The Benefit and Safety of Older Generation Anti-Epileptic Drugs (AEDs) in Drug-Resistant Epilepsy Children

Study Overview
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Brief Summary
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The goal of this interventional study is to learn about the efficacy and safety of first line anti epileptic drugs (AEDs) as substitution therapy for children who are resistant to second-line AEDs. The main question to answer it aims are : how much the difference proportion of responders (responders are children who achieve the decrease of seizure frequencies by 50%) how much time it is needed to achieve the decrease of seizure frequencies by 50% The patients who are eligible for the study and have given their consent, will be enrolled, divided into 2 groups, the control and intervention. The participant should follow the 14 weeks of intervention that consists of 6 phases : baseline, initial dose, titration dose, maintenance dose, tapering-off dose, and new combination maintenance dose.

Detailed Description
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Each phase of the study is described below In baseline phase, data such as demographic, clinical characteristic including seizure frequency, seizure type, seizure onset, medication history, family history of seizure, and also developmental stages, will be recorded from electronic medical record. Besides, the CT-scan or MRI are also collected from the same source. After that, their quality of life will be assessed by QOLCE-55 validated questionnaire through self-guided report. Furthermore, the laboratory investigation and EEG will be performed. The next phase is intervention phase, started from initial phase and ended by the maintenance of new combination therapy phase, takes with overall 12 weeks. Initially, the substitution drugs with each initial dose are consumed. The drugs consist of valproic acid for the generalized and carbamazepine for focal epilepsies. On the other hand, the control group will take lamotrigine or clobazam for generalized and oxcarbazepine for focal ones. The phase continuous to titration dose, in which, the dose is raised gradually until it causes 50% of seizure reduction, and the next step is maintained the dose for about 2 weeks. - The following is tapering-off and after that stopping the substituted drug, levetiracetam or topiramate, which is determined by considering individual condition. Yet, if the seizures increase more than one and a half time of the previous frequency during the phases, the intervention will be ended immediately. On the contrary, if the condition is better, then the children go to the maintenance of new combination, that is the substitution drug and the old drugs in which the seizures do not go up or even better keep going down.

Official Title
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The Efficacy and Safety of First-Line Anti-Epileptic Drugs (AEDs) as Substitution Therapy in Children Who Are Resistant to Second-Line AEDs

Conditions
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Drug Resistant Epilepsy

Intervention / Treatment
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* Drug: Valproic acid
* Drug: Carbamazepin
* Drug: Phenytoin
* Drug: Lamotrigine
* Drug: Clobazam
* Drug: Oxcarbazepine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Children age at 1 - 18 years old Children diagnosed as drug-resistant epilepsy by pediatric neurologists, diagnosis was based on the ILAE 2017 criteria Children will have got at least 3 months of combination therapy that consists of levetiracetam of topiramate with optimal dosage but haven't got seizure reduction Exclusion Criteria: Non-convulsive epilepsy Suffered from status epilepticus in the prior 3 months before the study begins Past medical history of idiosyncrasies or severe adverse drug reactions caused by the substitution therapy that will be given

