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    Clinical Trial Results:
    Emergency Treatment with Levetiracetam or Phenytoin in Status Epilepticus in Children (EcLiPSE) – an open label randomised controlled trial

    Summary
    EudraCT number
    		 2014-002188-13
    Trial protocol
    		 GB  
    Global end of trial date
    21 May 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Nov 2018
    First version publication date
    22 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UoL001087
    Additional study identifiers
    ISRCTN number
    		 ISRCTN22567894
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alder Hey NHS Foundation Trust
    Sponsor organisation address
    Eaton Road, Liverpool, United Kingdom, L12 2AP
    Public contact
    Nadia Al-Najjar, Medicines for Children Clinical Trials Unit, +44 01517958755, eclipse@liverpool.ac.uk
    Scientific contact
    Nadia Al-Najjar, Medicines for Children Clinical Trials Unit, +44 01517958755, eclipse@liverpool.ac.uk
    Sponsor organisation name
    University of Liverpool
    Sponsor organisation address
    2nd Floor Block D Waterhouse Building, 3 Brownlow Street, Liverpool, United Kingdom, L69 3GL
    Public contact
    Nadia Al-Najjar, Medicines for Children Clinical Trials Unit, +44 01517958755, eclipse@liv.ac.uk
    Scientific contact
    Nadia Al-Najjar, Medicines for Children Clinical Trials Unit, +44 01517958755, eclipse@liv.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
    21 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 May 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    21 May 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    1. To determine whether intravenous phenytoin or intravenous levetiracetam is the more efficacious second-line anticonvulsant for the emergency management of convulsive status epilepticus (CSE) in children. 2. To determine if intravenous levetiracetam is associated with fewer adverse effects than intravenous phenytoin
    Protection of trial subjects
    Both treatments used in the EcLiPSE clinical trial (Levetiracetam and Phenytoin) are licensed for their use to treat the clinical condition investigated in the study - Convulsive Status Epilepticus. The administration of the trial treatments was done so by trained medical professionals in a hospital environment using standard, routine procedures. All those who oversaw treatment were trained on the study, which is evidenced by the collection of site training 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 tasks. All members of site staff who approached the participant’s family for consent were trained on the study, this equipped them with sufficient knowledge to answer any trial related questions. In addition, these members of staff also had the required clinical skills to provide additional support to those families that were emotionally distressed by their child’s condition. Patient information was collected at site using CRFs specifically designed for the EcLiPSE trial. All collected information was pseudo-anonymised and transferred to the Clinical Trial Research Centre (CTRC) in an agreed secure format. The management of the study was done in line with Ethical, Regulatory and CTRC policies/procedures.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jul 2015
    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: 286
    Worldwide total number of subjects
    286
    EEA total number of subjects
    286
    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)
    118
    Children (2-11 years)
    155
    Adolescents (12-17 years)
    13
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients aged 6 months up to 18 years presenting to the ED with generalised tonic-clonic, generalised clonic or focal cloned status epilepticus that requires second-line treatment were assessed by clinical staff and randomised if they fulfilled the eligibility criteria. The study opened to recruitment on 17/07/2015, and was closed on 10/04/2018.

    Pre-assignment
    Screening details
    		 1432 children were assessed for eligibility. 1028 (72%) were excluded: 833 children did not meet the inclusion criteria, eligibility was missing for 3 children, and 192 children were excluded for other reasons.

    Period 1
    Period 1 title
    Randomised
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Levetiracetam
    Arm description
    		 Patients randomised to Levetiracetam.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Levetiracetam should be administered as a single dose, at a dosage of 40mg/kg (maximum dose 2500mg) of body weight (estimated according to the child’s age). The treatment should be administered intravenously as an infusion over 5 minutes in a large vein. Levetiracetam should be diluted to a maximum of 50mg/mL with sodium chloride 0.9% before administration

