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

NCT04926844 | Completed Phase 2

• 1 other identifier: Soh-Med-21-06-07
• Study Type: interventional
• Target: 144
• Locations: 1 country
• Sites: 1

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.

Conditions

Status Epilepticus; Generalized Convulsive Status Epilepticus; Status Epilepticus, Generalized; Status Epilepticus, Generalized Convulsive

Keywords

Status epilepticus; Convulsions; Children; Seizures; Benzodiazepines; Midazolam; Levetiracetam

Outcome Measures

Primary Outcomes (1)

• Cessation of seizures

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

  20 minutes

Secondary Outcomes (8)

• Need for repeating midazolam

  20 minutes

• Cessation of seizures

  40 minutes

• Seizure control

  24 hours

• Hypotension

  24 hours

• Need for mechanical ventilation

  24 hours

Study Arms (2)

Study group

EXPERIMENTAL

Children receiving levetiracetam + midazolam

Drug: Levetiracetam; Drug: Midazolam

Control group

PLACEBO COMPARATOR

Children receiving placebo + midazolam

Drug: Midazolam; Drug: Placebo

Interventions

Levetiracetam DRUG

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

Also known as: Keppra, Tiratam

Study group

Midazolam DRUG

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

Control group; Study group

Placebo DRUG

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

Control group

Eligibility Criteria

• Age: 1 Month - 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Sohag University: lead

Study Sites (1)

Department of Pediatrics - Sohag University Hospital

Sohag, 82524, Egypt

Location

Related Publications (10)

• Glauser T, Shinnar S, Gloss D, Alldredge B, Arya R, Bainbridge J, Bare M, Bleck T, Dodson WE, Garrity L, Jagoda A, Lowenstein D, Pellock J, Riviello J, Sloan E, Treiman DM. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr. 2016 Jan-Feb;16(1):48-61. doi: 10.5698/1535-7597-16.1.48.

  PMID: 26900382 BACKGROUND

• McKenzie KC, Hahn CD, Friedman JN. Emergency management of the paediatric patient with convulsive status epilepticus. Paediatr Child Health. 2021 Jan 21;26(1):50-66. doi: 10.1093/pch/pxaa127. eCollection 2021 Feb.

  PMID: 33552322 BACKGROUND

• Singh A, Stredny CM, Loddenkemper T. Pharmacotherapy for Pediatric Convulsive Status Epilepticus. CNS Drugs. 2020 Jan;34(1):47-63. doi: 10.1007/s40263-019-00690-8.

  PMID: 31879852 BACKGROUND

• Hamano SI, Sugai K, Miki M, Tabata T, Fukuyama T, Osawa M. Efficacy, safety, and pharmacokinetics of intravenous midazolam in Japanese children with status epilepticus. J Neurol Sci. 2019 Jan 15;396:150-158. doi: 10.1016/j.jns.2018.09.035. Epub 2018 Oct 4.

  PMID: 30472551 BACKGROUND

• Navarro V, Dagron C, Elie C, Lamhaut L, Demeret S, Urien S, An K, Bolgert F, Treluyer JM, Baulac M, Carli P; SAMUKeppra investigators. Prehospital treatment with levetiracetam plus clonazepam or placebo plus clonazepam in status epilepticus (SAMUKeppra): a randomised, double-blind, phase 3 trial. Lancet Neurol. 2016 Jan;15(1):47-55. doi: 10.1016/S1474-4422(15)00296-3. Epub 2015 Nov 28.

  PMID: 26627366 BACKGROUND

• Alvarez V, Rossetti AO. Monotherapy or Polytherapy for First-Line Treatment of SE? J Clin Neurophysiol. 2016 Feb;33(1):14-7. doi: 10.1097/WNP.0000000000000217.

  PMID: 26840871 BACKGROUND

• Lynch BA, Lambeng N, Nocka K, Kensel-Hammes P, Bajjalieh SM, Matagne A, Fuks B. The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam. Proc Natl Acad Sci U S A. 2004 Jun 29;101(26):9861-6. doi: 10.1073/pnas.0308208101. Epub 2004 Jun 21.

  PMID: 15210974 BACKGROUND

• Klitgaard H, Pitkanen A. Antiepileptogenesis, neuroprotection, and disease modification in the treatment of epilepsy: focus on levetiracetam. Epileptic Disord. 2003 May;5 Suppl 1:S9-16.

  PMID: 12915336 BACKGROUND

• Misra UK, Kalita J, Maurya PK. Levetiracetam versus lorazepam in status epilepticus: a randomized, open labeled pilot study. J Neurol. 2012 Apr;259(4):645-8. doi: 10.1007/s00415-011-6227-2. Epub 2011 Sep 6.

  PMID: 21898137 BACKGROUND

• Sharpe C, Reiner GE, Davis SL, Nespeca M, Gold JJ, Rasmussen M, Kuperman R, Harbert MJ, Michelson D, Joe P, Wang S, Rismanchi N, Le NM, Mower A, Kim J, Battin MR, Lane B, Honold J, Knodel E, Arnell K, Bridge R, Lee L, Ernstrom K, Raman R, Haas RH; NEOLEV2 INVESTIGATORS. Levetiracetam Versus Phenobarbital for Neonatal Seizures: A Randomized Controlled Trial. Pediatrics. 2020 Jun;145(6):e20193182. doi: 10.1542/peds.2019-3182. Epub 2020 May 8.

  PMID: 32385134 BACKGROUND

MeSH Terms

Conditions

Status Epilepticus; Seizures

Interventions

Levetiracetam; Midazolam

Condition Hierarchy (Ancestors)

Neurologic Manifestations; Nervous System Diseases; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Acetamides; Amides; Organic Chemicals; Acetates; Acids, Acyclic; Carboxylic Acids; Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring

Study Officials

• Abdelrahim A Sadek, MD, PhD

  Sohag University

  STUDY CHAIR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Pediatric Resident

Model Details: Two groups of children with continuing seizures after stabilization phase (5 minutes): 1. 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). 2. 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.

Study Record Dates

• First Submitted: June 14, 2021
• First Posted: June 15, 2021
• Study Start: June 20, 2021
• Primary Completion: August 30, 2022
• Study Completion: September 1, 2022
• Last Updated: September 21, 2022

Record last verified: 2022-09

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL
• Time Frame: After publication for 3 years
• Access Criteria: Contact the principal investigator

Locations

EG (1)