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

Status Epilepticus Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04926844
• Other study ID #: Soh-Med-21-06-07
• Status: Completed
• Phase: Phase 2
• Start date: June 20, 2021
• Est. completion date: September 1, 2022

Study information

• Verified date: September 2022
• Source: Sohag University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 144
• Est. completion date: September 1, 2022
• Est. primary completion date: August 30, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 1 Month to 16 Years

Eligibility

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

Related Conditions & MeSH terms

• Generalized Convulsive Status Epilepticus
• Status Epilepticus

Intervention

Drug:
• Levetiracetam
Intravenous levetiracetam 60 mg/kg (max 4500 mg) over 5 minutes (diluted with isotonic saline to a concentration of 50 mg/ml).
• Midazolam
Intravenous midazolam 0.2 mg/kg (maximum 10 mg) over 2 minutes
• Placebo
Intravenous isotonic saline (1.2 ml/kg) over 5 minutes

Locations

Country	Name	City	State
Egypt	Department of Pediatrics - Sohag University Hospital	Sohag

Sponsors (1)

Lead Sponsor	Collaborator
Sohag University

Country where clinical trial is conducted

Egypt, 

References & Publications (10)

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. Review. — View Citation

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. — View Citation

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. — View Citation

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

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. Epub 2004 Jun 21. — View Citation

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. Review. English, French. — View Citation

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. — View Citation

Navarro V, Dagron C, Elie C, Lamhaut L, Demeret S, Urien S, An K, Bolgert F, Tréluyer 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. — View Citation

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). pii: e20193182. doi: 10.1542/peds.2019-3182. Epub 2020 May 8. Erratum in: Pediatrics. 2021 Jan;147(1):. — View Citation

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. Review. — View Citation

Outcome

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