Clinical trial NCT02834793: Study of Perampanel as Adjunctive Treatment for Inadequately Controlled Seizures Associated With Lennox-Gastaut Syndrome
Official title: A Multicenter, Double-Blind, Randomized, Placebo-Controlled Trial With an Open-Label Extension Phase of Perampanel as Adjunctive Treatment in Subjects at Least 2 Years of Age With Inadequately Controlled Seizures Associated With Lennox-Gastaut Syndrome
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Lennox-Gastaut Syndrome (LGS)
Keywords: Lennox-Gastaut Syndrome (LGS)
Inadequately controlled seizures
Lead sponsor: Eisai Inc.
Sponsor class: INDUSTRY
First posted: 2016-07-15
Enrollment: 101
Sex: ALL
Minimum age (years): 2
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study is being conducted to demonstrate that perampanel given as adjunctive anti-epileptic treatment is superior to placebo in reducing the number of drop seizures in participants with inadequately controlled seizures associated with Lennox-Gastaut Syndrome (LGS).

Detailed description: This is a multicenter, double-blind, randomized, placebo-controlled, parallel-group study of perampanel as adjunctive therapy in participants with inadequately controlled seizures associated with LGS. The study will consist of 3 phases: Prerandomization (4 to 8 weeks), Randomization (18 weeks), and an Extension A (52 weeks). An additional Extension B with open-label treatment will be available for optional participation to participants who reside in Japan and in countries where an expanded access program (EAP) cannot be implemented or has not yet been implemented.

Eligibility criteria: Inclusion Criteria:

* Participants must have a diagnosis of LGS as evidenced by:

  1. more than one type of generalized seizure, including drop seizures (atonic, tonic, or myoclonic) for at least 6 months before Visit 1;
  2. an electroencephalogram (EEG) reporting diagnostic criteria for LGS at some point in their history (abnormal background activity accompanied by slow, spike, and wave pattern \<2.5 hertz \[Hz\]).
* Participants must be at least 2 years old at the time of consent/assent
* Participants must have been \<11 years old at the onset of LGS
* Participants must have experienced an average of at least 2 drop seizures per week in the 4-week Baseline Period preceding randomization
* Participants must have been receiving 1 to 4 concomitant antiepileptic drugs (AEDs) at a stable dose for at least 30 days before Visit 1 (vagal nerve stimulation (VNS) and ketogenic diet do not count as AEDs). Use of cannabidiol (CBD) products is allowed and is counted as one of the 4 maximum allowed concomitant AEDs. CBD dose and product must have remained stable for at least 30 days before Visit 1 and is to remain the same throughout the course of the Core Study
* In the investigator's opinion, parents or caregivers must be able to keep accurate seizure diaries
* Body weight at least 8 kilogram (kg)

Exclusion Criteria:

* Presence of progressive neurological disease
* Presence of drop seizure clusters where individual seizures cannot be reliably counted (seizure clusters are defined as ≥2 drop seizures with \<5 minutes between any 2 consecutive seizures)
* Prior treatment with perampanel with discontinuation due to safety issues (related to perampanel)
* Prior treatment with perampanel within 30 days before Visit 1
* Evidence of clinically significant disease (eg, cardiac, respiratory, gastrointestinal, renal disease, hepatic disease) that in the opinion of the investigator(s) could affect the participant's safety or study conduct
* Scheduled for epilepsy-related surgery or any other form of surgery during the projected course of the study
* Ketogenic diet and VNS, unless stable and ongoing for at least 30 days before Visit 1
* Treatment with an investigational drug or device within 30 days before Visit 1
* Status epilepticus within 12 weeks of Visit 1
* If felbamate is used as a concomitant AED, participants must be on felbamate for at least 1 year, with a stable dose for 60 days before Visit 1. They must not have a history of white blood cell (WBC) count below ≤2500/microliters (μL), platelets \<100,000/μL, liver function tests (LFTs) \>3 times the upper limit of normal (ULN), or other indication of hepatic or bone marrow dysfunction while receiving felbamate
* Concomitant use of vigabatrin: participants who took vigabatrin in the past must be discontinued for at least 5 months before Visit 1, and must have documentation showing no evidence of a vigabatrin-associated clinically significant abnormality in an automated visual perimetry test
* Have had multiple drug allergies or a severe drug reaction to an AED(s), including dermatological (eg, Stevens-Johnson syndrome), hematological, or organ toxicity reactions
* Evidence of significant active hepatic disease. Stable elevations of liver enzymes, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) due to concomitant medication(s) will be allowed if they are \< 3 times the ULN
* Adrenocorticotropic hormone within the 6 months before Visit 1
* Had history of anoxic episodes requiring resuscitation within 6 months before Visit 1
* Females who are breastfeeding or pregnant at Screening or Baseline (as documented by a positive beta human chorionic gonadotropin \[ß-hCG\] with a minimum sensitivity of 25 International Units per Liter (IU/L) or equivalent units of ß-hCG or hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug.
* Females of childbearing potential who: a. had unprotected sexual intercourse within 30 days before study entry and who do not agree to use a highly effective method of contraception (eg, total abstinence, an intrauterine device, a double-barrier method \[such as condom plus diaphragm with spermicide\], a contraceptive implant, an oral contraceptive, or have a vasectomized partner with confirmed azoospermia) throughout the entire study period or for 28 days after study drug discontinuation. Females using hormonal contraceptives containing levogesterol must be on another form of contraception as well. b. Are currently abstinent, and do not agree to use a double-barrier method (as described above) or refrain from sexual activity during the study period or for 28 days after study drug discontinuation. c. Are using hormonal contraceptives but are not on a stable dose of the same hormonal contraceptive product for at least 4 weeks before dosing and who do not agree to use the same contraceptive during the study or for 28 days after study drug discontinuation. (NOTE: All females will be considered to be of childbearing potential unless they are postmenopausal \[amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause\] or have been sterilized surgically \[i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing\])
* Had intermittent use of benzodiazepine of more than 4 single administrations in the month before Visit 1
* A prolonged QT/QTc interval (QTc \>450 milliseconds \[ms\]) as demonstrated by a repeated electrocardiogram (ECG)
* Hypersensitivity to the study drug or any of the excipients
* Any history of a medical condition or a concomitant medical condition that in the opinion of the investigator(s) would compromise the participant's ability to safely complete the study
* Known to be human immunodeficiency virus (HIV) positive
* Active viral hepatitis (B or C) as demonstrated by positive serology at Screening
* Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics or prior suicide attempt(s) within approximately the last 2 years
* History of drug or alcohol dependency or abuse within approximately the last 2 years; use of illegal recreational drugs
* Concomitant use of medications known to be inducers of cytochrome P450 (CYP3A) including, but not limited to: rifampin, troglitazone, St. John's Wort, efavirenz, nevirapine, glucocorticoids (other than topical usage), modafinil, pioglitazone, and rifabutin
* Use of AEDs not recommended by Epilepsy Treatment Guidelines for use in LGS including, but not limited to carbamazepine, gabapentin, oxcarbazepine, phenytoin, pregabalin, tiagabine, and vigabatrin
* Any suicidal ideation with intent with or without a plan within 6 months before Visit 2 (that is, answering "Yes" to questions 4 or 5 on the Suicidal Ideation section of the Columbia Suicide Severity Rating Scale (C -SSRS) in participants aged 8 and above.
* Participants with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption.