    Arm title
    		 Phenytoin
    Arm description
    		 Patients randomised to Phenytoin.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Phenytoin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Phenytoin should be administered as a single dose, at a dosage of 20mg/kg (maximum dose 2000mg) of estimated body weight (estimated according to the child’s age). The total maximum dose of phenytoin administered should be 2000mg. However, sites should confirm prior to study start if their local procedure states that the maximum phenytoin dose is less than 2000mg. If this is the case then the maximum dose for phenytoin should be as per local procedure and should be adhered to. The treatment should be administered intravenously as an infusion in a large vein: - Infusion time for phenytoin dose ≤1000mg: 20 minutes - Infusion time for phenytoin dose >1000mg and ≤1500mg: Between 20 – 30 minutes - Infusion time for phenytoin dose >1500mg and ≤2000mg: Between 30 – 40 minutes The final concentration of phenytoin in the solution for infusion should be a maximum of 10mg/ml with 0.9% sodium chloride.

    Number of subjects in period 1
    		Levetiracetam Phenytoin
    Started
    212
    192
    Completed
    152
    134
    Not completed
    60
    58
         Unknown
    1
    5
         Declined consent
    8
    11
         Second-line treatment not required
    51
    42
    Period 2
    Period 2 title
    Treated
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Levetiracetam
    Arm description
    		 Patients randomised to Levetiracetam and treated.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Levetiracetam
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Levetiracetam should be administered as a single dose, at a dosage of 40mg/kg (maximum dose 2500mg) of body weight (estimated according to the child’s age). The treatment should be administered intravenously as an infusion over 5 minutes in a large vein. Levetiracetam should be diluted to a maximum of 50mg/mL with sodium chloride 0.9% before administration

    Arm title
    		 Phenytoin
    Arm description
    		 Patients randomised to Phenytoin and treated.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Phenytoin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Phenytoin should be administered as a single dose, at a dosage of 20mg/kg (maximum dose 2000mg) of estimated body weight (estimated according to the child’s age). The total maximum dose of phenytoin administered should be 2000mg. However, sites should confirm prior to study start if their local procedure states that the maximum phenytoin dose is less than 2000mg. If this is the case then the maximum dose for phenytoin should be as per local procedure and should be adhered to. The treatment should be administered intravenously as an infusion in a large vein: - Infusion time for phenytoin dose ≤1000mg: 20 minutes - Infusion time for phenytoin dose >1000mg and ≤1500mg: Between 20 – 30 minutes - Infusion time for phenytoin dose >1500mg and ≤2000mg: Between 30 – 40 minutes The final concentration of phenytoin in the solution for infusion should be a maximum of 10mg/ml with 0.9% sodium chloride.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Baseline characteristics are only reported for those patients who were randomised and treated (Period 2), as specified in the Statistical Analysis Plan version 2.0 15/05/2018.
    Number of subjects in period 2
    		Levetiracetam Phenytoin
    Started
    152
    134
    Completed
    152
    134

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    		 Patients randomised to Levetiracetam and treated.

    Reporting group title
    Phenytoin
    Reporting group description
    		 Patients randomised to Phenytoin and treated.

    Reporting group values
    		 Levetiracetam Phenytoin Total
    Number of subjects
    		 152 134 286
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 65 53 118
        Children (2-11 years)
    		 81 74 155
        Adolescents (12-17 years)
    		 6 7 13
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 2.73 (1.27 to 5.88) 2.72 (1.59 to 5.59) -
    Gender categorical
    Units: Subjects
        Female
    		 77 62 139
        Male
    		 75 72 147
    Weight
    Units: Subjects
        0 to <12kg
    		 52 42 94
        12kg to 36kg
    		 86 80 166
        >36kg
    		 14 12 26
    Weight
    Units: kilogram(s)
        median (inter-quartile range (Q1-Q3))
    		 12.10 (10 to 19) 12.00 (10 to 18) -

    End points

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    End points reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    		 Patients randomised to Levetiracetam.

    Reporting group title
    Phenytoin
    Reporting group description
    		 Patients randomised to Phenytoin.
    Reporting group title
    Levetiracetam
    Reporting group description
    		 Patients randomised to Levetiracetam and treated.

    Reporting group title
    Phenytoin
    Reporting group description
    		 Patients randomised to Phenytoin and treated.

