Study of Perampanel as Adjunctive Treatment for Inadequately Controlled Seizures Associated With Lennox-Gastaut Syndrome
Condition: Lennox-Gastaut Syndrome (LGS)
MeSH terms: Seizures; Lennox Gastaut Syndrome; Syndrome
Intervention: Placebo; Perampanel
Intervention description: Participants will receive matching placebo in Randomization phase.; Participants will receive perampanel in Randomization phase, open-label Extension A, and open-label Extension B.
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 101.0
Sex: All
Minimum age: 2 Years
Healthy volunteers: No
Keywords: Lennox-Gastaut Syndrome (LGS); Inadequately controlled seizures

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).
    

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.