Investigate Efficacy and Safety of Carisbamate as Adjunctive Treatment for Seizures Associated With LGS in Children and Adults

Официальное название

A Randomized, Double-Blind, Placebo-Controlled Study to Investigate the Efficacy and Safety of Carisbamate (YKP509) as Adjunctive Treatment for Seizures Associated With Lennox-Gastaut Syndrome in Children and Adults, With Optional Open-Label Extension

Обзор

The primary objective is to evaluate the efficacy of carisbamate (YKP509) as adjunctive treatment in reducing the number of drop seizures (tonic, atonic, and tonic-clonic) compared with placebo in pediatric and adult subjects (age 4-55 years) diagnosed with Lennox Gastaut Syndrome (LGS).

Подробное описание

The secondary objectives are:

* To evaluate the efficacy of carisbamate (YKP509) as adjunctive treatment in reducing the total number of seizures compared with placebo in pediatric and adult subjects diagnosed with Lennox Gastaut Syndrome (LGS) * Evaluate the safety, tolerability of carisbamate in the LGS population * Evaluate steady-state pharmacokinetics of carisbamate in subjects with Lennox Gastaut.

Вмешательства

• Препарат Carisbamate
  Adolescent subjects 12 to 18 years old will receive the same dose as adults. Subjects 4 to \< 12 years old in the carisbamate 200 mg BID arm will receive 4 mg/kg BID (not to exceed 200 mg BID \[or a total of 400 mg per day\]). Subjects 4 to \< 12 years old in the carisbamate 300 mg BID arm will receive 5.5 mg/kg BID (not to exceed 300 mg BID \[or a total of 600 mg per day\]).

Первичные конечные точки

• Primary outcome will be the percentage change from baseline in the total frequency (average per 28 days) of countable drop seizures with potential to fall (tonic, atonic, tonic-clonic) seizures during the double-blind treatment period. [Срок оценки: 3 years]

Вторичные конечные точки (3)

• The percentage of subjects with at least a 50% reduction from baseline in the total frequency of drop seizures (tonic, atonic, tonic-clonic) during the double-blind treatment period. [Срок оценки: 3 years]
• Percentage change from baseline in the frequency of all types of seizures (total seizures) during the double-blind treatment period. [Срок оценки: 3 years]
• Subject/Caregiver Global Impression of Change (S/CGIC) in overall condition score at the last visit. [Срок оценки: 3 years]

Критерии участия

Критерии включения

• Subject must have a documented history of Lennox-Gastaut syndrome by:

• Evidence of more than one type of seizure, of which at least one should be an atonic or tonic seizure
• History of an electroencephalogram (EEG) reporting diagnostic criteria for LGS (abnormal background activity accompanied by slow, spike and wave pattern <3.0 Hz)
• History of developmental delay
• Male or female subjects
• Subjects must be age 4-55 years at the time of consent/assent
• Must have been <11 years old at the onset of LGS
• Subjects must have experienced at least 2 drop seizures with potential to fall (tonic, atonic, tonic-clonic) during the 4-week Baseline period preceding randomization (minimum of 4 drop seizures in the first two weeks and 4 in the last two weeks). Drop seizures are defined as a seizure involving the entire body, trunk, or head that led or could have led to a fall, injury, slumping in a chair, or hitting the subject's head on a surface. All drop seizure types must be countable (either as isolated seizures or as countable isolated seizures in a cluster).
• Subjects must have been receiving 1 to 4 concomitant anti-seizure medications (ASMs) at a stable dose for at least 4 weeks before Visit 1
• If not taking Epidiolex, subjects may take other approved cannabidiol or over the counter cannabidiol products. If taking cannabidiol other than Epidiolex, consult Medical Monitor to determine if it counts as a concomitant ASM.
• Dietary therapy and any CNS stimulator settings must be stable for 4 weeks prior to baseline and maintain stable regimen throughout the study. The dietary therapy and CNS stimulators are not counted as an ASM.
• Parents or caregivers must be able to keep accurate seizure diaries
• Subject is either not of childbearing potential, defined as premenarchal, postmenopausal for at least 1 year or surgically sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy), if of childbearing potential, must comply with an acceptable method of birth control during the study, for at least 4 weeks prior to study entry and for 4 weeks following completion of the study, if able.
• Subject and/or caregiver(s)/legal representative must be willing and able to give informed assent/consent for participation in the study
• Subject and their caregiver must be willing and able (in the investigator's opinion) to comply with all study requirements
• History of COVID-19 vaccination is permitted

