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    Summary
    EudraCT Number:2021-002480-22
    Sponsor's Protocol Code Number:TAK-935-3001
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2021-07-30
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2021-002480-22
    A.3Full title of the trial
    A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Parallel Group Study to Evaluate the Efficacy, Safety, and Tolerability of Soticlestat as Adjunctive Therapy in Pediatric and Young Adult Subjects With Dravet Syndrome (DS)
    Estudio multicéntrico, aleatorizado, doble ciego, controlado con placebo y de grupos paralelos para evaluar la eficacia, la seguridad y la tolerabilidad de soticlestat como tratamiento adyuvante en sujetos pediátricos y en adultos jóvenes con síndrome de Dravet (SD)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of Soticlestat as Adjunctive Therapy in Pediatric and Young Adult Subjects With Dravet Syndrome
    Estudio de soticlestat como tratamiento adyuvante en sujetos pediátricos y en adultos jóvenes con síndrome de Dravet
    A.4.1Sponsor's protocol code numberTAK-935-3001
    A.7Trial is part of a Paediatric Investigation Plan Yes
    A.8EMA Decision number of Paediatric Investigation PlanP/317/2020
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorTakeda Development Center Americas, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportTakeda Development Center Americas, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationTakeda Development Center Americas, Inc.
    B.5.2Functional name of contact pointMedical Director
    B.5.3 Address:
    B.5.3.1Street Address95 Hayden Avenue
    B.5.3.2Town/ cityLexington, MA
    B.5.3.3Post code02421
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34900 834 223
    B.5.6E-mailRegistroEspanolDeEstudiosClinicos@druginfo.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namesoticlestat
    D.3.2Product code TAK-935
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPGastroenteral use
    Oral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNsoticlestat
    D.3.9.1CAS number 1429505-03-2
    D.3.9.2Current sponsor codeTAK-935
    D.3.9.4EV Substance CodeSUB198078
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namesoticlestat
    D.3.2Product code TAK-935
    D.3.4Pharmaceutical form Film-coated tablet
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPGastroenteral use
    Oral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNsoticlestat
    D.3.9.1CAS number 1429505-03-2
    D.3.9.2Current sponsor codeTAK-935
    D.3.9.4EV Substance CodeSUB198078
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboFilm-coated tablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Dravet Syndrome (DS)
    Síndrome de Dravet (SD)
    E.1.1.1Medical condition in easily understood language
    seizures
    convulsiones
    E.1.1.2Therapeutic area Diseases [C] - Nervous System Diseases [C10]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10073682
    E.1.2Term Dravet syndrome
    E.1.2System Organ Class 100000004850
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    - To assess the efficacy of soticlestat in reducing convulsive seizure frequency as add-on therapy to SOC as compared with placebo during the full treatment period (titration + maintenance).

    - To assess the efficacy of soticlestat in reducing convulsive seizure frequency as add-on therapy to SOC compared with placebo during the maintenance period only.
    - Evaluar la eficacia de soticlestat en la reducción de la frecuencia de crisis convulsivas como tratamiento complementario del tratamiento habitual en comparación con un placebo durante el período de tratamiento completo (ajuste + mantenimiento).

    - Evaluar la eficacia de soticlestat en la reducción de la frecuencia de crisis convulsivas como tratamiento complementario del tratamiento habitual en comparación con un placebo únicamente durante el período de mantenimiento.
    E.2.2Secondary objectives of the trial
    To assess the following in subjects taking soticlestat as compared with placebo during the full treatment period, unless otherwise noted:
    - Proportion of treatment responders defined as those with >=50% reduction in convulsive seizures from baseline during the maintenance period and the full treatment period.
    - Effect on total seizure frequency of all seizure types during the maintenance period and the full treatment period.
    - Change from baseline in proportion of convulsive seizure-free days.
    - Longest convulsive seizure-free interval.
    - Number of days when rescue antiseizure medications (ASMs) are used.
    - Effect on the Clinical Global Impression of Improvement (CGI-I) (clinician) and Caregiver Global Impression of Improvement (Care GI-I).
    - Effect on CGI-I Seizure Intensity and Duration.
    - Effect on the CGI-I Nonseizure Symptoms completed by clinician with input from the caregivers.
    - Effect on Quality of Life Inventory-Disability (QI-Disability).