Primary outcomes:
measure: Core Study Phase: Median Percent Change in Drop Seizure Frequency Per 28 Days During Double-blind Treatment Relative to the Prerandomization Phase (Baseline)
timeFrame: Baseline up to 18 weeks
Secondary outcomes:
measure: Core Study Phase: Median Percent Change in Total Seizure Frequency Per 28 Days During Double-blind Treatment Relative to the Prerandomization Phase (Baseline)
timeFrame: Baseline up to 18 weeks
measure: Core Study Phase: Percentage of Participants With 50% Response in the Maintenance Period of the Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) for Drop Seizures
timeFrame: Baseline up to 18 weeks
measure: Core Study Phase: Percentage of Participants With 50% Response in the Maintenance Period of the Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) for Total Seizures
timeFrame: Baseline up to 18 weeks
measure: Core Study Phase: Median Percent Change in Non-drop Seizure Frequency Per 28 Days During Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline)
timeFrame: Baseline up to 18 weeks
measure: Core Study Phase: Percentage of Participants With 75% Response in the Maintenance Period of the Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) for Drop Seizures, Non-drop Seizures and Total Seizures
timeFrame: Baseline up to 18 weeks
measure: Core Study Phase: Percentage of Participants With 100% Response in the Maintenance Period of the Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) for Drop Seizures, Non-drop Seizures and Total Seizures
timeFrame: Baseline up to 18 weeks
measure: Core Study Phase: Percentage of Participants With 50% Response in the Maintenance Period of the Double-blind Treatment Phase Relative to the Prerandomization Phase (Baseline) for Non-drop Seizures
timeFrame: Baseline up to 18 weeks
measure: Core Study Phase: Percentage of Participants With Clinical Global Impression of Change Scores (CGIC) in the Double-blind Treatment Phase
timeFrame: Baseline up to 18 weeks
measure: Number of Participants With Any Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs)
timeFrame: From the date of the first administration of the study drug up to 28 days after the last dose of the study drug (up to 192 weeks)
measure: Number of Participants With Treatment-emergent Markedly Abnormal Laboratory Values
timeFrame: From the date of the first administration of the study drug up to 28 days after the last dose of the study drug (up to 192 weeks)
measure: Number of Participants With Clinically Significant Vital Signs
timeFrame: From the date of the first administration of the study drug up to 28 days after the last dose of the study drug (up to 192 weeks)
measure: Core Study Phase: Model Predicted Average Perampanel Concentrations at Steady State (Cav,ss) During the Maintenance Period of Core Study Phase
timeFrame: Up to Week 18
Other outcomes:
Locations:
city: Little Rock
country: United States
facility: University of Arkansas for Medical Sciences
state: Arkansas
city: Palo Alto
country: United States
facility: Stanford University
state: California
city: Gulf Breeze
country: United States
facility: Northwest Florida Clinical Research Group, LLC
state: Florida
city: Jacksonville
country: United States
facility: University of Florida Jacksonville
state: Florida
city: Loxahatchee Groves
country: United States
facility: Pediatric Neurologists of Palm Beach
state: Florida
city: Loxahatchee Groves
country: United States
facility: Axcess Medical Research
state: Florida
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Orlando
country: United States
facility: Pediatric Neurology PA
state: Florida
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta
state: Georgia
city: Boise
country: United States
facility: Consultants In Epilepsy and Neurology PLLC
state: Idaho
city: Urbana
country: United States
facility: Carle Foundation Hospital
state: Illinois
city: Bethesda
country: United States
facility: Midatlantic Epilepsy and Sleep Center
state: Maryland
city: Detroit
country: United States
facility: Children's Hospital of Michigan
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Grand Rapids
country: United States
facility: Mercy Health Saint Mary's Campus
state: Michigan
city: Saint Paul
country: United States
facility: Minnesota Epilepsy Group PA
state: Minnesota
city: Kansas City