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The subjects will be randomized into 2 groups : intervention and control. The subjects will be recruited by consecutive sampling technique
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: intervention<br>valproic acid 15 - 60 mg/kg body weight/day, divided into 2 dosages/day for 12 weeks ; carbamazepine 10 - 30 mg/kg body weight/day, divided into 2 dosages/day for 12 weeks ; phenytoin 5-7 mg/kg body weight/day, divided into 2 dosages/day for 12 weeks | Drug: Valproic acid<br>* valproic acid is used for general epilepsy type, used in experimental group<br>* Other names: depaken;Drug: Carbamazepin<br>* carbamazepine is used for focal type epilepsy, used in experimental group<br>* Other names: bamgetol;Drug: Phenytoin<br>* phenytoin is used for both general or focal epilepsy in case valproic acid or carbamazepine is contraindicated, used in experimental group<br>* Other names: kutoine;|
| Active Comparator: control<br>lamotrigine 0.2 mg/kg body weight/day, divided into 2 dosages/day for 12 weeks ; clobazam 0.1 - 0.8 body weight/day, divided into 2 dosages/day for 12 weeks ; oxcarbazepine10 - 30 mg/kg body weight/day, divided into 2 dosages/day for 12 weeks | Drug: Lamotrigine<br>* lamotrigine is used for general epilepsy type, used in control group<br>* Other names: lamictal;Drug: Clobazam<br>* clobazam is used for both general or focal epilepsy in case if lamotrigine or oxcarbazepine is not possible to be administered and is used particularly in myoclonic jerk , used in control group<br>* Other names: frisium;Drug: Oxcarbazepine<br>* oxcarbazepine is used for focal type epilepsy, used in control group<br>* Other names: trileptal;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| the different proportion of responders between groups who get first-line anti-epileptic drugs (intervention) and second-line anti-epileptic drugs (control) | responders are children who get the reduction of seizure frequency by 50% | trough the study completion, about 14 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| time to achieve the reduction of seizure frequency by 50% or more among responders | time that is counted in week and is divided into 3 categories , 2-<4 weeks, 4-<8 weeks and 8-12 weeks | during intervention, about 12 weeks | 
| the difference of quality of life between groups who get first-line anti-epileptic drugs (intervention) and second-line anti-epileptic drugs (control) | quality of life is assessed by validated instrument QOLCE-55. It has 55 questions including cognitive (22 items), emotional (17 items), social (7 items) and also physical (9 items) function. Items are rated on a five-point Likert scale, 0 = very often, 1 = fairly often, 2 = sometime, 3 = almost never, 5 = never. The composite score is the unweighted average of the four subscales, ranging from 1-100, higher score indicates better quality of life. b. Differences in quality of life: quality of life assessment using QOLCE-55 instrument. The average of each function (cognitive, emotional, social and physical functions) and the average of the total functions are assessed. This variable is categorized into: Different, if there is a difference in the average quality of life Not different, if there is no difference in the average quality of life | at baseline phase in the 1st week (before intervention) and after intervention in the 14th week | 
| the difference of the electroencephalography (EEG) changing between groups who get first-line anti-epileptic drugs (intervention) and second-line anti-epileptic drugs (control) | The EEG examination is operated two times, at the baseline and post intervention phase, with high density machine (Caldwell Easy III) is done twice, pre- and post-intervention. The machine will operate for about 45 minutes including 5 minutes each for eye-open and eye-close in every subjects. Beginning with acquisition, EEG recordings use standard parameter to analyze brain activity at various frequencies to gain good quality and artefact-free result. The printed results of the EEG is available for about 4-7 days after the examination. EEG recording results are categorized into: Normal : does not show of hypofunction/asymmetry/epileptiform waves Abnormal: shows a picture of hypofunction/asymmetry/epileptiform waves or a combination of 1 or more of these features The subjects who show changes in their EEG are later grouped into groups of abnormal to normal or abnormalities that showed improvement. Abnormalities that show improvement, for example are hypofunction (slowing down) | at baseline phase in the 1st week (before intervention) and after intervention in the 14th week | 
| the description of age in percentage | the data is taken from electronic medical record, age is categorized into <5 years, 5-<10 years, and >/= 10 years | at baseline phase in the 1st week (before intervention) | 
| the description of seizure onset in percentage | the data is taken from electronic medical record, seizure onset is categorized into <5 years, 5-<10 years, and >/= 10 years | at baseline phase in the 1st week (before intervention) | 
| the description of gender in percentage | the data is taken from electronic medical record, gender is categorized into male and female | at baseline phase at 1st week (before intervention) | 
| the description duration of anti epileptic drug medication | the data is taken from electronic medical record, the duration is categorized into <1 year , 1 - <2 year, 2 - 5 year, and > 5 year | at baseline phase at 1st week (before intervention) | 
| The brain CT or brain MRI | The brain CT or brain MRI are taken from electronic medical record, categorized into normal and abnormal findings. it is categorized as normal if the brain, liquor cerebrospinal and skull is within normal range (no deformation of skull, no hydrocephalus, the brain volume is normal, and no signs of infection such as enhancement, no hemorrhage, no calcification) | at baseline phase at 1st week (before intervention) | 
| The adverse drug reaction profile in percentage | The adverse drug reaction profile are taken from the diary card, it is categorized into neurology system, gastrointestinal system, musculocutaneous system, renal function, liver function and electrolyte | during intervention, about 12 weeks | 
| seizure frequency | the frequency is how many times in a month, it is categorized into <5 times, 5-10 times, 10-20 times and > 20 times | during intervention, about 12 weeks | 
| the history of developmental delayed | the data is taken from electronic medical record, categorized into yes or no. it is named as delayed if the development does not follow the milestone in one or more developmental sectors (language, gross motor skill, fine motor skill, personal social) | at baseline phase at 1st week (before intervention) | 
| the number of anti-epileptic drug is consumed | the data is taken from electronic medical record, it is categorized into 2 , 3 , or >3 drugs | at baseline phase at 1st week (before intervention) | 
| the history of seizure in the family | the data is taken from electronic medical record, it is categorized into yes or no | at baseline phase at 1st week (before intervention) | 
| the association between age and seizure reduction | the age is categorized into <5 years, 5-<10 years, and >/= 10 years ; seizure reduction is categorized into responder and non-responder | after intervention in the 14th week | 
| the association between seizure onset and seizure reduction | seizure onset is categorized into <5 years, 5-<10 years, and >/= 10 years ; seizure reduction is categorized into responder and non-responder | after intervention in the 14th week | 
| the association between gender and seizure reduction | gender is categorized into male and female ; seizure reduction is categorized into responder and non-responder | after intervention in the 14th week | 
| the association between duration of anti epileptic drug medication and seizure reduction | he duration is categorized into <1 year , 1 - <2 year, 2 - 5 year, and > 5 year ; seizure reduction is categorized into responder and non-responder | after intervention in the 14th week | 
| the association of the brain CT or brain MRI and seizure reduction | the brain CT or brain MRI categorized into normal and abnormal findings. it is categorized as normal if the brain, liquor cerebrospinal and skull is within normal range (no deformation of skull, no hydrocephalus, the brain volume is normal, and no signs of infection such as enhancement, no hemorrhage, no calcification). Seizure reduction is categorized into responder and non-responder | after intervention in the 14th week | 
| the association of seizure frequency and seizure reduction | the frequency is how many times in a month, it is categorized into <5 times, 5-10 times, 10-20 times and > 20 times. Seizure reduction is categorized into responder and non-responder | after intervention in the 14th week | 
| the association between the history of developmental delayed and seizure reduction | the history of developmental delayed is categorized into yes or no. it is named as delayed if the development does not follow the milestone in one or more developmental sectors (language, gross motor skill, fine motor skill, personal social). Seizure reduction is categorized into responder and non-responder | after intervention in the 14th week | 
| the association of the number of anti-epileptic drug is consumed and seizure reduction | number of anti-epileptic drug consumed is categorized into 2 , 3 , or >3 drugs. Seizure reduction is categorized into responder and non-responder | after intervention in the 14th week | 
| the association between the history of seizure in the family and seizure reduction | the history of seizure in the family is categorized into yes or no. Seizure reduction is categorized into responder and non-responder | after intervention in the 14th week | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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anti-epilepsy drug, children, epilepsy, resistant