    Evaluar lo siguiente:
    - Proporción de pacientes con respuesta al tratamiento, definida como aquellos con una reducción >=50 % de las crisis convulsivas con respecto al momento basal durante el período de mantenimiento y el período de tratamiento completo
    - Efecto sobre la frecuencia total de crisis de todos los tipos durante el periodo de mantenimiento y el periodo de tratamiento completo
    - Variación con respecto al momento basal de la proporción de días sin crisis convulsivas
    - Mayor intervalo sin crisis convulsivas
    - Número de días en que se utilizan antiepilépticos de rescate
    - Efecto en la Impresión clínica global de mejoría (CGI-I) (médico) y la Impresión global de mejoría del cuidador (Care GI-I)
    - Efecto en la CGI-I de la intensidad y duración de las crisis
    - Efecto en los síntomas no convulsivos en la CGI-I completado por el médico con la información aportada por los cuidadores.
    - Efecto en el cuestionario de calidad de vida-discapacidad (QI-discapacidad)
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. In the opinion of the investigator, the subject and/or parent or legal guardian is capable of understanding and complying with protocol requirements including the use of digital tools, complete appropriate assessments, maintain an accurate and complete daily seizure diary and take study drug for the duration of the study.
    2. The subject or the subject’s parent or legal guardian are willing and able to read, understand, and sign and date a written or an electronic informed consent form (ICF), assent form (if applicable), and any required privacy authorization prior to the initiation of any study procedures.
    3. The subject is male or female and aged 2 to 21 years, inclusive, at the time of informed consent.
    4. Documented clinical diagnosis of DS supported by:
    - Onset of seizures usually in the first year of life.
    - History of fever-induced prolonged seizure as determined by the investigator:
    - May include prolonged (approximately 15 minutes or longer) hemi-clonic seizures.
    - Multiple seizure types, which may include:
    – Generalized tonic-clonic.
    – Focal to bilateral tonic-clonic.
    – Clonic.
    – Myoclonic seizures.
    - History of developmental delay/intellectual disability presenting after onset of seizures and usually presenting after 12 months of age.
    - Documented genetic mutation consistent with DS is not required, but results of genetic testing will be collected if available. If genetic testing was not performed previously or if the SCN1A result is negative (without any other positive gene reported that is consistent clinically with DS), testing for SCN1A will be offered at the time of screening.
    5. Has >=4 convulsive seizures in each 1-month period in the 3 months before screening based on the historical information and has >=4 convulsive seizures per 28 days during the 4- to 6- week prospective baseline period.
    6. Weighs >=10 kg at the screening visit (Visit 1).
    7. Failure to control seizures despite appropriate trials of at least 2 ASMs based on historical information and is currently on an antiseizure therapy (eg ASMs, vagus nerve stimulation (VNS), ketogenic/modified Atkins diet) or other treatment options considered as SOC.
    8. Currently taking 0 to 4 ASMs at stable doses for at least 4 weeks before the screening visit (Visit 1); benzodiazepines used chronically (daily) to treat seizures are considered ASMs. ASM dosing regimen must remain constant throughout the study.
    9. If using a VNS, the subject must have had VNS placed at least 3 months before the screening visit with stable settings for >1 month; VNS parameters must remain constant throughout the study (VNS will not be counted as an ASM).
    10. If on ketogenic diet (or any other diet used for treatment of epilepsy, such as modified Atkins diet), the subject must have started the diet at least 3 months before the screening visit (Visit 1), and the subject’s diet should be stable for 1 month before the screening visit (Visit 1); the subject should continue this diet throughout the duration of the study (ketogenic diet, or any
    other diet for the treatment of epilepsy will not be counted as an ASM).
    11. The use of felbamate is allowed provided that the subject does not meet the liver function test (LFT) exclusion criteria, the dose has been stable for at least 6 months before screening, and the subject has had stable liver function (as determined by serum aspartate aminotransferase [AST] and alanine aminotransferase [ALT] levels) and hematology laboratory tests during the
    course of treatment.
    12. Approved to participate by the sponsor and/or designee (ie, TESC) after review of medical history and seizure classification.
    13. Female subjects of childbearing potential (defined as first menarche) must have a negative pregnancy test and agree to use an effective method of birth control during the study and for 30 days following the last dose of study drug.
    Effective contraceptive methods are as follows:
    - Double-barrier method (contraceptive sponge, diaphragm, or cervical cap with spermicidal jellies or creams PLUS male condom).
    - Progestogen-only hormonal contraception, where inhibition of ovulation is not the primary mode of action, PLUS condom with or without spermicide.