    Primary: Time to seizure cessation

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    End point title
    		 Time to seizure cessation
    End point description
    End point type
    Primary
    End point timeframe
    24 hours from randomisation
    End point values
    		 Levetiracetam Phenytoin
    Number of subjects analysed
    152
    134
    Units: Seizure cessation
        Number of events (seizure cessation)
    106
    86
        Number of censored times (RSI)
    46
    48
    Statistical analysis title
    		 Time to seizure cessation
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1992
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Time to seizure cessation adjusted Cox-PH
    Statistical analysis description
    Time to seizure cessation adjusted Cox-PH: Allocation (Levetiracetam vs. Phenytoin)
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.299 [1]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.57
    Notes
    [1] - This analysis was adjusted for weight, gender, whether it is a patients’ first seizure, site of initial access, and whether any additional anticonvulsants were administered alongside the infusion. Site was included in the model as a random effect.

    Secondary: Need for further anticonvulsant(s) to manage the seizure after the initial agent

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    End point title
    		 Need for further anticonvulsant(s) to manage the seizure after the initial agent
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours from randomisation
    End point values
    		 Levetiracetam Phenytoin
    Number of subjects analysed
    152
    134
    Units: Need for further anticonvulsant(s)
        Yes
    57
    50
        No
    95
    84
    Statistical analysis title
    		 Chi-squared results
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.974
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.74
         upper limit
    		 1.36
    Statistical analysis title
    		 Logistic regression
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.75 [2]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.65
         upper limit
    		 1.83
    Notes
    [2] - This analysis was adjusted for weight, gender, whether it is a patients’ first seizure, site of initial access, and whether any additional anticonvulsants were administered alongside the infusion. Site was included in the model as a random effect.

    Secondary: Need for rapid sequence induction (RSI) with thiopentone or another agent (e.g. propofol) due to ongoing CSE

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    End point title
    		 Need for rapid sequence induction (RSI) with thiopentone or another agent (e.g. propofol) due to ongoing CSE
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours from randomisation
    End point values
    		 Levetiracetam Phenytoin
    Number of subjects analysed
    152
    134
    Units: Need for rapid sequence induction (RSI)
        Yes
    44
    47
        No
    108
    87
    Statistical analysis title
    		 Chi-squared results
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.267
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    0.83
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.59
         upper limit
    		 1.16
    Statistical analysis title
    		 Logistic regression results
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.367
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.47
         upper limit
    		 1.32

    Secondary: Need to be admitted to critical care

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    End point title
    		 Need to be admitted to critical care
    End point description
    End point type
    Secondary
    End point timeframe
    24 hours from randomisation
    End point values
    		 Levetiracetam Phenytoin
    Number of subjects analysed
    152
    134
    Units: Need to be admitted to critical care
        Yes
    97
    72
        No
    55
    62
    Statistical analysis title
    		 Chi-squared results
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.084
    Method
    		 Chi-squared
    Parameter type
    		 Risk ratio (RR)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.97
         upper limit
    		 1.45
    Statistical analysis title
    		 Logistic regression results
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.101 [3]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.52
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.92
         upper limit
    		 2.5
    Notes
    [3] - This analysis was adjusted for weight, gender, whether it is a patients’ first seizure, site of initial access, and whether any additional anticonvulsants were administered alongside the infusion. Site was included in the model as a random effect.

    Other pre-specified: Sensitivity analysis 1

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    End point title
    		 Sensitivity analysis 1
    End point description
    Time to seizure cessation from infusion
    End point type
    Other pre-specified
    End point timeframe
    24 hours from randomisation
    End point values
    		 Levetiracetam Phenytoin
    Number of subjects analysed
    152
    134
    Units: Seizure cessation
        Number of events (seizure cessation)
    106
    86
        Number of censored times (RSI)
    46
    48
    Statistical analysis title
    		 Sensitivity analysis 1
    Comparison groups
    Phenytoin v Levetiracetam
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3195
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Sensitivity analysis 1: adjusted Cox-PH
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.512 [4]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.82
         upper limit
    		 1.48
    Notes
    [4] - This analysis was adjusted for weight, gender, whether it is a patients’ first seizure, site of initial access, and whether any additional anticonvulsants were administered alongside the infusion.