Критерии исключения

• Etiology of subject's seizures is a progressive neurologic disease. Subjects with tuberous sclerosis will not be excluded from study participation, unless there is a progressive brain tumor
• Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease, hepatic disease) that in the opinion of the investigator(s) could affect the subject's safety or study conduct
• Subjects who were on adrenocorticotropic hormone (ACTH) therapy in the 6 months prior to baseline
• Subject on dietary therapy for less than 4 weeks prior to screening visit (Visit 1) or suffers from frequent stooling
• Current use of felbamate with less than 18 months of continuous exposure
• Concomitant use of vigabatrin: subjects 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, if able.
• Subject who had a history of hypoxia which needed emergency resuscitation within 12 months prior to baseline
• Status epilepticus within 12 weeks prior to Visit 1
• Any clinically significant illness (including COVID-19) in the 4 weeks prior to Visit 1, as evaluated by the Investigator
• Subject has clinically significant abnormal laboratory values, in the investigator's opinion, at Visit 1 or time of randomization (Visit 2)
• Subject has a history of any serious drug-induced hypersensitivity, e.g., toxic epidermal necrolysis, or Drug Reaction with Eosinophilia and Systemic Symptoms \[DRESS\]) or any drug-related rash requiring hospitalization
• Vagus Nerve Stimulation (VNS), Deep Brain Stimulation (DBS), Responsive Neurostimulator System (RNS) or other neurostimulation for epilepsy device implanted or activated <5 months year prior to enrollment. Stimulation parameters that have been stable for <4 weeks, or Battery life of unit not anticipated to extend for duration of trial.
• Subject is pregnant, may be pregnant, lactating or planning to be pregnant
• Any suicidal ideation with intent, with or without a plan within 6 months before Visit 2 (i.e., answering "Yes" to questions 4 or 5 in the Suicidal Ideation section of the age- specific Columbia-Suicide Severity Rating Scale (C-SSRS) in subjects aged 6 and above who are able to be evaluated
• Any suicidal behavior within 2 years before Visit 2 (i.e., answering YES to any question in the Suicidal behavior section of the age-specific Columbia-Suicide Severity Rating Scale (C-SSRS) in subjects aged 6 and above who are able to be evaluated.
• 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 x ULN
• Subject with total bilirubin \[TBL\] >2 x ULN (except for Gilbert's syndrome).
• Active viral hepatitis (B or C) as demonstrated by positive serology at the Screening visit (Visit 1)
• History of positive antibody/antigen test for human immunodeficiency virus (HIV)
• If taking Epidiolex, subject may not use other approved cannabidiol or over the counter cannabidiol products
• Scheduled for epilepsy-related surgery, VNS insertion, or any other stimulators/surgery during the projected course of the study
• Subject who has taken or used any investigational drug or device in the 4 weeks prior to the screening visit (Visit 1)
• Concomitant use of medications known to be strong inducers of cytochrome P450 (CYP3A) including, but not limited to: phenobarbital, phenytoin, carbamazepine, primidone, rifampin, troglitazone, St. John's Wort, efavirenz, nevirapine, glucocorticoids (other than topical usage), modafinil, pioglitazone, and rifabutin
• Evidence of cardiac disease, including unstable angina, myocardial infarction, within the past 2 years, uncontrolled heart failure, major arrhythmias, congenital short QT syndrome
• Subject with a short QTc interval (<340 msec) or long QTc interval (>460 msec) as confirmed by a repeated electrocardiogram (ECG)
• Benzodiazepine rescue administered on average more than once a week in the month before Visit 1
• Previous exposure to carisbamate or sensitivity/allergy to components of the oral suspension.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Двойное слепое