    - Sexual abstinence:
    i. Sexual abstinence may be considered as a method only if defined as refraining from heterosexual intercourse and determined to be the usual lifestyle before entering the study with reliability of abstinence for the duration of the study participation and for
    30 days after last dose of study drug.
    - Sterilization:
    ii. Bilateral tubal occlusion.
    iii. Vasectomized partner (provided that the partner is the sole sexual partner of the subject and the absence of sperm in the ejaculate has been confirmed).
    1.Según la opinión del investigador, el sujeto y/o padre, madre o tutor legal es capaz de comprender y cumplir los requisitos del protocolo, incluido el uso de herramientas digitales, realizar las evaluaciones pertinentes, mantener un diario de crisis exacto y completo y tomar el fármaco del estudio durante todo el estudio.
    2.El sujeto o el padre, madre o tutor legal del sujeto está dispuesto y es capaz de leer, entender y firmar y fechar un documento de consentimiento informado (DCI) por escrito o electrónico, un documento de asentimiento (si corresponde) y cualquier autorización sobre protección de datos necesaria antes del inicio de los procedimientos del estudio.
    3. Pacientes de ambos sexos, de 2 a 21 años, ambos inclusive, en el momento de firmar el consentimiento informado.
    4. Diagnóstico clínico documentado de SD respaldado por:
    -Aparición de las crisis generalmente en el primer año de vida.
    - Antecedentes de crisis prolongadas inducidas por la fiebre según lo determinado por el investigador:
    - Puede incluir crisis hemiclónicas prolongadas (aproximadamente 15 minutos o más)
    - Diversos tipos de crisis, entre ellos:
    – Tonicoclónicas generalizadas.
    – Tonicoclónicas focales o bilaterales.
    – Clónicas.
    – Crisis mioclónicas.
    - Antecedentes de retraso del desarrollo/discapacidad intelectual que se manifiestan tras el inicio de las crisis y suele aparecer después de los 12 meses de edad.
    - No se precisan mutaciones genéticas documentadas compatibles con el SD, pero se recogerán los resultados del análisis genético si están disponibles. En caso de no haberse realizado pruebas genéticas con anterioridad o si el resultado de SCN1A es negativo (sin que se haya notificado ningún otro gen positivo que sea compatible clínicamente con el SD), se ofrecerá el análisis de SCN1A en el momento de la selección.
    5. Presencia de >=4 crisis convulsivas en cada período de 1 mes durante los 3 meses previos a la selección según la información histórica y presencia de >=4 crisis convulsivas por cada 28 días durante el período basal prospectivo de 4 a 6 semanas.
    6. Peso >=10 kg en la visita de selección (visita 1).
    7. Falta de control de las crisis a pesar de intentos adecuados de al menos 2 antiepilépticos basados en información de los antecedentes y tratamiento antiepiléptico en curso (p. ej., antiepilépticos, estimulación del nervio vago, dieta cetógena/de Atkins modificada) u otras opciones terapéuticas consideradas tratamiento de referencia.
    8.Tratamiento actual con 0 a 4 antiepilépticos en dosis estables durante al menos 4 semanas antes de la visita de selección (visita 1); las benzodiacepinas utilizadas de forma crónica (a diario) para tratar las crisis se consideran antiepilépticos. La pauta posológica de antiepilépticos deberá mantenerse constante durante todo el estudio.
    9. Si se utiliza ENV, deberá haberse colocado al menos 3 meses antes de la visita de selección, manteniendo las configuraciones estables durante más de 1 mes; los parámetros de la ENV deben mantenerse constantes durante todo el estudio (la ENV no se contabilizará como AE).
    10. Si el paciente sigue una dieta cetógena (o cualquier otra dieta utilizada para el tratamiento de la epilepsia, como la dieta de Atkins modificada), deberá haberla empezado al menos 3 meses antes de la visita de selección (visita 1) y deberá haberse mantenido estable durante un mes antes de la visita de selección (visita 1); el paciente deberá seguir con esta dieta durante todo el estudio (la dieta cetógena o cualquier otra dieta para el tratamiento de la epilepsia no se contabilizará como AE).
    11. Se permite el uso de felbamato siempre que el paciente no cumpla los criterios de exclusión de las pruebas de función hepática (PFH), la dosis se haya mantenido estable durante al menos 6 meses antes de la selección y el paciente haya presentado una función hepática estable (determinada por las concentraciones séricas de aspartato aminotransferasa [AST] y alanina aminotransferasa [ALT]) y análisis hematológicos estables durante el tratamiento.