    Other pre-specified: Sensitivity analysis 2

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    End point title
    		 Sensitivity analysis 2
    End point description
    Time to seizure cessation including non-treated patients
    End point type
    Other pre-specified
    End point timeframe
    24 hours from randomisation
    End point values
    		 Levetiracetam Phenytoin
    Number of subjects analysed
    203
    176
    Units: Seizure cessation
        Number of events (seizure cessation)
    106
    86
        Number of censored times (RSI)
    97
    90
    Statistical analysis title
    		 Sensitivity analysis 2
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1992
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Sensitivity analysis 2: adjusted Cox-PH
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    379
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.299 [5]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.57
    Notes
    [5] - This analysis was adjusted for weight, gender, whether it is a patients’ first seizure, site of initial access, and whether any additional anticonvulsants were administered alongside the infusion. Site was included in the model as a random effect.

    Other pre-specified: Sensitivity analysis 3

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    End point title
    		 Sensitivity analysis 3
    End point description
    Time to seizure cessation censoring at time of 2nd second-line treatment
    End point type
    Other pre-specified
    End point timeframe
    24 hours from randomisation
    End point values
    		 Levetiracetam Phenytoin
    Number of subjects analysed
    152
    134
    Units: Seizure cessation
        Number of events (seizure cessation)
    98
    85
        Number of censored times (RSI)
    41
    45
        Number of censored times (2nd second-line)
    13
    4
    Statistical analysis title
    		 Sensitivity analysis 3
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3349
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Sensitivity analysis 3: adjusted Cox-PH
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.415 [6]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.84
         upper limit
    		 1.53
    Notes
    [6] - This analysis was adjusted for weight, gender, whether it is a patients’ first seizure, site of initial access, and whether any additional anticonvulsants were administered alongside the infusion.

    Other pre-specified: Sensitivity analysis 4

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    End point title
    		 Sensitivity analysis 4
    End point description
    Time to seizure cessation using Gray’s test for competing risks where the competing risk is RSI
    End point type
    Other pre-specified
    End point timeframe
    24 hours from randomisation
    End point values
    		 Levetiracetam Phenytoin
    Number of subjects analysed
    152
    134
    Units: Seizure cessation
        Number of events (seizure cessation)
    106
    86
        Number of competing events (RSI)
    46
    48
    Statistical analysis title
    		 Sensitivity analysis 4
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1735
    Method
    		 Fine and Gray
    Confidence interval
    Statistical analysis title
    		 Sensitivity analysis 4: adjusted Fine and Gray
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    286
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.299 [7]
    Method
    		 Fine and Gray model
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.87
         upper limit
    		 1.57
    Notes
    [7] - This analysis was adjusted for weight, gender, whether it is a patients’ first seizure, site of initial access, and whether any additional anticonvulsants were administered alongside the infusion.

    Other pre-specified: Sensitivity analysis 5

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    End point title
    		 Sensitivity analysis 5
    End point description
    Time to seizure cessation excluding patients with imputed times
    End point type
    Other pre-specified
    End point timeframe
    24 hours from randomisation
    End point values
    		 Levetiracetam Phenytoin
    Number of subjects analysed
    150
    132
    Units: Seizure cessation
        Number of events (seizure cessation)
    105
    84
        Number of censored times (RSI)
    45
    48
    Statistical analysis title
    		 Sensitivity analysis 5
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1534
    Method
    		 Logrank
    Confidence interval
    Statistical analysis title
    		 Sensitivity analysis 5: adjusted Cox-PH
    Comparison groups
    Levetiracetam v Phenytoin
    Number of subjects included in analysis
    282
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.258 [8]
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.19
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.88
         upper limit
    		 1.59
    Notes
    [8] - This analysis was adjusted for weight, gender, whether it is a patients’ first seizure, site of initial access, and whether any additional anticonvulsants were administered alongside the infusion. Site was included in the model as a random effect.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All adverse events occurring from randomisation until 24 hours after the second-line treatment infusion has started.
    Adverse event reporting additional description
    If death or organ failure is noted at the 14 day safety follow up this should be recorded on the ‘14 day follow up’ CRF, however, no additional reporting is required unless the local investigator feels that the event(s) are related to the study medication.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18
    Reporting groups
    Reporting group title
    Levetiracetam
    Reporting group description
    		 Patients receiving Levetiracetam.

