristol hospitals 2. Removal of co-investigators in protocol 3. Removal of Matthew's Friends as a recruiting centre 4. Clarification of wording 5. Notification of previous change in food diary
    02 Jan 2018
    1. Updates to the reference safety information for the following SPCs: Levetiracetam, Phenytoin infatabs, Rufinamide, Sodium Valproate, Epilim 400mg Powder and Solvent for solution for injection/infusion, Topiramate and Zonisamide. 2. A no cost extension to recruitment to end on 31 October 2018.
    25 Mar 2019
    1. Recruitment end date on 30 April 2021. 2. Manchester PI updated from Dr Timothy Martland to Dr Jeen Tan 3. Protocol - amended the wording of exclusion criterion 11 on page 20 for protocol clarification – so patients who have been prescribed Phenobarbital are not excluded. 4. Trial Manager updated from Siobhan Titre-Johnson to Dr Laura Lyons. 5. Maryam Balogun added as the Research Administrator to the trial team. 6. Sponsor details updated to remove Nimrita Verma and include Misha Ladva
    14 Jun 2019
    1. Addition of two research sites in England: 2. Dr Manish Prasad, Nottingham University Hospitals NHS Trust 3. Dr Rohini Rattihalli, Oxford University Hospitals NHS Foundation Trust 4. Addition of four research sites in Scotland: - Dr Elma Stephen, Royal Aberdeen Children’s Hospital - NHS Grampian - Professor Andreas Brunklaus, Royal Hospital for Children - NHS Greater Glasgow and Clyde - Prof Martin Kirkpatrick, Tayside Children’s Hospital - NHS Tayside (Dundee) - Dr Ailsa McLellan, Royal Hospital for Sick Children - NHS Lothian (Edinburgh)
    21 Apr 2020
    SmPC updates as follows: Tegretol (carbamazepine) Liquid 100mg, Novartis Pharmaceuticals UK Limited Tegretol (carbamazepine) 100mg,200mg,400mg tablets, Novartis Pharmaceuticals UK Limited Frisium (clobazam) 10mg tablets, Sanofi Clonazepam 2mg/5ml oral, Rosemont Pharmaceuticals Limited Clonazepam 0.5mg/5ml oral, Rosemont Pharmaceuticals Limited Zarontin (ethosuximide) 250mg, previously Pfizer Limited and now Aristo Pharma Limited Vimpat (lacosamide) 50 mg 100 mg 150 mg 200mg film-coated tablets, UCB Pharma Limited Lamictal (lamotrigine) 25/50/100/200mg tablets, GlaxoSmithKline UK Keppra (levetiracetam) 250 mg film-coated tablets, UCB Pharma Epilim (sodium valproate) 400mg Powder and Solvent, Sanofi Topamax (topiramate) 25mg tablets, Janssen-Cilag Ltd Sabril (vigabatrin) 500 mg film, Sanofi
    06 Jul 2020
    1. Consent can be taken over the phone with confirmation of consent via email or post and signature gained at the next face – to – face visit. 2. Existing bloods which are less than 6 weeks old can be used for screening. 3. Visits may be carried out remotely and data such as diaries and questionnaires can be collected via remote methods such as email, post or over the phone. 4. Flexibility window for visits has been increased. 5. Bloods may be taken locally (e.g. participants GP or local hospital) and results sent to the site. 6. A contingency plan has been added if the central lab is unable to accept new samples. The sites will store the samples until the lab is ready to reopen."
    31 Mar 2021
    1. Protocol update regarding informed consent procedure obtained during a telephone consultation. 2. Update of the RSI of the following SmPCs: Carbamazepine tablets (Tegretol) 100mg/200mg/400 mg tablets Clobazam Oral suspension 5 mg/5ml and 10mg/5ml Clobazam (Frisium) 10mg tablets Clonazepam Rivotril 0.5mg tablets Levetiracetam (Keppra) 250/500/750/1000 mg film-coated tablets, 100 mg/ml, oral solution, 100 mg/ml concentrate for solution for infusion Nitrazepam tablets (Mogadon 5mg tablets) Rufinamide (Inovelon) 100/200/400 mg film-coated tablets, 40 mg/ml oral suspension Topiramate (Topamax) 25mg, 50mg, 100mg film-coated tablets; 15mg, 25mg, 50mg sprinkle capsules; Vigabatrin (Sabril 500mg film-coated tablets) 3. An extension to the recruitment period to end on 31 September 2021 and trial end date to 28 February 2022 4. Edit of Trial Manager email address on protocol"

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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