Combined Ketamine and Midazolam for Generalized Convulsive Status Epilepticus

NCT05779657 | Completed Phase 2

• 1 other identifier: Soh-Med-23-03-12MS
• Study Type: interventional
• Target: 144
• Locations: 1 country
• Sites: 1

Brief Summary

Generalized convulsive status epilepticus (GCSE) is a common neurological emergency in children. Benzodiazepines are the recommended first line antiseizure medication (ASMs), but they fail to control seizures in a third of cases. Combination of benzodiazepines with another ASM that has a different mechanism of action may be a promising option for faster control of GCSE. In this study, the investigators aim to evaluate the efficacy and safety of ketamine plus midazolam versus midazolam alone as first-line therapy of pediatric GCSE.

Conditions

Generalized Convulsive Status Epilepticus

Keywords

Status epilepticus; Ketamine; Drug combination; Children; Pediatric

Outcome Measures

Primary Outcomes (1)

• Cessation of seizures at 5 minutes

  Cessation of clinical seizures at 5 minutes study timepoint

  5 minutes

Secondary Outcomes (12)

• Need for repeating midazolam

  15 minutes

• Cessation of seizures at 15 minutes

  15 minutes

• Cessation of seizures at 35 minutes

  35 minutes

• Cessation of seizures at 55 minutes

  55 minutes

• Seizure recurrence

  24 hours

Study Arms (2)

Study group (Ket-Mid)

EXPERIMENTAL

Children receiving ketamine + midazolam

Drug: Ketamine; Drug: Midazolam

Control group (Pla-Mid)

PLACEBO COMPARATOR

Children receiving placebo + midazolam

Drug: Midazolam; Drug: Placebo

Interventions

Ketamine DRUG

Intravenous ketamine 2 mg/kg (max 60 mg) over 2 minutes (diluted with isotonic saline to 5 mg/ml concentration)

Also known as: Ketalar

Study group (Ket-Mid)

Midazolam DRUG

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

Control group (Pla-Mid); Study group (Ket-Mid)

Placebo DRUG

Intravenous isotonic saline 0.4 ml/kg (max 12 ml) over 5 minutes

Control group (Pla-Mid)

Eligibility Criteria

• Age: 6 Months - 16 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age from 6 month to 16 years.
• Generalized convulsive status epilepticus, defined as \> 5 minutes of clinically observed continuous or recurrent generalized, tonic-clonic seizure activity without regaining of consciousness.

You may not qualify if:

• Failure to obtain informed consent.
• Previous treatment with any antiseizure medication for the presenting seizure episode.
• Hypertension
• Alcohol intake
• Conditions associated with increased intracranial pressure (e.g., central nervous system mass lesions, hydrocephalus)
• Glaucoma
• Known allergy or contraindications to any of the study drugs.
• End-stage kidney disease.
• End stage liver disease
• Arrhythmia, severe heart disease, or pulmonary hypertension.
• Hyperthyroidism
• Pheochromocytoma
• Hypoglycemia or hyperglycemia.
• Inborn errors of metabolism.
• Known or suspected psychiatric disorder.

Sponsors & Collaborators

• Sohag University: lead

Study Sites (1)

Sohag University Hospital

Sohag, 82524, Egypt

Location

Related Publications (10)

• Trinka E, Cock H, Hesdorffer D, Rossetti AO, Scheffer IE, Shinnar S, Shorvon S, Lowenstein DH. A definition and classification of status epilepticus--Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia. 2015 Oct;56(10):1515-23. doi: 10.1111/epi.13121. Epub 2015 Sep 4.

  PMID: 26336950 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

• 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

• Naylor DE. Treating acute seizures with benzodiazepines: does seizure duration matter? Epileptic Disord. 2014 Oct;16 Spec No 1:S69-83. doi: 10.1684/epd.2014.0691.

  PMID: 25323468 BACKGROUND

• Rosati A, L'Erario M, Ilvento L, Cecchi C, Pisano T, Mirabile L, Guerrini R. Efficacy and safety of ketamine in refractory status epilepticus in children. Neurology. 2012 Dec 11;79(24):2355-8. doi: 10.1212/WNL.0b013e318278b685. Epub 2012 Nov 28.

  PMID: 23197747 BACKGROUND

• Gaspard N, Foreman B, Judd LM, Brenton JN, Nathan BR, McCoy BM, Al-Otaibi A, Kilbride R, Fernandez IS, Mendoza L, Samuel S, Zakaria A, Kalamangalam GP, Legros B, Szaflarski JP, Loddenkemper T, Hahn CD, Goodkin HP, Claassen J, Hirsch LJ, Laroche SM. Intravenous ketamine for the treatment of refractory status epilepticus: a retrospective multicenter study. Epilepsia. 2013 Aug;54(8):1498-503. doi: 10.1111/epi.12247. Epub 2013 Jun 12.

  PMID: 23758557 BACKGROUND

• Niquet J, Baldwin R, Norman K, Suchomelova L, Lumley L, Wasterlain CG. Midazolam-ketamine dual therapy stops cholinergic status epilepticus and reduces Morris water maze deficits. Epilepsia. 2016 Sep;57(9):1406-15. doi: 10.1111/epi.13480. Epub 2016 Aug 8.

  PMID: 27500978 BACKGROUND

• Martin BS, Kapur J. A combination of ketamine and diazepam synergistically controls refractory status epilepticus induced by cholinergic stimulation. Epilepsia. 2008 Feb;49(2):248-55. doi: 10.1111/j.1528-1167.2007.01384.x. Epub 2007 Oct 15.

  PMID: 17941842 BACKGROUND

• Buratti S, Giacheri E, Palmieri A, Tibaldi J, Brisca G, Riva A, Striano P, Mancardi MM, Nobili L, Moscatelli A. Ketamine as advanced second-line treatment in benzodiazepine-refractory convulsive status epilepticus in children. Epilepsia. 2023 Apr;64(4):797-810. doi: 10.1111/epi.17550. Epub 2023 Mar 2.

  PMID: 36792542 BACKGROUND

• Sidharth, Sharma S, Jain P, Mathur SB, Malhotra RK, Kumar V. Status Epilepticus in Pediatric patients Severity Score (STEPSS): A clinical score to predict the outcome of status epilepticus in children- a prospective cohort study. Seizure. 2019 Oct;71:328-332. doi: 10.1016/j.seizure.2019.09.005. Epub 2019 Sep 11.

  PMID: 31536850 BACKGROUND

MeSH Terms

Conditions

Status Epilepticus

Interventions

Ketamine; Midazolam

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Cyclohexanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Abdelrahim A Sadek, MD, PhD

  Faculty of Medicine, 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: Enrolled children will be equally randomized into study and control group using computer generated numbers, which will be sealed into sequentially numbered opaque envelopes by a person not belonging to the research team. For each enrolled participant, the envelope in order will be opened, and the assigned study drug will be used. A pharmacist 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: Principal Investigator

Model Details: Two groups of children with continuing seizures after stabilization phase (5 minutes) Study group (Ket-Mid): will receive intravenous ketamine 2 mg/kg (max 60 mg) over 2 minutes. Control group (Pla-Mid): 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: March 9, 2023
• First Posted: March 22, 2023
• Study Start: March 21, 2023
• Primary Completion: August 26, 2024
• Study Completion: August 30, 2024
• Last Updated: October 29, 2024

Record last verified: 2024-10

Data Sharing

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

Locations

EG (1)