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

Sponsor

Sohag University (Other)

Overall Status

Recruiting

CT.gov ID

NCT04926844

Collaborator

(none)

144

Enrollment

Location

Arms

11.4

Anticipated Duration (Months)

12.7

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Status Epilepticus Generalized Convulsive Status Epilepticus Status Epilepticus, Generalized Status Epilepticus, Generalized Convulsive	Drug: Levetiracetam Drug: Midazolam Drug: Placebo	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

144 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention 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.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 (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Each enrolled child will be assigned a unique identification number. Pharmacy will fill the active and placebo preparations in similar containers with sealed code for identification. Participants' families, treating clinicians, and investigators will be unaware of group assignment and drug/placebo therapy.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Jun 20, 2021

Anticipated Primary Completion Date :

May 1, 2022

Anticipated Study Completion Date :

Jun 1, 2022

Arms and Interventions

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

Arm

Intervention/Treatment

Experimental: Study group

Children receiving levetiracetam + midazolam

Drug: Levetiracetam

Intravenous levetiracetam 60 mg/kg (max 4500 mg) over 5 minutes (diluted with isotonic saline to a concentration of 50 mg/ml).

Other Names:

Keppra

Tiratam

Drug: Midazolam

Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes

Placebo Comparator: Control group

Children receiving placebo + midazolam

Drug: Midazolam

Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes

Drug: Placebo

Intravenous isotonic saline (1.2 ml/kg) over 5 minutes

Outcome Measures

Primary Outcome Measures

Cessation of seizures [20 minutes]
Cessation of clinical seizures at 20 minutes timepoint (end of first therapy phase)

Secondary Outcome Measures

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

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Month to 16 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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