E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Epilepsy with partial onset seizures |
Epilepsia con crisis de inicio parcial |
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E.1.1.1 | Medical condition in easily understood language |
Epilepsy with partial onset seizures |
Epilepsia con crisis de inicio parcial |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nervous System Diseases [C10] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 18.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10015037 |
E.1.2 | Term | Epilepsy |
E.1.2 | System Organ Class | 10029205 - Nervous system disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
The primary objective of this study is to evaluate the efficacy of LCM administered concomitantly with 1 to 3 AEDs in subjects >=1 month to <4 years of age with epilepsy who currently have uncontrolled partial-onset seizures. |
El objetivo principal de este estudio es evaluar la eficacia de la LCM administrada de forma concomitante con FAE (de 1 a 3) en pacientes con epilepsia de >= 1 mes a < 4 años de edad que actualmente presentan crisis de inicio parcial no controladas. |
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E.2.2 | Secondary objectives of the trial |
The secondary objective is to evaluate the safety and tolerability of LCM in subjects >=1 month to <4 years of age with epilepsy who currently have uncontrolled partial-onset seizures. |
El objetivo secundario es evaluar la seguridad y la tolerabilidad de la LCM en pacientes con epilepsia de >=1 mes a < 4 años de edad que actualmente presentan crisis de inicio parcial no controladas. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Subject is male or female from >=1 month (ie, 4 weeks after full term [37 weeks gestational age]) to <4 years of age. -Subject has a diagnosis of epilepsy with partial-onset seizures. The results of >=1 prior EEG and >=1 magnetic resonance imaging/computerized tomography scan should be consistent with this diagnosis. -Subject weighs >=4kg to <30kg at Visit 1. - Subject has uncontrolled partial-onset seizures after an adequate course of treatment (in the opinion of the investigator) with >=2 AEDs (concurrently or sequentially). -Subject has experienced >=2 partial-onset seizures with or without secondary generalization during each consecutive 7-day period during the 2 weeks prior to Visit 1. - Subject has >=2 partial-onset seizures with or without secondary generalization during the 72-hour Baseline video-EEG. -Subject is on a stable (concurrently or sequentially) dosage regimen of 1 to 3 AEDs. The dosage regimen of concomitant AED therapy must be kept constant for a period of >=2 weeks prior to Visit 1. A stable daily dosage regimen of a concomitant benzodiazepine (BZD) will be considered as a concomitant AED. -Vagus nerve stimulation is allowed and will not be counted as a concomitant AED. The VNS device must have been implanted for >=6 months prior to Visit 1; device settings must be kept stable for >=2 weeks prior to Visit 1 and kept stable during the Baseline, Treatment, and Transition Periods. Use of the VNS device magnet is allowed. -Subject is an acceptable candidate for venipuncture |
- El paciente es varón o mujer y tiene una edad entre >=1 mes (es decir, 4 semanas, después de un parto normal con una edad gestacional de 37 semanas) y < 4 años. - El paciente ha recibido un diagnóstico de epilepsia con crisis de inicio parcial. Los resultados de >=1 EEG anteriores y de >=1 exploraciones de resonancia magnética o tomografía computarizada deben concordar con este diagnóstico. -El peso del paciente es >=4 kg e < 30 kg en la visita 1. -El paciente sufre crisis de inicio parcial no controladas tras haber seguido correctamente (a juicio del investigador) un tratamiento mediante >=2 FAE (de forma simultánea o secuencial). -El paciente ha experimentado al menos >=2 crisis de inicio parcial, con o sin generalización secundaria, durante cada periodo de 7 días consecutivos en las 2 semanas previas a la visita 1. -El paciente sufre >=2 crisis de inicio parcial, con o sin generalización secundaria, durante el video-EEG basal de 72 horas. -El paciente sigue una pauta posológica estable con de 1 a 3 FAE (simultáneos o secuenciales). La pauta posológica del tratamiento con FAE concomitantes debe mantenerse constante durante un periodo >=2 semanas antes de la visita 1. Una pauta posológica diaria estable con una benzodiacepina (BZD) concomitante será considerada como FAE concomitante. -Se permite la estimulación del nervio vago, que no se considerará como FAE concomitante. El dispositivo de ENV debe haber estado implantado durante >=6 meses antes de la visita 1; la configuración del dispositivo debe haberse mantenido estable durante >=2 semanas antes de la visita 1 y a lo largo de los periodos basal, de tratamiento y de transición. Se permite utilizar el imán para ENV. -El paciente es un candidato aceptable para venopunción. |
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E.4 | Principal exclusion criteria |