    12. Aprobación para participar por el promotor y/o su representante (es decir, TESC) tras la revisión de los antecedentes médicos y la clasificación de las crisis.
    13. Las mujeres con capacidad reproductiva (definidas como la primera menarquia) deberán tener una prueba de embarazo negativa y comprometerse a utilizar un método anticonceptivo eficaz durante el estudio y durante 30 días después de la última dosis del fármaco del estudio.
    Métodos anticonceptivos eficaces:
    Método de doble barrera.
    Anticonceptivos hormonales solo con progestágenos, cuyo mecanismo de acción principal no sea la inhibición de la ovulación, MÁS preservativo con o sin espermicida
    Abstinencia sexual
    Esterilización (Ligadura de trompas bilateral, vasectomía de la pareja)
    E.4Principal exclusion criteria
    1. Investigator site personnel directly affiliated with this study and/or their immediate family. Note: Immediate family is defined as a spouse, parent, child, or sibling, whether biological or legally adopted.
    2. Takeda employees or immediate family members.
    3. Currently enrolled in a clinical study involving an investigational product or nonapproved use of a drug or device (other than the investigational product used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study. Note: Compatibility will be determined based on consultation with the medical monitor or the sponsor.
    4. Participated in a clinical study involving another study drug in the last 30 days (or 5 half-lives of the study drug, whichever is longer) before screening (Visit 1).
    5. Received soticlestat in a previous clinical study.
    6. Known hypersensitivity to any component of the soticlestat formulation.
    7. Admitted to a medical facility and intubated for treatment of status epilepticus 2 or more times in the 3 months immediately before screening (Visit 1). Status epilepticus is defined as continuous seizure activity lasting longer than 5 minutes or repeated seizures without return to baseline in between seizures.
    8. Unstable, clinically significant neurologic (other than the disease being studied), psychiatric, cardiovascular, ophthalmologic, pulmonary, hepatic, renal, metabolic, gastrointestinal, urologic, immunologic, hematopoietic, endocrine disease, malignancy including progressive tumors, or other abnormality that may impact the ability to participate in the study or that may potentially confound the study results. It is the responsibility of the investigator to assess the clinical significance; however, consultation with the medical monitor may be warranted.
    9. Any history of alcohol, opioid, or other drug use disorder, as per the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-V), within the 2 years immediately before the screening visit (Visit 1).
    10. Considered by the investigator to be at imminent risk of suicide or injury to self, others, or property, or the subject has attempted suicide within 12 months before the screening visit (Visit 1). Subjects who have positive answers on item numbers 4 or 5 on the C-SSRS before randomization (Visit 2) are excluded. This scale will only be administered to subjects aged ≥6 years.
    11. History of HIV infection (subject has tested positive for HIV-1 or HIV-2 antibodies), history of hepatitis B infection, or current active hepatitis C infection. Note: Subjects who have been vaccinated against hepatitis B (hepatitis B surface antibody-positive] and who test negative for other markers of prior hepatitis B infection (eg, negative for hepatitis B core antibody) are eligible. Also note that subjects who test positive for hepatitis C antibody are eligible if they have a negative hepatitis C viral load by quantitative polymerase chain reaction.
    12. Abnormal and clinically significant ECG abnormality at screening (Visit 1) or before randomization (Visit 2), including QT interval with Fridericia correction method (QTcF) >450 ms confirmed with a repeat ECG using manual measurement of QTcF. Clinically significant ECG abnormalities should be discussed with the medical monitor.
    13. Abnormal clinical laboratory test results at screening (Visit 1) that suggest a clinically significant underlying disease that would compromise the well-being of the subject. If the subject has serum ALT and/or AST level >2.5 times the upper limit of normal (ULN), the medical monitor should be consulted.
    14. Unable to withhold the use of strong inducers and inhibitors of cytochrome P450 (CYP) 3A4 during the entire clinical trial, except for ASMs (eg, carbamazepine, phenobarbital, phenytoin).
    15. Unwilling to withhold the fruit and juice of grapefruit, Seville oranges, and starfruit from their diet during the entire clinical trial.
    16. Use of herbal preparations (when used as an ASM) or artisanal cannabidiol (CBD) during the entire clinical trial.
    17. Currently pregnant or breastfeeding or is planning to become pregnant within 30 days of the last dose of study drug.
    1. Personal del centro de investigación relacionado directamente con este estudio y/o sus familiares inmediatos.
    Nota: se consideran familiares inmediatos cónyuge, padre, madre, hijo/a o hermano/a, ya sea biológico o adoptado legalmente.
