Clinical trial NCT05684978: Efficacy and Safety of Perampanel in the Treatment of Refractory Status Epilepticus
Official title: Efficacy and Safety of Perampanel in the Treatment of Refractory Status Epilepticus
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: PHASE4
Conditions: Refractory Status Epilepticus
Keywords: Status Epilepticus
Epilepticus
Epilepsy
Perampanel
Clinical trial for epilepsy
Epilepsy treatment
Seizure
seizure treatment
generalized tonic-clonic seizures
focal seizures
Refractory status epilepticus
(RSE)
fycompa
Lead sponsor: Wayne State University
Sponsor class: OTHER
First posted: 2023-01-13
Enrollment: 25
Sex: ALL
Minimum age (years): 18
Maximum age (years): 100
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: OTHER

Brief summary: This project is aiming to better understand the use of perampanel as an appropriate standard-of-care therapy for treatment refractory status epilepticus (RSE), to identify determinants of outcomes, and establish safety. The study will recruit 25 patients at WSU. The study will last for about 96 weeks and will involve a screening visit and two in clinic visits at 3 and 6 months. If the subjects give written informed consent and meet all eligibility criteria they will be clinically evaluated and will be given the study drug. This study will involve recording of patients medical history, drug history and epilepsy history. A physical exam and a and neurological exam will also be performed to study the heath status of the participant. Results and patient information will be stored in a database for analysis to find commonality among key factors that have been seen in past research.

Detailed description: ILAE (International league against epilepsy) defines status epilepticus (SE) as generalized tonic-clonic seizures \> 5 minutes or focal impaired awareness seizure \> 15 min or recurrent seizures with alteration of consciousness in between seizures.

Refractory status epilepticus (RSE) is defined as failure to respond to first line benzodiazepines and one antiepileptic drug (AED). It often requires treatment with anesthetic drugs and continuous EEG monitoring for diagnosis and titration of medications. Status epilepticus (SE) is estimated to be refractory in about 30 % of cases, associated with increased morbidity and mortality and requires continuous EEG monitoring to guide treatment \[1\]. It is seen across all ages, and around 200,000 cases are seen in the United States annually resulting in significant morbidity and mortality \[2\]. Morbidity and mortality of SE and especially RSE is due to prolonged stay in the ICU and at times treatment from IV anesthetics including hemodynamic instability, and related infections of the ICU stays.

Standard of Care treatment of SE and RSE

Rapid termination of the SE is the primary goals of SE treatment with evidence indicating that if left untreated, SE becomes harder to terminate \[3,4\]. In a patient with SE, the first AED should be started at the onset concomitantly with the first line benzodiazepine or soon after. The agents of choice are typically those available in IV (intravenous) formulation with purpose of fast and safe administration in a seizing patient. These include phenytoin (PHT)/fosphenytoin, valproic acid (VPA), levetiracetam (LEV); lacosamide (LCM) with no clear evidence that one drug is superior \[5,6\]. Beyond the introduction of a second seizure medication, there is no unified consensus or clear evidence to guide treatment at that stage of RSE.

Other AED are used as add-on therapy in the treatment of SE when benzodiazepine (1st agent) and IV AED (2nd agent) fail. These have been demonstrated to be efficacious in different cohorts and case series and include but not limited to clobazam, topiramate, oxcarbazepine and eslicarbazepine \[7\].

Perampanel

Perampanel (PMP) has recently been shown to be efficacious in the treatment of variable subsets of SE including simple partial SE, refractory SE, and super-refractory SE \[8, 9\]. Efficacy of 75% was also demonstrated in a very difficult to treat subset of patient with nonconvulsive SE in post-anoxic patients. Systematic qualitative analysis of publications in use of PMP for status epilepticus revealed highly variable results in highly variable populations \[10\]. More homogeneous single-center outcomes are needed. In a multi-centered study looking at 52 patients receiving PMP for treatment of SE, PMP was the last drug added in 61.5 % of patients and a positive response attributed to PMP in 36.5% and PMP was well tolerated with minimal side effects and no discontinuation \[11\].

