Evaluation of Anti-Seizure Treatment with Esketamine, Lorazepam, and Midazolam in Comatose Cardiac Arrest Patients with Status Epilepticus

The primary objective of the study is to determine if **seizure suppression** through stepwise anti-seizure treatment improves the outcome of comatose patients following cardiac arrest with electroencephalographic status epilepticus (ESE), compared to no anti-seizure treatment. This is clinically relevant as it addresses the potential for improved neurological outcomes and survival rates in a critical patient population, thereby informing treatment protocols and potentially enhancing patient care in intensive care settings.

Secondary objectives include evaluating the impact on healthcare costs of seizure suppression by stepwise anti-seizure treatment in comatose patients after cardiac arrest with ESE, as compared with no anti-seizure treatment. This analysis is crucial for understanding the economic implications of treatment strategies, which can influence healthcare policy and resource allocation.

The clinical trial involves a study population comprising both **male** and **female** participants, aged 18 years and older, who are in a **comatose** state following an out-of-hospital **cardiac arrest** and subsequent resuscitation. The trial specifically targets individuals who meet the criteria of having a Glasgow Coma Scale score of 8 or less. Participants are required to have continuous EEG monitoring initiated within 24 hours after the return of spontaneous circulation, with at least eight electrodes in place. The presence of electrographic status epilepticus (ESE) or possible ESE, as defined by the Salzburg and ACNS criteria, is a prerequisite for inclusion. The trial population is considered vulnerable, and the selection process ensures the possibility of commencing treatment within three hours after ESE detection. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **randomized**, double-blind, controlled study to evaluate the efficacy of anti-seizure treatment in comatose patients following cardiac arrest, specifically those with **status epilepticus** as detected on continuous EEG. The trial aims to determine if seizure suppression through stepwise anti-seizure treatment improves patient outcomes compared to no treatment. The study will involve the administration of various intravenous medications, including **esketamine**, **lorazepam**, **midazolam hydrochloride**, **levetiracetam**, **propofol**, **sodium valproate**, **diazepam**, and **lacosamide**. The trial is expected to commence recruitment on January 1, 2025, and conclude by December 31, 2031.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as a Glasgow Coma Scale score of 8 or less after out-of-hospital cardiac arrest and resuscitation, age of 18 years or older, and the presence of **status epilepticus** on EEG. The treatment must be initiated within three hours of detecting **status epilepticus**. Follow-up visits will be scheduled to monitor the participants' response to treatment and any adverse effects. The primary endpoint is functional recovery, assessed by the extended Glasgow Outcome Scale at six months post-cardiac arrest, evaluated through a standardized telephone interview by an independent investigator blinded to treatment allocation. Secondary endpoints include cost-effectiveness analysis outcomes such as Quality Adjusted Life Years (QALYs) and Incremental Cost Effectiveness Ratio (ICER).

The expected duration of participant involvement is up to six months, with the possibility of early termination if significant adverse events occur or if the participant withdraws consent. The trial is categorized as a low-intervention study, ensuring minimal risk to participants while providing valuable insights into the management of **status epilepticus** in comatose cardiac arrest patients.

The clinical trial involves the administration of several **experimental medications**. **Esketamine**, marketed as Esketiv 25 mg/ml, is provided as a **solution for injection**. It is administered intravenously with a maximum daily dose of 240 mg/kg and a total maximum dose of 10080 mg/kg over a treatment period of up to 6 weeks. The pharmaceutical form is a solution for injection, and the product is manufactured by Eurocept International BV.

**Lorazepam**, under the brand name Lorazepam Macure 4 mg/ml, is also a **solution for injection**. It is administered intravenously with a maximum daily dose of 4 mg and a total maximum dose of 4 mg, with a treatment period limited to 1 day. This product is manufactured by Macure Pharma APS.

**Midazolam Hydrochloride** is available as Midazolam Eugia 1 mg/ml, a **solution for injection/infusion**. It is administered via intravenous infusion with a maximum daily dose of 96 mg/kg and a total maximum dose of 4032 mg/kg over a 6-week period. The product is provided by Eugia Pharma (Malta) Ltd.

**Levetiracetam**, marketed as Keppra 100 mg/ml, is a **concentrate for solution for infusion**. It is administered intravenously with a maximum daily dose of 4500 mg and a total maximum dose of 189 g over a 6-week period. UCB Pharma S.A. is the manufacturer of this product.

**Propofol**, available as Propofol 10 mg/ml MCT/LCT Fresenius, is an **emulsion for injection/infusion**. It is administered intravenously with a maximum daily dose of 120 mg/kg and a total maximum dose of 5040 mg/kg over a 6-week period. This product is manufactured by Fresenius Kabi Nederland B.V.

**Sodium Valproate**, under the brand name Depakine i.v. 400, is a **solution for injection**. It is administered intravenously with a maximum daily dose of 3000 mg and a total maximum dose of 126 g over a 6-week period. The product is provided by Sanofi B.V.

**Diazepam**, marketed as Diazepam CF 5 mg/ml, is a **solution for injection**. It is administered intravenously with a maximum daily dose of 20 mg and a total maximum dose of 20 mg, with a treatment period limited to 1 day. This product is manufactured by Centrafarm B.V.

**Lacosamide**, available as Vimpat 10 mg/ml, is a **solution for infusion**. It is administered intravenously with a maximum daily dose of 600 mg and a total maximum dose of 25.2 g over a 6-week period. UCB Pharma S.A. (Anderl BE) is the manufacturer of this product.

All medications are administered intravenously, and participant compliance is monitored throughout the trial. The trial aims to evaluate the efficacy of these treatments in improving outcomes for comatose cardiac arrest patients with status epilepticus on continuous EEG.

Efficacy in the clinical trial titled "Treatment of Electroencephalographic Status Epilepticus After Cardiopulmonary Resuscitation-2 (TELSTAR-2)" will be assessed primarily through the measurement of functional recovery. This will be expressed as the score on the extended Glasgow Outcome Scale (eGOS) at six months following cardiac arrest. The eGOS scores will be obtained via a standardized telephone interview conducted by an independent investigator who is blinded to the treatment allocation and EEG pattern. This approach ensures objectivity in the assessment of the primary endpoint.

Secondary efficacy endpoints include a cost-effectiveness analysis, which will evaluate outcomes such as Quality Adjusted Life Years (QALYs), costs, Incremental Cost Effectiveness Ratio (ICER), incremental cost-effectiveness plane, and incremental cost-effectiveness acceptability curve. These analyses will provide a comprehensive understanding of the economic impact and value of the anti-seizure treatment in the context of the trial. The trial is designed to determine if seizure suppression through stepwise anti-seizure treatment improves outcomes in comatose patients after cardiac arrest with **status epilepticus** (ESE), compared to no anti-seizure treatment.