Lessons from the Established Status Epilepticus Treatment Trial

Abstract

Convulsive status epilepticus (SE) is a relatively common emergency condition affecting individuals of all ages. The primary goal of treatment is prompt termination of seizures. Where first-line treatment with benzodiazepine has failed to achieve this, a condition known as established SE (ESE), there is uncertainty about which agent to use next. The Established Status Epilepticus Treatment Trial (ESETT) is a 3-arm (valproate (VPA), fosphenytoin (FOS), levetiracetam (LEV)), phase III, double-blind randomized comparative effectiveness study in patients aged 2 years and above with established convulsive SE. Enrollment was completed in January 2019, and the results are expected later this year. We discuss lessons learnt during the conduct of the study in relation to the following: ethical considerations; trial design and practical implementation in emergency settings, including pediatric and adult populations; quality assurance; and outcome determination where treating emergency clinicians may lack specialist expertise. We consider that the ESETT is already informing both clinical practice and future trial design. This article is part of the Special Issue "Proceedings of the 7th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures".

Keywords: Clinical trial; Levetiracetam; Methodology; Phenytoin; Status epilepticus; Valproate.

Figure 1.. Effective treatment options for established status epilepticus

(fos)Phenytoin doses shown are for phenytoin, or phenytoin equivalents for fosphenytoin. ¹Relative contraindication. Status epilepticus also poses a risk to the woman, and her unborn child. In an emergency situation, especially in a generalized epilepsy or where Levetiracetam is contraindicated, seizure control should take priority. ² Relative contraindication. This patient group anyway at high risk of fatigue and mood disorders, so may be more vulnerable to these adverse effects on levetiracetam.

Figure 2

A. Open “use next” study kit. From top to bottom, left to right: dose administration chart, instruction card, the protocol assist device, charging cable and plug, coiled colour coded length estimation tape, space for study medication. The dosing chart included guidance based on estimated weight (top of chart as shown) or length (colour coded, bottom) B. Colour coded “use next study boxes”. Coded by age stratification groups (2-17years; 18 – 65 years; 66 years and older)

Figure 3.. Protocol assist device screenshots

Illustrative screenshots from a protocol assist device. Top row left to right: Start screen; Confirmation eligibility followed by protocol start; audible and visual prompts for the clinical team reminding them verbal comments can be audio-recorded throughout; prompt to stop infusion at 10 minutes. Bottom row left to right: prompts for assessment seizure control (2 questions at each time point) at 20miutes, and 60 minutes; submission results; facility for emergency unblinding if required.