The mechanism of action unique to PMP may be key in its success in this disease state. Perampanel (PMP) is a selective noncompetitive AMPA receptor antagonist. Blockade of excitatory mechanisms become important in SE given that prolonged SE may result in postsynaptic internalization of GABA-A receptors and subsequent reduced efficacy of GABAergic drugs \[12\]. In addition, PMP is rapidly absorbed by the GI system and peak plasma concentrations are achieved as early as 0.5 hours (0.5-2.5hours) with 100% bioavailability; features which make the drug attractive even in its oral form in the treatment of SE.

Two studies (E2007-A001-024 and E2007-A001-023) in healthy recreational drug users evaluated safety and abuse potential of perampanel and submitted with PMP NDA (#202834) to the FDA. Data was established at 8mg, 24mg, and 36 mg in both studies (Table 1). Increasing the dose to 36 mg was not associated with significant safety or tolerability issues. \[Somnolence and dizziness were the most common side effects. Hemodynamics (systolic blood pressure, diastolic blood pressure, and heart rate) were not impacted. Kidney and liver functions were also largely not impacted with the exception of a single-incident of liver enzyme elevation. In order to reach steady state, simulation data reveals that steady state is reached immediately with a 4-5:1 dosing (loading dose to maintenance dose) Thus, the established safety confirmed a 36 mg loading dose as safe and tolerable. Hence, the investigators have chosen this as the loading dose for our study. Given that this is not an FDA approved dosage or indication, the investigators have obtained FDA authorization as an investigational new drug (IND 157959) to conduct this study.

Eligibility criteria: Inclusion Criteria:

* Adults patients equal or greater than 18 years
* Patients in RSE that require IV anesthetic infusions. Note: RSE is defined as status epilepticus that fails to terminate after an adequate dose of benzodiazepines (1st line agents) and an AED (2nd line agent). Adequate doses have been defined in the screening (below).
* Patients taking oral contraception who will be on the study long term should be informed about additional alternative methods of contraception.

Exclusion Criteria:

* Childbearing potential female who has a positive pregnancy test result or is otherwise known to be pregnant. Hypoglycemia or hyperglycemia induced seizures
* Mild, moderate or severe hepatic impairment
* Severe renal impairment or on hemodialysis
* History of psychiatric illness or suicidal behavior/ideation
* Previous or current use of PMP
* Known severe allergy to any AED
* Anoxic brain injury as etiology of status epilepticus
* Use caution in patients taking moderate and strong CYP3A4 Inducers (including carbamazepine, oxcarbazepine, and phenytoin)
* Patients on other forms of strong CYP3A4 (e.g. Rifampin, St John's Wart, etc).

Primary outcomes:
measure: Primary Outcomes
timeFrame: Within 48 hours of stopping intravenous anesthetics
Secondary outcomes:
measure: Secondary Outcomes
timeFrame: 3 months and 6 months
measure: 2. Total duration of intravenous anesthetic infusion.
timeFrame: 90 Days
measure: 3. The number of antiseizure medications used.
timeFrame: 90 Days
measure: 3. Total duration of intubation
timeFrame: 90 days
measure: Total ICU and in-hospital length of stay
timeFrame: 90 days
measure: 5. Mortality rate
timeFrame: ICU and hospital discharge
measure: 6. Functional impairment
timeFrame: Hospital discharge, 3 months, 6 months
measure: 7. Favorable outcome
timeFrame: Hospital discharge, 3 months, 6 months
measure: 8. Favorable discharge location
timeFrame: Hospital discharge
measure: Seizure Control
timeFrame: Determined by percentages of the patients that do not experience seizure recurrence
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
Study officials:
affiliation: Wayne State University
name: Maysaa Basha, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Wayne State University
name: Wazim Mohamed, MD
role: PRINCIPAL_INVESTIGATOR
References: