Vigabatrin With High Dose Prednisolone Combination Therapy vs Vigabatrin Alone for Infantile Spasm

Study Overview
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Brief Summary
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Infantile spasms (IS) are seizures associated with a severe infantile epileptic encephalopathy. Both cessation of spasms and electrographic response are necessary for the best neurodevelopmental outcomes. Adrenocorticotrophic hormone (ACTH), or prednisolone, or vigabatrin are considered the first-line treatment individually. However, ACTH expense and availability are the barriers in developing countries including Thailand. Vigabatrin, therefore, is the first recommended by Epilepsy Society of Thailand due to ACTH unavailability. Recently, combined steroid treatments (either ACTH or high dose prednisolone) with vigabatrin are superior in cessation of spasms compared to steroid treatment alone. Thus, this study is aimed to compare the efficacy of vigabatrin with high dose prednisolone combination therapy and vigabatrin alone.

Detailed Description
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Infantile spasms are recognized as epileptic encephalopathy which include the hypsarrhythmia or variants electroencephalographic (EEG) features and psychomotor regression. Various underlying conditions are associated with the infantile spasm included cerebral malformation, hypoxic ischemic encephalopathy, genetic disorders (Down syndrome), tuberous sclerosis complex (TSC), etc. Although vigabatrin has the evidence to use as the first line treatment for infantile spasm related with TSC. Adrenocorticotrophic hormone (ACTH), or high dose prednisolone, or vigabatrin are the first line treatment of IS in non-TSC. The effectiveness of ACTH versus high dose prednisolone question have not yet definitely answered. Furthermore, ACTH expense and availability are the barriers in developing countries including Thailand. Vigabatrin, therefore, is the first option of therapy recommended by Epilepsy Society of Thailand due to ACTH unavailability. Recently, combined steroid treatments (either ACTH or high dose prednisolone) with vigabatrin are superior in cessation of spasms compared to steroid treatment alone. Questions about the clinical cessation of IS and electrographic remission by combination treatment with vigabatrin and high dose prednisolone compare to vigabatrin alone have not fully elucidated. Thus, this study is aimed to compare the efficacy of vigabatrin with high dose prednisolone combination therapy and vigabatrin alone.

Official Title
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Efficacy of Vigabatrin With High Dose Prednisolone Combination Therapy Versus Vigabatrin Alone for Infantile Spasm: a Randomized Trial

Conditions
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Infantile Spasm, West Syndrome

Intervention / Treatment
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* Drug: Combination therapy with vigabatrin and prednisolone
* Drug: Vigabatrin Tablets


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age at 2-14 months at date of enrollment Clinical diagnosis of infantile spasm assessed by pediatric neurologist and hypsarrhythmic pattern or variants interpreted by pediatric epileptologist Thai nationality Exclusion Criteria: Previous treatment (within the last 28 days) with vigabatrin or corticosteroid Previous diagnosis of epileptic encephalopathy e.g. early infantile epileptic encephalopathy and early myoclonic epileptic encephalopathy Has a clinical suspicious or diagnosis of tuberous sclerosis complex characterized by one of these; known affected parent, previously diagnosed cardiac rhabdomyoma, hypomelanotic macules, forehead fibrous plaque, shagreen patch, retinal phakoma, or known polycystic kidneys A contraindication to vigabatrin or corticosteroid such as recent varicella or herpes zoster infection, gastrointestinal hemorrhage etc. Thai language ability of the parents or guardians is that they may not understand what is being requested of them. Predictable lack of availability of follow up

Ages Eligible for Study
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Minimum Age: 2 Months
Maximum Age: 14 Months

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: A pragmatic parallel group randomised trial comparing vigabatrin with high dose prednisolone to vigabatrin treatment alone in the treatment of infantile spasm.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Combination therapy with vigabatrin and prednisolone<br>Vigabatrin (tablet of 500 mg) dose based on weight divided in two times. The protocol for vigabatrin dose is 50 mg/kg/day at Day 1, 100 mg/kg/day at Day 2, and increase to 150 mg/kg/day if seizures still occur after 72 hours after treatment. Vigabatrin will be continued for 3 months, then reduced and completely off within 4 weeks. Prednisolone (tablet of 5 mg), 40 mg of prednisolone (10 mg oral 4 times a day) for 14 days. Prednisolone will be increased to 60 mg/day (20 mg oral 3 times a day) if seizures still occur at Day 7 or recur within Day 8 - 14. Then, prednisolone will be reduced every 5 day until completely off within 1 month. Total prednisolone duration is 1 month. | Drug: Combination therapy with vigabatrin and prednisolone<br>* High dose prednisolone (40 - 60 mg/day) for 1 month combined with vigabatrin treatment (50-150 mg/kg/day) twice daily for 4 months<br>* Other names: Sabril with prednisolone;|
| Active Comparator: Vigabatrin alone<br>Vigabatrin (500 mg/tab) dose will be calculated on weight basis divided in two times. The protocol for vigabatrin dose is 50 mg/kg/day at Day 1, 100 mg/kg/day at Day 2, and increase to 150 mg/kg/day if seizures still occur after 72 hours after treatment. Vigabatrin will be continued for 3 months, then reduced and completely off within 4 weeks. | Drug: Vigabatrin Tablets<br>* Vigabatrin (50-150 mg/kg/day) twice daily for 4 months<br>* Other names: Sabril;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cessation of spasms | Defined as no witnessed spasms (either clusters or single spasms) from Day 14 to Day 42 inclusive. | Assessed during Day 14 to Day 42 after treatment. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Electrographic response | Disappearance of hypsarrhythmia defined by Burden of Amplitudes and Epileptiform Discharges (BASED) scoring system < 2 at Day 14 and Day 43 after treatment. | Assessed during Day 14 and Day 43 after treatment. | 
| Electroclinical response | the cessation of spasms with the addition of absence of hypsarrhythmia (BASED score < 2) on the Day 14 EEG. Valid Day 14 EEGs will be undertaken between Day 14 and Day 21 inclusive. | Between Day 14 and Day 21. | 
| Extended electroclinical response | Electroclinical response with the addition of absence of hypsarrhythmia (BASED score < 2) on the Day 42 EEG. Valid Day 42 EEGs will be undertaken between Day 42 and Day 49 inclusive. | Between Day 42 and Day 49. | 
| The time taken to absence of spasms | Duration for clinical cessation of spasms after initiation treatment | Day 1 to Day 14 | 
| Relapse of spasms | Defined when a cluster of more than one spasm in reported after Day 42. No EEG is required. | Day 42 to 3 months after treatment | 
| Adverse reactions | Each adverse event will be evaluated by the principal investigator to determine whether in their view it is an adverse reaction. If considered an adverse reaction, it will be reported by using the standard classification. | Day 1 to Day 14, from Day 15 to Day 42, and from Day 43 to 4 months into the trial | 
| Epilepsy outcome at age 18 months | Epilepsy status and antiepileptic drugs (AEDs) will be recorded by using the following categories: 1) Infantile spasms (clusters of spasms), 2) Any other epileptic seizure including febrile seizures, and 3) Names of any preventive AEDs prescribed | From Day 42 to age 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Infantile Spasm, Vigabatrin, Prednisolone, Treatment, West Syndrome