country: United States
facility: Children's Mercy Hospital
state: Missouri
city: New Brunswick
country: United States
facility: Children's Hospital at Saint Peter's University Hospital
state: New Jersey
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center - PIN
state: Ohio
city: Cleveland
country: United States
facility: Cleveland Clinic
state: Ohio
city: Pittsburgh
country: United States
facility: Allegheny General Hospital
state: Pennsylvania
city: Pittsburgh
country: United States
facility: The University of Pittsburgh
state: Pennsylvania
city: Austin
country: United States
facility: Austin Epilepsy Care Center
state: Texas
city: San Antonio
country: United States
facility: Road Runner Research Ltd
state: Texas
city: Temple
country: United States
facility: Baylor Scott and White Research Institute
state: Texas
city: Salt Lake City
country: United States
facility: Clinical Neurosciences Center
state: Utah
city: Richmond
country: United States
facility: Virginia Commonwealth University
state: Virginia
city: Tacoma
country: United States
facility: MultiCare Institute for Research and Innovation
state: Washington
city: Madison
country: United States
facility: University of Wisconsin Hospital and Clinics
state: Wisconsin
city: Milwaukee
country: United States
facility: Columbia Saint Mary's
state: Wisconsin
city: Wauwatosa
country: United States
facility: Medical College of Wisconsin
state: Wisconsin
city: South Brisbane
country: Australia
facility: Queensland Children's Hospital
state: Queensland
city: Heidelberg
country: Australia
facility: Austin Health
state: Victoria
city: Brisbane
country: Australia
facility: Royal Brisbane & Women's Hospital
city: Melbourne
country: Australia
facility: Royal Melbourne Hospital
city: Melbourne
country: Australia
facility: St Vincent's Hospital Melbourne
city: Melbourne
country: Australia
facility: The Alfred Hospital
city: Bruxelles
country: Belgium
facility: Cliniques Universitaires Saint-Luc
state: Brussels
city: La Louvière
country: Belgium
facility: Hôpital Universitaire des Enfants Reine Fabiola
state: Hainaut
city: Bruxelles
country: Belgium
facility: Hôpital Erasme
city: Jette
country: Belgium
facility: UZ Brussel
city: Ottignies-Louvain-la-Neuve
country: Belgium
facility: Centre Neurologique William Lennox
city: Poruba
country: Czechia
facility: Fakultni nemocnice Ostrava
city: Praha
country: Czechia
facility: Thomayerova nemocnice
city: Ahmedabad
country: India
facility: Synexus Affiliate - Panchshil Hospital
state: Gujarat
city: Surat
country: India
facility: Synexus Affiliate - Nirmal Hospitals Pvt. Ltd
state: Gujarat
city: Mangalore
country: India
facility: Synexus Affiliate - Mallikatta Neuro Center
state: Karnataka
city: Kochi
country: India
facility: Synexus Affiliate - Amrita Institute of Medical Sciences and Research Centre
state: Kerala
city: Mumbai
country: India
facility: Synexus Affiliate - Jaslok Hospital and Research Centre
state: Maharashtra
city: Mumbai
country: India
facility: Synexus Affiliate - Kokilaben Dhirubhai Ambani Hospital & Medical Research Institute
state: Maharashtra
city: Pune
country: India
facility: Synexus Affiliate - Bharati Hospital
state: Maharashtra
city: Hyderabad
country: India
facility: Nizams Institute of Medical Sciences
city: New Delhi
country: India
facility: Synexus Affiliate - Sir Ganga Ram Hospital
city: Fukuoka
country: Japan
facility: Eisai Trial Site #1
city: Fukuoka
country: Japan
facility: Eisai Trial Site #3
city: Hakodate
country: Japan
facility: Eisai Trial Site #7
city: Kagoshima-city
country: Japan
facility: EIsai Trial Site #9
city: Niigata
country: Japan
facility: Eisai Trial Site #4
city: Osaka
country: Japan
facility: EIsai Trial Site #8
city: Sapporo
country: Japan
facility: Eisai Trial Site #6
city: Shizuoka
country: Japan
facility: Eisai Trial Site #2
city: Daegu
country: Korea, Republic of
facility: Kyungpook National University Chilgok hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System - PPDS
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center - PPDS
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
Study officials:
References:
citation: Brigo F, Jones K, Eltze C, Matricardi S. Anti-seizure medications for Lennox-Gastaut syndrome. Cochrane Database Syst Rev. 2021 Apr 7;4(4):CD003277. doi: 10.1002/14651858.CD003277.pub4.