Fast Acute Sedation at Intensive Care vs. High-dose i.v. Anti-seizure Medication for Treatment of Non-convulsive Status Epilepticus (FAST-trial)

Study Overview
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Brief Summary
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This open-label, randomized multicenter trial aims at clarifying the standard of care of patients with non-convulsive status epilepticus not responding to treatment with benzodiazepines and at least one high-dose intra venous anti-seizure medication.

Detailed Description
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Persistent epileptic seizures, aka. status epilepticus (SE), are the second most common neurological cause of acute admissions. Around halv of the patients suffers from SE without prominent visible seizures (convulsions), which is referred to as non-convulsive status epilepticus (NCSE) and is afflicted with a long-term mortality of >50% also in patients without concomittant acute brain disease. There are no evidence-based treatment guidelines for NCSE but patients usually receive treatment with benzodiazepines followed by i.v. anti-seizure medication. If seizures continues, further treatment is controversial. The participating centers have long-standing experience in treating NCSE but use different, internationally accepted treatment strategies. Some initiate aggressive treatment with fast sedation at intensive care aiming at immediate seizure control, other estimate that the side effects of sediation does not outweigh the potential benefit and try high-dose i.v. anti-seizure medication that only slightly impair conciousness - often with success. This randomized, open label, multicenter trial (Eudract 2021-003392-34) aims at clarifying the treatment of patients with NSCE not responding to standard therapy. Patients with verified NCSE based on clinical parameter or using electroencephalography (EEG) are randomized into a fast acute sedation group and a group that receives at least one additional, high-dose anti-seizure mediciation. Primary objective endpoint is treatment failure 24 h after randomization as determined by EEG. Secondary endpoints are e.g. seizure-induced neurological damage, treatment-related complications and neurological long-term outcome. The statistical planing aims at showing superiority of aggressive treatment, 140 patients shall be included in a three years period at the University Hospitals in Aarhus, Odense, Roskilde and Copenhagen.

Official Title
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Fast Acute Sedation at Intensive Care vs. High-dose i.v. Anti-seizure Medication for Treatment of Non-convulsive Status Epilepticus (FAST-trial)

Conditions
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Non-Convulsive Status Epilepticus

Intervention / Treatment
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* Drug: Rapid sedation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult patients (older than 18 years) with EEG-verified NCSE, according to the Salzburg criteria, who have not responded to appropriate treatment with benzodiazepines and at least one 2nd line i.v. anti-seizure medication according to the current Danish national neurological treatment guidelines (Levetiracetam, Fosfenytoin or Valproate). Exclusion Criteria: patients with epilepticus status due to acute neuroinfection (e.g. bacterial meningitis or viral encephalitis) acute traumatic or spontaneous intracranial hemorrhage suspicion of cerebral anoxia / hypoxia / hypoglycemia / epileptic encephalopathy contraindications to anti-seizure medication defined in the protocol contraindications to anesthesia treatment in intensive care focal motor status epilepticus without relevant conscious influence (Glasgow Coma Scale> 13) known epileptic encephalopathy Clinical need for acute intubation

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 120 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: Comparison of two treatment strategies
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Non-sedative medical treatment<br>The patient is treated with an additional high-dose intravenous antiepileptic drug, which is selected by the treating neurologist. If NCSE continues to be detected at cEEG or clinically> 3 hours after starting treatment, the patient should receive standard treatment (i.e. sedation in the intensive care unit or addition of additional intravenous antiepileptic drugs) in accordance with local guidelines and the assessment of the treating neurologist. The following preparations are permitted as additional treatment: Levetiracetam (60 mg / kg as saturation dose followed by maintenance dose of 2-4 g / day), valproate (60 mg / kg as saturation dose followed by maintenance dose of 20 mg / kg / day), phosphenytoin (20 PE as saturation dose followed by maintenance dose 5 mg PE / kg / day), lacosamide (400 mg as a saturation dose followed by a maintenance dose of 200-400 mg / day), topiramate (200-400 mg per probe as a saturation dose followed by a maintenance dose of 200-400 mg / day). | |
| Experimental: Fast sedation<br>Within a maximum of 60 minutes after the diagnosis of NCSE (EEG or clinical), the patient must be sedated with high-dose Propofol (bolus 3-5 g / kg, maintenance dose 5-10 mg / kg / hour) to - 5 on the Richmond agitation sedation scale (RASS) for 20 hours, and a single anti-epileptic drug should be added as adjunctive therapy. Addition of low-dose Midazolam (max. 0.1 mg / kg / h) is permitted if deep sedation (defined clinically by RASS -5) is not possible with Propofol alone. After 20 hours, the sedation should be completely phased out within 3 hours. | Drug: Rapid sedation<br>* High-dose Propofol (bolus 3-5 g / kg, maintenance dose 5-10 mg / kg / hour) to - 5 on the Richmond agitation sedation scale (RASS) for 20 hours, and a single anti-epileptic drug should be added as adjunctive therapy. Addition of low-dose Midazolam (max. 0.1 mg / kg / h) is permitted if deep sedation (defined clinically by RASS -5) is not possible with Propofol alone.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of patients with continued NCSE on EEG after 24 h (treatment failure) | NCSE diagnosed using EEG and defined by the Salzburg criteria for NCSE (e.g. Leitinger et al. Lancet Neurology, 2016) | 24 hours after randomisation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of treatment related complications | e.g. tracheostoma, infections | at discharge, on average after 7 days | 
| New neurological deficit | Neurological deficits are quantified using National Institute of Health Stroke Scale (NIHSS, maximum possible score is 42, the minimum score - indicating no deficits - is 0) at admission and discharge. New neurological deficit is defined as increase of NIHSS >5 at discharge | at discharge, on average after 7 days |