    2. Empleados de Takeda o familiares directos.
    3. Participación actual en un estudio clínico con un producto en investigación o uso no aprobado de un fármaco o producto sanitario (distinto del producto en investigación utilizado en este estudio), o participación simultánea en otro tipo de investigación médica que no se considere científica o médicamente compatible con este estudio.
    Nota: La compatibilidad se determinará previa consulta con el monitor médico o el promotor.
    4. Participación en un estudio clínico con otro fármaco en investigación en los últimos 30 días (o el equivalente a 5 semividas del fármaco del estudio, lo que suponga más tiempo) antes de la selección (visita 1).
    5. Tratamiento con soticlestat en un estudio clínico previo.
    6. Hipersensibilidad conocida a cualquier componente de la formulación de soticlestat.
    7. Ingreso en un centro médico e intubación para tratamiento del estado epiléptico en 2 o más ocasiones en los 3 meses inmediatamente anteriores a la selección (visita 1). El estado epiléptico se define como una actividad convulsiva continua de más de 5 minutos de duración o crisis repetidas sin recuperación del valor basal entre las crisis.
    8. Enfermedad neurológica (aparte de la estudiada), psiquiátrica, cardiovascular, oftalmológica, pulmonar, hepática, renal, metabólica, digestiva, urológica, inmunológica, hematopoyética o endocrina inestable y de importancia clínica, neoplasia maligna, incluidos los tumores progresivos, u otra anomalía que pueda influir en la capacidad para participar en el estudio o que pueda confundir los resultados del estudio. Es responsabilidad del investigador evaluar la importancia clínica; sin embargo, puede estar justificada la consulta con el monitor médico.
    9. Antecedentes de trastorno por consumo de alcohol, opiáceos u otras drogas, según el Manual diagnóstico y estadístico de los trastornos mentales, quinta edición (DSM-V), en los 2 años inmediatamente anteriores a la visita de selección (visita 1).
    10. En opinión del investigador, riesgo inminente de suicidio o de autolesiones, lesiones a los demás o daños a la propiedad, o el paciente ha intentado suicidarse en los 12 meses previos a la visita de selección (visita 1). Se excluirá a los pacientes con respuestas positivas en los apartados 4 o 5 de la escala C-SSRS antes de la aleatorización (visita 2). Esta escala sólo se aplicará a pacientes de 6 años o más.
    11. Antecedentes de infección por el VIH (el paciente ha dado positivo para anticuerpos contra el VIH-1 o el VIH-2), antecedentes de infección por el virus de la hepatitis B o infección activa por el virus de la hepatitis C.
    Nota: Podrán participar los pacientes vacunados contra la hepatitis B (anticuerpos contra el antígeno de superficie del virus de la hepatitis B positivos) que no presenten otros marcadores de infección previa por la hepatitis B (por ejemplo, negatividad para anticuerpos contra el antígeno central del virus de la hepatitis B). Hay que señalar también que los pacientes con anticuerpos contra la hepatitis C son aptos si tienen una carga viral de hepatitis C negativa mediante reacción en cadena de la polimerasa cuantitativa.
    12. Anomalía del ECG de importancia clínica en la selección (visita 1) o antes de la aleatorización (visita 2), incluido un intervalo QT con el método de corrección de Fridericia (QTcF) >450 ms, confirmada con un nuevo ECG utilizando medición manual del QTcF. Las anomalías ECG de importancia clínica se comentarán con el monitor médico.
    13. Resultados anómalos en los análisis clínicos realizados en la selección (visita 1) que indiquen una enfermedad subyacente de importancia clínica que pueda comprometer el bienestar del sujeto. Si el paciente presenta una concentración sérica de ALT y/o AST >2,5 veces el límite superior de la normalidad (LSN), se consultará al monitor médico.
    14. Imposibilidad de suspender el uso de inductores e inhibidores potentes de la enzima 3A4 del citocromo P450 (CYP) durante todo el ensayo clínico, excepto los AE (por ejemplo, carbamazepina, fenobarbital o fenitoína).
    15. Falta de disposición a eliminar de la dieta el pomelo y zumo de pomelo, las naranjas amargas y la carambola durante todo el ensayo clínico.
