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    Summary
    EudraCT Number:2016-000474-38
    Sponsor's Protocol Code Number:ZX008-1504
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-04-07
    Trial results View 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 number2016-000474-38
    A.3Full title of the trial
    A Multicenter, 2-Cohort Trial to First Assess the Pharmacokinetic and Safety Profile of a Single Dose of ZX008 (Fenfluramine Hydrochloride) Oral Solution When Added to Standard of Care (Cohort 1), Followed by a Randomized, Double-blind, Placebo-controlled Parallel Group Evaluation of the Efficacy, Safety, and Tolerability of ZX008 as Adjunctive Antiepileptic Therapy to Stiripentol Treatment in Children and Young Adults with Dravet Syndrome (Cohort 2)
    Ensayo multicéntrico, de 2 cohortes, para evaluar primero el perfil farmacocinético y de seguridad de una sola dosis de ZX008 (clorhidrato de fenfluramina) en solución oral cuando se añade al tratamiento convencional (cohorte 1), seguido de una evaluación aleatorizada, con doble enmascaramiento, controlada con placebo y con grupos paralelos de la eficacia, seguridad y tolerabilidad de ZX008 como terapia antiepiléptica complementaria al tratamiento con estiripentol en niños y jóvenes adultos con síndrome de Dravet (cohorte 2)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Multicenter, Trial to First Assess the Pharmacokinetic and Safety Profile of a Single Dose of ZX008 Oral Solution When Added to Standard of Care, Followed by a Randomized, Double-blind, Placebo-controlled Parallel Group Evaluation of the Efficacy, Safety, and Tolerability of ZX008 as Adjunctive Antiepileptic Therapy to standar treatment in Children and Young Adults with Dravet Syndrome
    Ensayo multicéntrico, para evaluar primero el perfil farmacocinético y de seguridad de una sola dosis de ZX008 en solución oral cuando se añade al tratamiento convencional, seguido de una evaluación aleatorizada, con doble enmascaramiento, controlada con placebo y con grupos paralelos de la eficacia, seguridad y tolerabilidad de ZX008 como terapia antiepiléptica complementaria al tratamiento habitual en niños y jóvenes adultos con síndrome de Dravet
    A.4.1Sponsor's protocol code numberZX008-1504
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorZogenix International Limited
    B.1.3.4CountryUnited Kingdom
    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 supportZogenix International Limited
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationZogenix International Limited
    B.5.2Functional name of contact pointArun Mistry
    B.5.3 Address:
    B.5.3.1Street AddressSiena Court, Broadway
    B.5.3.2Town/ cityMaidenhead
    B.5.3.3Post codeSL6 1NJ
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number+44776 055 9223
    B.5.6E-mailamistry@zogenix.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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1219
    D.3 Description of the IMP
    D.3.1Product nameFenfluramine hydrochloride
    D.3.2Product code ZX008
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFENFLURAMINE HYDROCHLORIDE
    D.3.9.1CAS number 404-82-0
    D.3.9.4EV Substance CodeSUB02115MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number1.25
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1219
    D.3 Description of the IMP
    D.3.1Product nameFenfluramine hydrochloride
    D.3.2Product code ZX008
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFENFLURAMINE HYDROCHLORIDE
    D.3.9.1CAS number 404-82-0
    D.3.9.4EV Substance CodeSUB02115MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2.5
    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: 3
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1219
    D.3 Description of the IMP
    D.3.1Product nameFenfluramine hydrochloride
    D.3.2Product code ZX008
    D.3.4Pharmaceutical form Oral solution
    D.3.4.1Specific paediatric formulation Yes
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNFENFLURAMINE HYDROCHLORIDE
    D.3.9.1CAS number 404-82-0
    D.3.9.4EV Substance CodeSUB02115MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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 placeboOral solution
    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's syndrome
    Síndrome de Dravet
    E.1.1.1Medical condition in easily understood language
    Dravet's syndrome
    Síndrome de Dravet
    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 19.1
    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 demonstrate that ZX008 is superior to placebo as adjunctive therapy in the treatment of symptoms of Dravet syndrome in children and young adults based on change in the frequency of convulsive seizures between baseline and the combined Titration and Maintenance Periods (T+M) in Cohort 2.