-Subject has experienced febrile seizures exclusively. The occurrence of febrile seizures in addition to partial-onset seizures is not exclusionary. -Subject is on a ketogenic or other specialized diet for the treatment of epilepsy. If the subject was on a ketogenic or other specialized diet in the past, they must be off this diet for >=2 months prior to Visit 1. -Subject has an alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total bilirubin level >=2 times the upper limit of normal (ULN), or creatinine clearance <30mL/minute. - Subject has a clinically relevant ECG abnormality, in the opinion of the investigator (eg, second or third degree heart block at rest or a corrected QT interval [QTc] >=450ms). -Subject has a hemodynamically significant congenital heart disease. -Subject has an arrhythmic heart condition requiring medical therapy. - Subject has a known history of severe anaphylactic reaction secondary to medication intake or serious blood dyscrasias. -Subject has nonepileptic events that could be confused with seizures. Subjects may be included if epileptic events can be clearly distinguished and the frequency meets the study inclusion criteria. -Subject has a current diagnosis of Lennox-Gastaut syndrome, epilepsia partialis continua, primary generalized epilepsy, or seizures that are not of partial-onset origin. -Subject has a history of status epilepticus <=2 months prior to Screening (Visit 1). -Subject has been treated with ethosuximide. -Subject is currently being treated with vigabatrin or has discontinued use <12 months prior to Visit 1. Subjects who were previously treated with vigabatrin and have discontinued use >12 months prior to Visit 1 are eligible. - Subject has been treated with felbamate and has experienced any serious toxicity issues (defined as liver failure, aplastic anemia) with this treatment. Subjects treated with felbamate for <12 months are excluded. Subjects treated with felbamate for >=12 months prior to Visit 1 and who have not experienced serious toxicity issues are eligible. - Subject has an acute or subacutely progressive central nervous system disease. Subject has epilepsy secondary to a progressing cerebral disease or any other progressively neurodegenerative disease (malignant brain tumor or Rasmussen Syndrome). -Subject has a known sodium channelopathy, such as Brugada syndrome. |
-El paciente solo ha experimentado crisis febriles. La aparición de crisis febriles junto a crisis de inicio parcial no es motivo de exclusión. -El paciente sigue una dieta cetógena u otra dieta especial para el tratamiento de la epilepsia. Si el paciente ha seguido en el pasado una dieta cetógena u otra dieta especial, debe haberla abandonado >=2 meses antes de la visita 1. -El paciente presenta un nivel de alanina aminotransferasa (ALT), de aspartato aminotransferasa (AST) o de bilirrubina total >=2 veces más alto que el límite superior de la normalidad (LSN) o un aclaramiento de creatinina < 30 ml/min. -El paciente presenta una anomalía clínicamente relevante en el ECG a juicio del investigador; por ejemplo, un bloqueo cardiaco de segundo o tercer grado en reposo o una prolongación del intervalo QT corregido (QTc) superior a 450 ms. -El paciente sufre una cardiopatía congénita hemodinámicamente significativa. -El paciente presenta una cardiopatía arrítmica que requiere tratamiento médico. -El paciente tiene antecedentes conocidos de reacción anafiláctica grave derivada de la toma de medicamentos o discrasias sanguíneas graves. -El paciente presenta actualmente un diagnóstico de síndrome de Lennox-Gastaut, epilepsia parcial continua, epilepsia generalizada primaria o crisis que no son de inicio parcial -El paciente tiene antecedentes de estado epiléptico <= 2 meses antes de la selección (visita 1). -El paciente ha sido tratado con etosuximida. -El paciente está sometido actualmente a tratamiento con vigabatrina o ha abandonado dicho tratamiento < 12 meses antes de la visita 1. Se consideran elegibles los pacientes que han sido tratados anteriormente con vigabatrina y han abandonado dicho tratamiento > 12 meses antes de la visita 1. -El paciente ha sido tratado con felbamato y ha experimentado problemas de toxicidad graves (definidos como insuficiencia hepática, anemia aplásica) con este tratamiento. Los pacientes tratados con felbamato durante < 12 meses quedan excluidos del estudio. Se consideran elegibles los pacientes que han sido tratados con felbamato durante >=12 meses antes de la visita 1 y no han experimentado problemas de toxicidad graves. -El paciente sufre una enfermedad aguda o subaguda progresiva del sistema nervioso central. El paciente tiene epilepsia secundaria a una enfermedad cerebral progresiva o a cualquier otra enfermedad neurodegenerativa progresiva (tumor cerebral maligno o síndrome de Rasmussen). -El paciente presenta una canalopatía de sodio conocida, como el síndrome de Brugada. |
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E.5 End points |
E.5.1 | Primary end point(s) |
1) The primary efficacy variable will be the proportion of responders where a responder is a subject experiencing a 50% or greater reduction in their ADF of electrographic partial-onset seizures recorded on the 72-hour End-of-Maintenance Period video-EEG compared to the 72-hour End-of-Baseline Period video-EEG. 2) Adverse events reported spontaneously by the subject's parent(s) and/or legal representative(s)/caregiver(s) (in accordance with local regulation) or observed by the investigator 3) Subject withdrawals due to AEs |