Основная цель

Лечение

Центры проведения

США · 22 центра

• Stanford University Hospital — Palo Alto
• University of Florida Health Science Center — Jacksonville
• AdventHealth — Orlando
• Pediatric Epilepsy and Neurology Specialists — Tampa
• University of South Florida — Tampa
• Axcess Medical Research — Wellington
• Consultants in Epilepsy and Neurology PLLC — Boise
• Bluegrass Epilepsy Research, LLC — Lexington
• … и ещё 14 центров

Италия · 6 центров

• Istituto G Gaslini Ospedale Pediatrico IRCCS - INCIPIT - PIN — Genoa
• ASST Fatebenefratelli Sacco - Ospedale dei Bambini Vittore Buzzi — Milan
• Fondazione IRCCS Di Rilievo Nazionale Instituto — Milan
• Azienda Ospedaliera Universitaria Integrata Di Verona — Verona
• Azienda Ospedaliero Universitaria A Meyer - INCIPIT - PIN — Florence
• ASST Santi Paolo E Carlo - Azienda Universitaria-Polo Universitaria - San Paolo — Milan

Колумбия · 5 центров

• Fundacion Hospital Universidad del Norte — Barranquilla
• Fundacion Valle del Lili/Clinic - Outpatient — Cali
• CliniSalud del Sur S.A.S - Centro de Investigación — Envigado
• Hospital Pabloe Tubon Uribe — Medellín
• Institutio Neurologico de Colombia — Medellín

Сербия · 5 центров

• Childrens University Hospital — Belgrade
• University Clinical Center of Serbia - PPDS — Belgrade
• University Clinical Center Kragujevac — Kragujevac
• University Clinical Center Nis — Niš
• Children and Youth Health Care Institute of Vojvodina — Novi Sad

Австралия · 4 центра

• Austin Hosptial — Heidelberg
• Alfred Health — Melbourne
• Perth's Children Hospital — Nedlands
• Queensland Children's Hospital — South Brisbane

Израиль · 4 центра

• Tela Viv Sourlasky Medical Center — Tel Aviv
• Soroka University Medical Centre — Beersheba
• Hadassah Medical Center — Jerusalem
• Sheba Medical Center — Ramat Gan

Португалия · 4 центра

• Centro Hospitalar de Lisboa Norte, EPE — Lisbon
• Centro Hospitalar de Lisboa Ocidental, EPE - Hospital Sao Francisco Xavier — Lisbon
• Centro Hospitalar de Sao Joao, EPE — Porto
• Hospital Garcia de Orta — Almada

Мексика · 3 центра

• Hospital Civil Fray Antonio Alcalde — Guadalajara
• Neurociencias Estudios Clinicos S.C. — Culiacán
• Clinstile, S.A. de C.V. — Mexico City

South Korea · 3 центра

• Kyungpook National University Chilgok Hospital — Daegu
• Samsung Medical Center — Seoul
• Seoul National University Hospital — Seoul

Испания · 3 центра

• Hospital Sant Joan de Deu - PIN — Esplugues de Llobregat
• Hospital Infantil Universitario Niño Jesus - PIN — Madrid
• Hospital Ruber Internacional (Grupo Quironsalud) — Madrid

Тайвань · 3 центра

• National Taiwan University Hospital — Taipei
• Taipei Veterans General Hospital — Taipei
• Chang Gung Memorial Hospital — Taoyuan

Аргентина · 2 центра

• Hospital de Ninos de La Santisma Trinidad — Córdoba
• Resolution Psychopharmacology Research Institute — Mendoza

Германия · 2 центра

• Universitatsklinikum Erangen — Erlangen
• Kleinwachau Sächsisches Epilepsiezentrum — Radeberg

Венгрия · 2 центра

• Orszagos Mentalis, Ideggyogyaszati es Idegsebezeti Intezet — Budapest
• Semmelweis Egyetem Idegsebeszeti es Neurointervencios Klinika — Budapest

Польша · 2 центра

• Szpital Kliniczny im.H.Swiecickiego Uniwersytetu Medycznego im.K.Marcinkowskiego w Poznani — Poznan
• Centrum Medyczne Plejady — Krakow

Греция · 1 центр

• Iaso Children's Hospital — Marousi

Идентификаторы

NCT: NCT05219617 · YKP509C003

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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