    Demostrar que ZX008 es superior a placebo como terapia complementaria en el tratamiento de los síntomas del síndrome de Dravet en niños y jóvenes adultos, en función del cambio en la frecuencia de crisis convulsivas entre el momento basal y los periodos combinados de ajuste posológico y mantenimiento (AP + M) en la cohorte 2
    E.2.2Secondary objectives of the trial
    The key secondary efficacy objectives of the study are related to Cohort 2 and include:
    To demonstrate that ZX008 is superior to placebo on the following endpoints:
    - The proportion of subjects who achieve a ≥40% reduction from baseline in convulsive seizure frequency.
    - The proportion of subjects who achieve a ≥50% reduction from baseline in convulsive seizure frequency.
    - The longest convulsive seizure-free interval.
    o Demostrar que ZX008 es superior a placebo en los siguientes criterios de valoración:
    Proporción de pacientes que logran una reducción ≥ 40 % con respecto al momento basal en la frecuencia de crisis convulsivas.
    Proporción de pacientes que logran una reducción ≥ 50 % con respecto al momento basal en la frecuencia de crisis convulsivas.
    Intervalo más largo sin crisis convulsivas
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Subject is male or non-pregnant, non-lactating female, age 2 to 18 years, inclusive as of the day of the Screening Visit. Female subjects of childbearing potential must not be pregnant or breast-feeding. Female subjects of childbearing potential must have a negative urine pregnancy test. Subjects of childbearing or child-fathering potential must be willing to use medically acceptable forms of birth control (see Section 4.4), which includes abstinence, while being treated on this study and for 90 days after the dose of study drug.
    2.Subject must have documented medical history to support a clinical diagnosis of Dravet syndrome, where convulsive seizures are not completely controlled by current antiepileptic drugs (AEDs).
    3. Subjects must meet all of the following 5 criteria:
    a.Onset of seizures in the first year of life in an otherwise healthy infant.
    b.A history of seizures that are either generalized tonic-clonic or unilateral clonic or bilateral clonic, and are prolonged.
    c.Initial development is normal.
    d.History of normal brain magnetic resonance imaging (MRI) without cortical brain malformation.
    e.Lack of alternative diagnosis.
    4.Subjects must meet at least one of the following 3 criteria:
    a.Emergence of another seizure type, including myoclonic, generalized tonic-clonic, tonic, atonic, absence and/or focal has developed after the first seizure type.
    b.Prolonged exposure to warm temperatures induces seizures and/or seizures are associated with fevers due to illness or vaccines, hot baths, high levels of activity and sudden temperature changes and/or seizures are induced by strong natural and/or fluorescent lighting, as well as certain visual patterns.
    c.Genetic test results consistent with a diagnosis of Dravet syndrome (pathogenic, likely pathogenic, variant of unknown significance, or inconclusive but unlikely to support an alternative diagnosis.)
    5.Subject must have had ≥ 4 convulsive seizures (tonic-clonic, tonic, clonic) per 4-week period for past 12 weeks prior to screening, by parent/guardian report to investigator or investigator medical notes [Cohort 2 only].
    6.All medications or interventions for epilepsy (including ketogenic diet [KD] and vagal nerve stimulation [VNS]) must be stable for at least 4 weeks prior to screening and are expected to remain stable throughout the study.
    7.Subject must be receiving a therapeutically relevant and stable dose of CLB, VPA, and STP for at least 4 weeks prior to screening and are expected to remain stable throughout the study [Cohort 2 only].
    8.Subject must be receiving a stable dose of CLB and VPA, administered twice daily (BID), to be eligible for Dose Regimen 1 and 2 or subject must be receiving a stable dose of CLB, VPA, and STP, administered BID, to be eligible for Dose Regimen 3 [Cohort 1 only].
    9.Subject agrees to provide a buccal swab for CYP2D6 (cytochrome P450 2D6) genotyping.
    10.Subject has been informed of the nature of the study and informed consent has been obtained from the legally responsible parent/guardian.
    11.Subject has provided assent in accordance with Institutional Review Board (IRB)/Independent Ethics Committee (IEC) requirements, if capable.
    12.Subject’s parent/caregiver is willing and able to be compliant with all study requirements and visit schedule. Subject’s parent/caregiver must also be willing and able to be compliant with diary completion and study drug accountability.
    1.Paciente varón o mujer no embarazada ni en periodo de lactancia, con una edad entre 2 y 18 años, inclusive, a partir del día de la visita de selección. Las mujeres con capacidad de concebir no deben estar embarazadas ni en periodo de lactancia. Las mujeres con capacidad de concebir deben presentar un resultado negativo en la prueba de embarazo en orina. Los pacientes con capacidad de concebir o engendrar un bebé deben estar dispuestos a utilizar métodos anticonceptivos aceptables desde un punto de vista médico (véase la sección 4.4), lo que incluye la abstinencia, mientras estén siendo tratados en este estudio y durante 90 días después de la última dosis de fármaco del estudio.
    2.El paciente debe tener antecedentes médicos documentados que respalden un diagnóstico clínico de síndrome de Dravet, en el que las crisis convulsivas no se controlen de manera completa con los fármacos antiepilépticos (FAE) actuales.
    3. Los pacientes deben cumplir todos los criterios siguientes (los 5):
    a. Inicio de las crisis en el primer año de vida en un niño que, por lo demás, está sano.
    b. Antecedentes de crisis que son o bien tónico-clónicas generalizadas, o bien clónicas unilaterales o clónicas bilaterales, y son prolongadas.
    c. El desarrollo inicial es normal.
    d. Antecedentes de resonancia magnética (RM) del cerebro normal sin malformación cerebral cortical.
    e. Ausencia de un diagnóstico alternativo.
    4.Los pacientes deben cumplir al menos uno de los 3 criterios siguientes:
    a. Después del primer tipo de crisis, se ha desarrollado la aparición de otro tipo de crisis, incluidas las mioclónicas, tónico-clónicas generalizadas, tónicas, atónicas, de ausencia y/o focales.
    b. La exposición prolongada a temperaturas cálidas induce la aparición de crisis y/o las crisis se asocian a fiebres debidas a enfermedad o vacunas, baños calientes, niveles altos de actividad y cambios repentinos de temperatura y/o las crisis son inducidas por la luz potente natural o fluorescente, así como por ciertos patrones visuales.
    c. Resultados del análisis genético que concuerdan con un diagnóstico de síndrome de Dravet (patogénico, probablemente patogénico, variante de significado incierto, o inconcluyente pero con pocas probabilidades de respaldar un diagnóstico alternativo).
    5.El paciente debe haber presentado ≥ 4 crisis convulsivas (tónico-clónicas, tónicas, clónicas) por cada periodo de 4 semanas durante las 12 semanas anteriores a la selección, según el informe del padre/madre/tutor al investigador o según las notas médicas del investigador [solo la cohorte 2].
    6. Todos los medicamentos e intervenciones para la epilepsia (incluida la dieta cetogénica [DC] y la estimulación del nervio vago [ENV]) deben ser estables durante al menos 4 semanas antes de la selección, y se espera que sigan siendo estables durante todo el estudio.
    7.Los pacientes deben estar recibiendo una dosis estable e importante desde un punto de vista terapéutico de CLB, VPA y STP durante al menos 4 semanas antes de la selección, y se espera que siga siendo estable durante todo el estudio [solo la cohorte 2].
    8.El paciente debe estar recibiendo una dosis estable de CLB y VPA, administrada dos veces al día, para ser apto para las pautas posológicas 1 y 2 o el paciente debe estar recibiendo una dosis estable de CLB, VPA y STP, administrada dos veces al día, para ser apto para la pauta posológica 3 [solo la cohorte 1].
    9.El paciente acepta proporcionar un frotis bucal para el genotipado de CYP2D6 (citocromo P450 2D6).
    10.Se ha informado al paciente sobre la naturaleza del estudio y se ha obtenido el consentimiento informado del padre/madre/tutor que sea el responsable legal.
    11.El paciente ha otorgado el asentimiento de acuerdo con los requisitos del Comités de Ética de la Investigación con medicamentos (CEIm), si es capaz.
    12.El padre/madre/cuidador del paciente está dispuesto y es capaz de cumplir con todos los requisitos del estudio y con el calendario de visitas. El padre/madre/cuidador del paciente también debe estar dispuesto y ser capaz de cumplir con la cumplimentación del diario y el recuento del fármaco del estudio.
    E.4Principal exclusion criteria
    1.Subject has a known hypersensitivity to fenfluramine or any of the excipients in the study medication.
    2.Subject has pulmonary arterial hypertension.
    3.Subject has current or past history of cardiovascular or cerebrovascular disease, such as cardiac valvulopathy, myocardial infarction or stroke.
    4.Subject has current or recent history of anorexia nervosa, bulimia, or depression within the prior year that required medical treatment or psychological treatment for a duration greater than 1 month.
    5.Subject has a current or past history of glaucoma.
    6.Subject has moderate or severe hepatic impairment.
    a.Asymptomatic subjects with mild hepatic impairment (aspartate aminotransferase [AST] and alanine aminotransferase [ALT] < 2x the upper limit of normal (ULN) and no elevations of gamma-glutamyltransferase [GGT], alkaline phosphatase, or total bilirubin indicative of more than mild hepatic impairment), may be entered into the study after review and approval by the Medical Monitor in conjunction with the sponsor, in consideration of comorbidities and concomitant medications [Cohort 1 only].
    b.Asymptomatic subjects with mild hepatic impairment (elevated liver enzymes < 3x the ULN and/or elevated bilirubin < 2x ULN) may be entered into the study after review and approval by the Medical Monitor in conjunction with the sponsor, in consideration of comorbidities and concomitant medications [Cohort 2 only].
    7.Subject is receiving concomitant therapy with: centrally-acting anorectic agents; monoamine-oxidase inhibitors; any centrally-acting compound with clinically appreciable amount of serotonin agonist or antagonist properties, including serotonin reuptake inhibition; triptans, atomoxetine, or other centrally-acting noradrenergic agonist; or cyproheptadine (see Appendix 1). (Note: Short-term medication requirements will be handled on a per case basis by the Medical Monitor.)
    8.Subject is currently receiving or has received STP in the past 21 days prior to Screening (only for Cohort 1 subjects allocated to Dose Regimen 1 or 2).
    9.Subject is currently taking carbamazepine, oxcarbazepine, eslicarbazepine, phenobarbital, or phenytoin, or has taken any of these within the past 30 days as maintenance therapy.
    10.Subject is unwilling to refrain from large or daily servings of grapefruits and/or Seville oranges, and their juices beginning with the Baseline Period and throughout the study.
    11.Subject has positive result on urine tetrahydrocannabinol (THC) Panel or whole blood cannabidiol (CBD) at the Screening Visit.
    12.Subject has participated in another clinical trial within the past 30 days.
    13.Subject is currently receiving an investigational product.
    14.Subject is unwilling or unable to comply with scheduled visits, drug administration plan, laboratory tests, other study procedures, and study restrictions.
    15.Subject has a clinically significant condition, or has had clinically relevant symptoms or a clinically significant illness in the 4 weeks prior to the Screening Visit, other than epilepsy, that would negatively impact study participation, collection of study data, or pose a risk to the subject.
    1. El paciente tiene una hipersensibilidad conocida a fenfluramina o a alguno de los excipientes en la medicación del estudio.
    2. El paciente tiene hipertensión arterial pulmonar.
    3. El paciente tiene presencia actual o antecedentes de enfermedad cardiovascular o cerebrovascular, como valvulopatía cardíaca, infarto de miocardio o accidente cerebrovascular.
    4. El paciente tiene presencia actual o antecedentes recientes de anorexia nerviosa, bulimia o depresión en el año anterior que requirió tratamiento médico o psicológico durante un periodo superior a 1 mes.
    5. El paciente tiene presencia actual o antecedentes de glaucoma.
    6. El paciente tiene deterioro hepático moderado o grave.
    a. Los pacientes asintomáticos con deterioro hepático leve (aspartato aminotransferasa [AST] y alanina aminotransferasa [ALT] < 2 x el límite superior de la normalidad [LSN] sin elevaciones de la gamma-glutamil transferasa (GGT), fosfatasa alcalina o bilirrubina total que indiquen un deterioro hepático más que leve) podrán entrar en el estudio después de la revisión y aprobación del supervisor médico junto con el promotor, teniendo en cuenta las comorbilidades y los medicamentos concomitantes [solo la cohorte 1].
    b. Los pacientes asintomáticos con deterioro hepático leve (enzimas hepáticas elevadas < 3 x LSN y/o bilirrubina elevada < 2 x LSN) podrán entrar en el estudio después de la revisión y aprobación del supervisor médico junto con el promotor, teniendo en cuenta las comorbilidades y los medicamentos concomitantes [solo la cohorte 2].
