Effectiveness of Combined Levetiracetam and Midazolam in Generalized Convulsive Status Epilepticus in Children

Study Overview
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Brief Summary
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Generalized status epilepticus is a common pediatric neurological emergency with significant mortality and morbidity. Benzodiazepines remain the first anticonvulsive line but benzo-diazepines don't control seizures in about 30% of cases. GCSE may be more rapidly stopped and controlled through combining another drug with benzodiazepines such as Levetiracetam, acting by different pathways. This study aims to evaluate the effectiveness of combined levetiracetam and midazolam in treatment of generalized convulsive status epilepticus in children.

Detailed Description
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Generalized convulsive status epilepticus (GCSE) is a common pediatric neurological emergency with an annual incidence of up to 73 episodes per 100,000 children and is associated with mortality in 2.7% of cases and overall morbidity in 10% - 20% of cases, including hemodynamic instability and long-term neurological impairments. The management of GCSE in children starts with emergency measures (stabilization phase) with monitoring and laboratory testing in the first 5 minutes. Benzodiazepines are used as first-line anticonvulsants for GCSE that persists for more than 5 minutes. However, studies have shown that benzo-diazepines don't control GCSE in about 30% of patients. GCSE may be more rapidly stopped and controlled through combining another drug with benzodiazepines, acting by different pathways. Levetiracetam is a recent broad-spectrum antiepileptic drug with a relatively high safety profile. The effectiveness of intravenous levetiracetam has been demonstrated as a second-line anticonvulsant in GCSE. In this study, we aim to evaluate the effectiveness and safety of levetiracetam plus midazolam versus midazolam alone as first-line therapy of GCSE in children.

Official Title
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Effectiveness of Combined Levetiracetam and Midazolam in Treatment of Generalized Convulsive Status Epilepticus in Children

Conditions
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Status Epilepticus, Generalized Convulsive Status Epilepticus, Status Epilepticus, Generalized, Status Epilepticus, Generalized Convulsive

Intervention / Treatment
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* Drug: Levetiracetam
* Drug: Midazolam
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Generalized convulsive status epilepticus, which is clinically defined at the time of presentation as continuous, generalized, tonic-clonic seizure activity or ≥ 2 generalized tonic-clonic seizures without recovery of consciousness for more than 5 minutes. Exclusion Criteria: Failure to obtain informed consent. Prior therapy with any anticonvulsant for the presenting episode of generalized convulsive status epilepticus. Epileptic patients on levetiracetam therapy. Known allergy or contraindications to any of the study drugs. End-stage kidney disease. Severe liver disease. Cardiac diseases. Hypoglycemia or hyperglycemia. Inborn errors of metabolism. Known mood/behavioral disorder. Failure to obtain intravenous access in the first 5 minutes. Cessation of seizures during the stabilization phase (0 - 5 minutes). Traumatic brain injury

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 16 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: Two groups of children with continuing seizures after stabilization phase (5 minutes): Study group; will receive intravenous levetiracetam 60 mg/kg (max 4500 mg) over 5 minutes (diluted with isotonic saline to a concentration of 50 mg/ml). Control group will receive intravenous isotonic saline (as a placebo) in the same way. At the same time, both groups will receive intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes.
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Study group<br>Children receiving levetiracetam + midazolam | Drug: Levetiracetam<br>* Intravenous levetiracetam 60 mg/kg (max 4500 mg) over 5 minutes (diluted with isotonic saline to a concentration of 50 mg/ml).<br>* Other names: Tiratam;Drug: Midazolam<br>* Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes<br>|
| Placebo Comparator: Control group<br>Children receiving placebo + midazolam | Drug: Midazolam<br>* Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes<br>Drug: Placebo<br>* Intravenous isotonic saline (1.2 ml/kg) over 5 minutes<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cessation of seizures | Cessation of clinical seizures at 20 minutes timepoint (end of first therapy phase) | 20 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Need for repeating midazolam | Need for repeating midazolam during the first therapy phase (5 - 20 min) | 20 minutes | 
| Cessation of seizures | Cessation of clinical seizures at 40 minutes timepoint (end of second therapy phase). | 40 minutes | 
| Seizure control | 24-hours seizure control (no visually observed recurrence of seizures after the end of second phase therapy with improved sensorium) | 24 hours | 
| Hypotension | Occurrence of hypotension | 24 hours | 
| Need for mechanical ventilation | Need for mechanical ventilation | 24 hours | 
| Skin rash | Occurrence of skin rash | 24 hours | 
| Agitation/aggression | Occurrence of agitation/aggression | 24 hours | 
| Mortality | Occurrence of death | 24 hours | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Status epilepticus, Convulsions, Children, Seizures, Benzodiazepines, Midazolam, Levetiracetam