Perampanel in Focal Status Epilepticus (PEPSI)

Efficacy of add-on PEramPanel in Focal Motor Status Epilepticus

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.

Study Overview

• Status: Terminated
• Conditions: Epilepticus; Status, Focal Motor
• Intervention / Treatment: Drug: Perampanel; Drug: Placebo

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 3

Contacts and Locations

Study Locations

• France
  • Lille, France, 59037
    • Urgences, CHU Lille (Hôpital Roger Salengro)
  • Lille, France
    • Neuro-physiologie clinique, CHU Lille (Hôpital Roger Salengro)
  • Lille, France
    • Réanimation polyvalente, CHU (Hopital Roger Salengro)
  • Paris, France, 75013
    • Hôpital Pitié Salpêtrière - ICU
  • Paris, France, 75013
    • Department of Neurology, Epilepsy Unit, Pitié-Salpêtrière Hospital
  • Paris, France, 75014
    • Réanimation Polyvalente, GH Paris Saint Joseph
  • Paris, France
    • Neurologie et Neurovasculaire, GH Paris Saint Joseph
  • Paris, France
    • S.A.U, Pitié-Salpêtrière Hospital
  • Versailles, France
    • Accueil des Urgences, Centre Hospitalier de Versailles - André Mignot
  • Ile De France
    • Versailles, Ile De France, France, 78157
      • Neurologie, Centre Hospitalier de Versailles - André Mignot

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. 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)
2. 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.
3. Affiliation to a French social security system (recipient or assign) excluding "Aide Médicale" Etat (AME)

Exclusion Criteria:

1. Known severe liver (Factor V <50 %) or kidney (glomerular filtration rate : 15-29 ml/min/1,72 m2) insufficiency
2. Women with known or clinically detected pregnancy
3. Patients with known allergies to perampanel or to any of the excipients mentioned in the summary of product characteristics(SmPC)
4. Patients with postanoxic status
5. Patients in coma (Glasgow<8)
6. Patients with motor events for which a nonepileptic psychogenic origin is suspected
7. Patients whose status epilepticus is linked to a pathological condition, such as trauma, who needed immediate surgery
8. Known current treatment by perampanel
9. Known galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases)
10. Known participation in another trial with medication and/or previously included in PEPSI study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Perampanel; immediate enteral administration of Perampanel, 12 mg	Drug: Perampanel; 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; Other Names: Experimental group
Placebo Comparator: Placebo; immediate enteral administration of placebo	Drug: Placebo; 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; Other Names: Control group

What is the study measuring?

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
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
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
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)

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Vincent Navarro, DDS,PhD, Groupe Hospitalier Pitie-Salpetriere

Study record dates

Study Major Dates

• Study Start (Actual): November 2, 2022
• Primary Completion (Actual): November 2, 2022
• Study Completion (Actual): November 13, 2023

Study Registration Dates

• First Submitted: December 4, 2019
• First Submitted That Met QC Criteria: March 12, 2020
• First Posted (Actual): March 16, 2020

Study Record Updates

• Last Update Posted (Actual): December 14, 2023
• Last Update Submitted That Met QC Criteria: December 8, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: Placebo; Antiepileptic drug; Perampanel
• Additional Relevant MeSH Terms: Nervous System Diseases; Neurologic Manifestations; Seizures; Status Epilepticus
• Other Study ID Numbers: P160949J; 2019-000882-19 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No