    7. El paciente recibe tratamiento concomitante con: agentes anorexígenos de acción central; inhibidores de la monoamino-oxidasa; cualquier compuesto de acción central con una cantidad clínicamente apreciable de propiedades agonistas o antagonistas de la serotonina, incluida la inhibición de la recaptación de serotonina; triptanos, atomoxetina u otros agonistas noradrenérgicos de acción central; o ciproheptadina (véase el Anexo 1). (Nota: los requisitos de medicación a corto plazo serán manejados caso por caso por el supervisor médico).
    8. El paciente recibe actualmente o ha recibido STP en los últimos 21 días previos a la selección (solo para pacientes de la cohorte 1 asignados a la pauta posológica 1 o 2).
    9. El paciente toma actualmente carbamazepina, oxcarbazepina, eslicarbazepina, fenobarbital o fenitoína, o ha tomado cualquiera de ellos en los últimos 30 días como tratamiento de mantenimiento.
    10. El paciente no está dispuesto a abstenerse de tomar zumos y porciones grandes o a diario de pomelo y/o naranjas amargas, empezando en el periodo basal y durante todo el estudio.
    11. El paciente tiene un resultado positivo en las pruebas de tetrahidrocannabinol (THC) en orina o de cannabidiol (CBD) en sangre completa en la visita de selección.
    12. El paciente ha participado en otro ensayo clínico en los últimos 30 días.
    13. El paciente recibe actualmente un producto en fase de investigación.
    14. El paciente no está dispuesto o es incapaz de cumplir con las visitas programadas, el plan de administración del fármaco, las pruebas analíticas, otros procedimientos del estudio y las restricciones del mismo.
    15. El paciente tiene una afección clínicamente significativa, o ha tenido síntomas de relevancia clínica o una enfermedad clínicamente significativa en las 4 semanas previas a la visita de selección, que no sean la epilepsia, que influirían negativamente en la participación en el estudio, la recopilación de datos del estudio o que supondrían un riesgo para el paciente.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) per 28 days between the Baseline and T+M periods
    El criterio de valoración primario de la eficacia es el cambio en la frecuencia media de convulsiones convulsivas (MCSF) por 28 días entre los períodos basal y T + M
    E.5.1.1Timepoint(s) of evaluation of this end point
    The primary efficacy endpoint is the change in the mean convulsive seizure frequency (MCSF) per 28 days between the Baseline and T+M periods
    El criterio de valoración primario de la eficacia es el cambio en la frecuencia media de convulsiones convulsivas (MCSF) por 28 días entre los períodos basal y T + M
    E.5.2Secondary end point(s)
    The first key secondary endpoint is the proportion of subjects who achieve a ≥40% reduction from baseline in convulsive seizure frequency
    El criterio de valoracion secundario es la proporción de pacientes que logran una reducción ≥ 40 % con respecto al momento basal en la frecuencia de crisis convulsivas.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The longest interval between convulsive seizures will be calculated for each subject over the entire T+M period
    El intervalo más largo entre convulsiones se calculará para cada sujeto durante todo el período T + M
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Cohort 1 = open with 3 treatment arms; Cohort 2 = double blind, controlled, with 2 treatment arms
    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 EEA19
    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
    Canada
    France
    Germany
    Netherlands
    Spain
    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
    Ultima visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    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: 105
    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: 68
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 37
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 5
    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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Children and adolescents
    Niños y adolescentes
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 110
    F.4.2.2In the whole clinical trial 110
    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)
    After completion, eligible subjects may enroll in an open-label extension study
    Depués de completar este estudio, los pacientes elegibles pueden ser reclutados en el estudio de extensión abierto
    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 Decision2017-05-31
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-05-10
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-06-05
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