    Reporting group title
    Phenytoin
    Reporting group description
    		 Patients receiving Phenytoin

    Reporting group title
    Levetiracetam and Phenytoin
    Reporting group description
    		 Patients receiving Levetiracetam and Phenytoin.

    Serious adverse events
    		 Levetiracetam Phenytoin Levetiracetam and Phenytoin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 132 (0.76%)
    2 / 130 (1.54%)
    1 / 24 (4.17%)
         number of deaths (all causes)
    0
    0
    2
         number of deaths resulting from adverse events
    0
    0
    1
    Vascular disorders
    Hypotension
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 130 (0.77%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 130 (0.00%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 130 (0.77%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intracranial pressure increased
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 130 (0.00%)
    1 / 24 (4.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Device malfunction
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 130 (0.77%)
    0 / 24 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Levetiracetam Phenytoin Levetiracetam and Phenytoin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 132 (12.12%)
    18 / 130 (13.85%)
    4 / 24 (16.67%)
    Injury, poisoning and procedural complications
    Mechanical ventilation complication
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 130 (0.77%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Vascular disorders
    Hypotension
         subjects affected / exposed
    2 / 132 (1.52%)
    3 / 130 (2.31%)
    1 / 24 (4.17%)
         occurrences all number
    2
    3
    1
    Hypertension
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 130 (1.54%)
    0 / 24 (0.00%)
         occurrences all number
    0
    2
    0
    Pallor
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 130 (0.77%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    1 / 132 (0.76%)
    3 / 130 (2.31%)
    1 / 24 (4.17%)
         occurrences all number
    1
    3
    1
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 130 (0.77%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Extravasation
         subjects affected / exposed
    0 / 132 (0.00%)
    4 / 130 (3.08%)
    1 / 24 (4.17%)
         occurrences all number
    0
    4
    1
    Catheter site related reaction
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 130 (0.77%)
    2 / 24 (8.33%)
         occurrences all number
    1
    1
    3
    Adverse reaction
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 130 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    Infusion site erythema
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 130 (0.77%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 130 (0.77%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Stridor
         subjects affected / exposed
    0 / 132 (0.00%)
    0 / 130 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    Wheezing
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 130 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 132 (1.52%)
    1 / 130 (0.77%)
    0 / 24 (0.00%)
         occurrences all number
    2
    1
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    11 / 132 (8.33%)
    4 / 130 (3.08%)
    0 / 24 (0.00%)
         occurrences all number
    11
    4
    0
    Confusional state
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 130 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Hallucination
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 130 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Apr 2015
    Protocol was updated to ensure key processes are clear within the protocol, such as screening, randomisation and consent. Patient follow up was also increased to 14 days following request of the EcLiPSE TSC. Minor typographical errors and clarifications were also made throughout to ensure consistency. Please refer to section 19.2 of the protocol to see the summary of changes.
    17 Jun 2015
    Protocol updated to clarify that the concentrations are a maximum of 10mg/mL and 50mg/mL for phenytoin and levetiracetam, respectively.
    27 Aug 2015
    Protocol was updated to increase the maximum dose of phenytoin to 2000mg and consequentially, the infusion times for phenytoin have also been increased. The increase in the maximum dose for phenytoin aligns with the maximum dose in the adult BNF and standard practise at some sites. The following updates were also made to the consent study: 1) Online questionnaire now available for completion. 2) Clarify that both parents can complete the questionnaire. 3) Allow the consent study team to follow up on missing consent study questionnaires if they are contacting families for consent study follow up, providing consent has been obtained for this. 4) Face-to-face interviews to occur when families live in (or close to) the Merseyside area, if this is preferred by the families.
    05 Apr 2017
    The protocol was updated to clarify the randomisation and consent process. This namely included additional information relating to timescales of obtaining consent and the follow up of non-treated participants. The distribution of a questionnaire to non-treated participants was added. Following this update, it was determined that participants classed as “non treated” would not be included in the trial recruitment figure. The protocol update provided clarification on the route of trial treatment administration and confirmation of the Levetiracetam and Phenytoin SmPC. The process for any serious breaches, protocol deviations and urgent safety measures was also added.

    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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