1) La variable principal de eficacia será la proporción de pacientes que presenten respuesta, entendiendo por tales a los pacientes que experimenten una reducción del 50% o superior en su FDM de crisis de inicio parcial electrográficas registradas en el video-EEG de 72 horas del final del periodo de mantenimiento con respecto al video-EEG de 72 horas del final del periodo basal. 2) Acontecimientos adversos comunicados espontáneamente por el padre o la madre (o ambos) y/o el/los representante/s legal/es o cuidador/es del paciente (conforme a la legislación local) u observados por el investigador. 3) Retiradas de pacientes debidas a AA. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1) End-of-Maintenance Period video-EEG (Visit 6) compared to the 72-hour End-of-Baseline Period video-EEG (Visits 2 and 3) 2) From Baseline to End-of-Treatment 3) From Baseline to End-of-Treatment |
5) Video-EEG del final del periodo de mantenimiento (Visita 6) comparado con el video-EEG de 72 horas del final del periodo basal (Visitas 2 y 3) 2) Desde el periodo basal al final del tratamiento. 3) Desde el periodo basal al final del tratamiento. |
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E.5.2 | Secondary end point(s) |
1) Percent and absolute change in ADF of electrographic partial-onset seizures from the End-of-Baseline Period video-EEG to the End-of-Maintenance Period video-EEG 2) Proportion of subjects who achieved "seizure-free" status (yes/no) for subjects who completed at least 48 hours of interpretable video-EEG recording during the End-of-Maintenance Period video-EEG 3) Proportion of subjects experiencing a >=25% to <50%, 50% to 75%, or >75% reduction in ADF of electrographic partial-onset seizures from the end-of-Baseline Period video-EEG to the End-of-Maintenance Period video-EEG 4) Proportion of subjects experiencing no change in ADF of electrographic partial-onset seizures (between <25% reduction and <25% increase) from the End-of-Baseline Period video-EEG to the End-of-Maintenance Period video-EEG 5) Proportion of subjects experiencing an increase in ADF of electrographic partial-onset seizures of >=25% from the End-of-Baseline Period video-EEG to the End-of-Maintenance Period video-EEG |
1) Variación porcentual y absoluta de la FDM de crisis de inicio parcial electrográficas entre el video-EEG del final del periodo basal y el video-EEG del final del periodo de mantenimiento. 2) Proporción de pacientes que alcanzan el estado "sin crisis" (sí/no) entre los pacientes que completan al menos 48 horas de registro de video-EEG interpretable durante el video-EEG del final del periodo de mantenimiento. 3) Proporción de pacientes que experimentan una reducción >=25% e < 50%, del 50% al 75% o > 75% en la FDM de crisis de inicio parcial electrográficas entre el video-EEG del final del periodo basal y el video-EEG del final del periodo de mantenimiento. 4) Proporción de pacientes que no experimentan ningún cambio en la FDM de crisis de inicio parcial electrográficas (entre una reducción < 25% y un aumento < 25%) entre el video-EEG del final del periodo basal y el video-EEG del final del periodo de mantenimiento. 5) Proporción de pacientes que experimentan un aumento en la FDM de crisis de inicio parcial electrográficas >=25% entre el video-EEG del final del periodo basal y el video-EEG del final del periodo de mantenimiento. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1) From the end-of-Baseline Period video-EEG (Visits 2 and 3) to the End-of-Maintenance Period video-EEG (Visit 6) 2) During the the end-of-Baseline Period video-EEG (Visit 6) 3) From the end-of-Baseline Period video-EEG (Visits 2 and 3) to the End-of-Maintenance Period video-EEG (Visit 6) 4) From the end-of-Baseline Period video-EEG (Visits 2 and 3) to the End-of-Maintenance Period video-EEG (Visit 6) 5) From the end-of-Baseline Period video-EEG (Visits 2 and 3) to the End-of-Maintenance Period video-EEG (Visit 6) |
1) Desde el video-EEG del final del periodo basal (Visitas 2 y 3) al video-EEG del final del periodo de mantenimiento (Visita 6). 2) Durante el video-EEG del final del periodo basal. (Visita 6) 3) Desde el video-EEG del final del periodo basal (Visitas 2 y 3) al video-EEG del final del periodo de mantenimiento (Visita 6). 4) Desde el video-EEG del final del periodo basal (Visitas 2 y 3) al video-EEG del final del periodo de mantenimiento (Visita 6). 5) Desde el video-EEG del final del periodo basal (Visitas 2 y 3) al video-EEG del final del periodo de mantenimiento (Visita 6). |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 87 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Argentina |
Australia |
Brazil |
Bulgaria |
Canada |
Chile |
Colombia |
Croatia |
Czech Republic |
France |
Georgia |
Germany |
Greece |
Hungary |
Israel |
Italy |
Korea, Republic of |
Mexico |
Moldova, Republic of |
Poland |
Romania |
Serbia |
Spain |
Taiwan |
Thailand |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |