Perampanel in Focal Status Epilepticus

Study Overview
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Brief Summary
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Randomized controlled trial on focal motor status epilepticus (SE), studying the add-on efficacy of the enteral administration of perampanel (PER) to a conventional intravenous antiepileptic drug.

Detailed Description
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In spite of the use of various antiepileptic drugs, the SE, generalized or focal, are refractory to the treatment in around 25 % of the cases. There is therefore a need to develop new therapy with novel synaptic targets. New antiepileptic drugs emerge as potential drugs for SE. Perampanel (PER) is a new drug available for add-on therapy in patients with a focal epilepsy. The mechanism of action of this drug is original, as it is a non-competitive α-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptor antagonist. Several studies suggested that AMPA-mediated glutamatergic transmission plays an important rule during the SE. In this study the investigator will focus on patients suffering from early focal motor SE, for several reasons: (i) There is no randomized controlled double-blind trial in this population, and therefore no evidence to help physicians. (ii) The investigator aims to perform a trial on early SE, after failure of only one drug (a benzodiazepine, recommended as first line treatment), in order to properly evaluate the effect of the tested drug (add-on of perampanel). (iii) The perampanel is available only for oral administration. Focal SE usually does not affect the vital prognosis and can be treated less aggressively. Use of oral loading doses of antiepileptic drugs is frequent, and therapies may be changed or adapted in the time-frame of hours or days. (iv) Patients with a focal SE, presenting motor symptoms, can be included without the need of an EEG. Similarly, the primary end-point, cessation of the motor events, does not require specific exam, and can also be done clinically.

Official Title
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Efficacy of add-on PEramPanel in Focal Motor Status Epilepticus

Conditions
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Epilepticus; Status, Focal Motor

Intervention / Treatment
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* Drug: Perampanel
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients aged 18 years or above, including the protected adults with a focal motor status epilepticus, defined by prominent clinically objective focal motor symptoms (clonic, tonic, myoclonic, adversive or oculoclonic), lasting for more than 10 minutes before any treatment or repeated focal motor seizures during this period (≥ 4 seizures in 10 min) The focal motor status continues (or patients show ≥ 2 focal motor seizures) 5 minutes or more after the beginning of administration of benzodiazepines. The delay between administration of benzodiazepines and randomization must not exceed 6 hours. Affiliation to a French social security system (recipient or assign) excluding Aide Médicale Etat (AME) Exclusion Criteria: Known severe liver (Factor V <50 %) or kidney (glomerular filtration rate : 15-29 ml/min/1,72 m2) insufficiency Women with known or clinically detected pregnancy Patients with known allergies to perampanel or to any of the excipients mentioned in the summary of product characteristics(SmPC) Patients with postanoxic status Patients in coma (Glasgow<8) Patients with motor events for which a nonepileptic psychogenic origin is suspected Patients whose status epilepticus is linked to a pathological condition, such as trauma, who needed immediate surgery Known current treatment by perampanel Known galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases) Known participation in another trial with medication and/or previously included in PEPSI study

Ages Eligible for Study
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Minimum Age: 18 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
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Perampanel<br>immediate enteral administration of Perampanel, 12 mg | Drug: Perampanel<br>* Single-dose of Perampanel 12 mg film-coated tablet, will be given orally in patients with status epilepticus that do not involve the oral and pharyngeal musculatures. In alternative, perampanel will be administered by a nasogastric feeding tube, a procedure which has been recently reported to be safe and tolerated in patients with generalised status epilepticus<br>* Other names: Experimental group;|
| Placebo Comparator: Placebo<br>immediate enteral administration of placebo | Drug: Placebo<br>* Single-dose of placebo of Perampanel, administered orally. Placebo of perampanel will be given orally, in patients with status epilepticus that do not involve the oral and pharyngeal musculatures. In alternative, Placebo of perampanel will be administered by a nasogastric feeding tube, a procedure which has been recently reported to be safe and tolerated in patients with generalised status epilepticus<br>* Other names: Control group;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Administration or not of either (i) an additional second-line antiepileptic drug, either intravenous or orally, or (ii) a third-line (anesthetic drug) | Administration or not of either (i) an additional second-line antiepileptic drug, either intravenous or orally, or (ii) a third-line (anesthetic drug), within the 6 hours following study drug (perampanel or placebo) administration | Within de 6 hours after the perampanel or placebo administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Seizure cessation | Seizure cessation is defined clinically by the interruption of any epileptic movements (clonic, tonic or myoclonic) | at 3 hours and 6 hours after the perampanel or placebo administration | 
| Time to seizure cessation |  | within the 6 hours after the administration of perampanel or placebo | 
| The need for endotracheal intubation |  | within the 24 hours after the administration of perampanel or placebo | 
| Percentage of patients with altered consciousness | Altered consciousness is defined as Glascow Coma Scale (GCS) <8 | at 3 hours and 6 hours after the perampanel or placebo administration | 
| Duration of hospitalization | Duration of overall hospitalization (ICU/step down/standard hospitalisation) and duration of hospitalization in ICU/step down unit, both censored 14 days after randomisation | From randomization untill 14 days after the administration of perampanel or placebo | 
| Rate of patient with seizure recurrence | Seizure recurrence is defined as focal motor seizure lasting less than 10 minutes, between hour 3 and hour 24 after the administration of perampanel or placeb. Recurrence is defined by reappearance of epileptic movements after a period of at least one hour of seizure cessation | From hour 3 until hour 24 after the administration of perampanel or placebo | 
| Rate of patient with status epilepticus recurrence, in patients with seizure cessation | Status epilepticus recurrence is defined as focal motor seizure lasting 10 minutes or more, or repeated focal motor seizures (≥4 seizures in 10 min), between hour 3 and hour 24 after the administration of perampanel or placebo. | From hour 3 until hour 24 after the administration of perampanel or placebo | 
| Rate of patients with secondary generalized seizures | Secondary generalized seizures is defined as convulsive tonic or clonic bilateral seizure lasting less than 5 minutes | From hour 0 until hour 24 after the administration of perampanel or placebo | 
| Progression to a convulsive generalized status epilepticus | Convulsive generalized status epilepticus is defined as convulsive tonic or clonic bilateral seizure lasting more than 5 minutes or more, or 2 or more seizures in 5 minutes without recovery of consciousness between the seizures | From hour 0 until hour 24 after the administration of perampanel or placebo | 
| Mortality rate at the end of the study period |  | Up to 14 days (end of hospitalization) or 14 days if the patient is still hospitalized | 
| Glasgow Outcome Scale score at the end of the study period | Glasgow Outcome Scale (GOS) is 5 values score from 1 (death) to 5 (resumption to normal life; there may be minor neurologic and/or psychological deficits). | Up to 14 days (end of hospitalization) or 14 days if the patient is still hospitalized | 
| Global neurological state at the end of the study period | The neurological state of patients will be evaluated for comparison with that before status epilepticus. Three states will be distinguished: unchanged, new neurological deficit or death | Up to 14 days (end of hospitalization) or 14 days if patient is still hospitalized | 
| Number of adverse events and their severity |  | from randomization until to 14 days after the administration of perampanel or placebo | 
| Subgroup analysis of the primary and secondary outcomes measure according to the etiology | Several etiological categories will be defined : acute symptomatic versus remote symptomatic versus cryptogenic causes identification of a brain lesion versus not | At H0 (below or above the median of SE duration | 
| Subgroup analysis of the primary and secondary outcomes measure according to duration of status epilepticus |  | At H0 (below or above the median of SE duration | 
| Subgroup analysis of the primary and secondary outcomes measure according to type of conventional antiepileptic drug administrated |  | At H0 (below or above the median of SE duration) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Perampanel, Placebo, Antiepileptic drug