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

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

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.

Study Overview

• Status: Recruiting
• Conditions: Drug Resistant Epilepsy
• Intervention / Treatment: Drug: Valproic acid; Drug: Carbamazepin; Drug: Phenytoin; Drug: Lamotrigine; Drug: Clobazam; Drug: Oxcarbazepine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Anticipated): 100
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Roro Rukmi Windi Perdani Pediatrician; Phone Number: +6281373679940; Email: rororwp@gmail.com
• Study Contact Backup: Name: Wawaimuli Arozal Ph.D; Phone Number: +6281808408680; Email: wawaimuli@gmail.com

Study Locations

• Indonesia
  • Jakarta, Indonesia, 11420
    • Recruiting
    • Harapan Kita Hospital
    • Contact: R. Anna Tjandrajani; Phone Number: +628129114513
  • Jakarta, Indonesia, 12430
    • Recruiting
    • Fatmawati Hospital
    • Contact: Deddy Ria; Phone Number: +628121050511
  • Jakarta
    • Jakarta Pusat, Jakarta, Indonesia, 10430
      • Recruiting
      • Cipto Mangunkusumo Hospital
      • Contact: Irawan Mangunatmadja; Phone Number: +6281314578483; Email: Irawanma2802@gmail.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year to 18 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Children age at 1 - 18 years old
2. Children diagnosed as drug-resistant epilepsy by pediatric neurologists, diagnosis was based on the ILAE 2017 criteria
3. 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:

1. Non-convulsive epilepsy
2. 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
3. substitution therapy that will be given

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: intervention; 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; valproic acid is used for general epilepsy type, used in experimental group; Other Names: sodium divalproex; depaken; Drug: Carbamazepin; carbamazepine is used for focal type epilepsy, used in experimental group; Other Names: tegretol; bamgetol; Drug: Phenytoin; phenytoin is used for both general or focal epilepsy in case valproic acid or carbamazepine is contraindicated, used in experimental group; Other Names: kutoine
Active Comparator: control; 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; lamotrigine is used for general epilepsy type, used in control group; Other Names: lamictal; Drug: Clobazam; 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; Other Names: frisium; Drug: Oxcarbazepine; oxcarbazepine is used for focal type epilepsy, used in control group; Other Names: trileptal

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Dr Cipto Mangunkusumo General Hospital
• Investigators: Principal Investigator: Roro Rukmi Windi Perdani Pediatrician, Cipto Mangunkusumo Hopsital - Medical Faculty of Indonesia University

Study record dates

Study Major Dates

• Study Start (Anticipated): March 1, 2023
• Primary Completion (Anticipated): May 30, 2023
• Study Completion (Anticipated): June 30, 2023

Study Registration Dates

• First Submitted: November 28, 2022
• First Submitted That Met QC Criteria: January 14, 2023
• First Posted (Estimate): January 26, 2023

Study Record Updates

• Last Update Posted (Estimate): January 26, 2023
• Last Update Submitted That Met QC Criteria: January 14, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Keywords: epilepsy; children; resistant; anti-epilepsy drug
• Additional Relevant MeSH Terms: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Drug Resistant Epilepsy; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Central Nervous System Depressants; Peripheral Nervous System Agents; Enzyme Inhibitors; Analgesics; Sensory System Agents; Analgesics, Non-Narcotic; Antipsychotic Agents; Tranquilizing Agents; Psychotropic Drugs; Membrane Transport Modulators; Anti-Anxiety Agents; GABA Agents; Anticonvulsants; Voltage-Gated Sodium Channel Blockers; Sodium Channel Blockers; Antimanic Agents; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Calcium-Regulating Hormones and Agents; Calcium Channel Blockers; Cytochrome P-450 CYP3A Inducers; GABA-A Receptor Agonists; GABA Agonists; Lamotrigine; Valproic Acid; Carbamazepine; Oxcarbazepine; Phenytoin; Clobazam
• Other Study ID Numbers: 22-09-1097

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No