    16. Uso de preparados a base de hierbas medicinales (cuando se utilizan como AE) o cannabidiol (CBD) artesanal durante todo el ensayo clínico.
    17. Paciente embarazada o en período de lactancia o que tiene intención de quedarse embarazada en los 30 días siguientes a la última dosis del fármaco del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    - Percent change from baseline in convulsive seizure frequency per 28 days in subjects receiving soticlestat as compared with placebo during the full treatment period.

    - Percent change from baseline in convulsive seizure frequency per 28 days in subjects receiving soticlestat as compared with placebo during the maintenance period.
    - Variación porcentual con respecto al momento basal de la frecuencia de crisis convulsivas en 28 días en los sujetos tratados con soticlestat en comparación con un placebo durante el período de tratamiento completo.

    - Variación porcentual con respecto al valor basal de la frecuencia de crisis convulsivas en 28 días en los sujetos tratados con soticlestat en comparación con un placebo durante el período de mantenimiento
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary end points will be assessed throughout the study.
    Los criterios de valoración principal se evaluarán a lo largo de todo el estudio
    E.5.2Secondary end point(s)
    - Proportion of responders defined as those with >=50% reduction from baseline in convulsive seizures during the maintenance period and the full treatment period.
    - Percent change from baseline in frequency of all seizures per 28 days during the maintenance period and the full treatment period.
    - Percent change from baseline in convulsive seizure frequency per 28 days during the maintenance period.
    - Responder analysis of the proportion of subjects with <=0%, >0% to <=25%, >25% to <=50%, >50% to <=75%, and >75% to <=100% reduction in convulsive seizures in a cumulative response curve.
    - Change from baseline in proportion of convulsive seizure-free days.
    - Longest convulsive seizure-free interval.
    - Number of days when rescue ASM is used.
    - CGI-I (clinician).
    - Care GI-I (caregiver).
    - CGI-I Seizure Intensity and Duration.
    - CGI-I Nonseizure Symptoms.
    - Change in QI-Disability score.
    - Proporción de pacientes con respuesta, definida como aquellos con una reducción >=50 % con respecto al momento basal de las crisis convulsivas durante el período de mantenimiento y el período de tratamiento completo.
    - Variación porcentual con respecto al momento basal de la frecuencia de todas las crisis en 28 días durante el periodo de mantenimiento y el periodo de tratamiento completo.
    - Variación porcentual con respecto al valor basal de la frecuencia de crisis convulsivas en 28 días durante el período de mantenimiento.
    - Análisis en los pacientes con respuesta de la proporción de sujetos con una reducción <=0 %, >0 % a <=25 %, >25 % a <=50 %, >50 % a <=75 % y >75 % a <=100 % de las crisis convulsivas en una curva de respuesta acumulada.
    - Variación con respecto al momento basal de la proporción de días sin crisis convulsivas.
    - Mayor intervalo sin crisis convulsivas.
    - Número de días en que se utilizan antiepilépticos de rescate.
    - CGI-I (médico).
    - Care GI-I (cuidador).
    - Intensidad y duración de las crisis en CGI-I.
    - Síntomas no convulsivos en CGI-I.
    - Variación de la puntuación en el QI-Discapacidad.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Secondary end points will be assessed throughout the study.
    Los Criterios de valoración secundarios se evaluarán a lo largo de todo el estudio
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA39
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Belgium
    Canada
    China
    France
    Greece
    Hungary
    Italy
    Japan
    Latvia
    Netherlands
    Poland
    Russian Federation
    Serbia
    Spain
    Ukraine
    United Kingdom
    United States
    E.8.7Trial 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
    LVLS
    Última Visita del Último Sujeto
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months22
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months22
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 100
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 64
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 36
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 42
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state14
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 100
    F.4.2.2In the whole clinical trial 142
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    Study drug will not be available upon completion of the subject’s participation in the study. The subject should be returned to the care of a physician and standard therapies initiated or resumed as required. However, following completion of the study, subjects will have the option to enroll in an OLE study, as per the OLE study’s inclusion/exclusion criteria.
    El medicamento del estudio no estará disponible después de que el sujeto complete su participación en el estudio. El sujeto deberá ser seguido por su médico e iniciar o continuar con la terapia habitual requerida. Sin embardo, tras completar el estudio, los pacientes tendrán la opción de participar en un estudio abierto de extensión de acuerdo a los criterios de inclusión/exclusión de este estudio.
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-10-15
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-08
    P. End of Trial
    P.End of Trial StatusOngoing
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