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    EudraCT Number:2011-000860-90
    Sponsor's Protocol Code Number:CRAD001M2304
    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:2012-12-21
    Trial results View results
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    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2011-000860-90
    A.3Full title of the trial
    A three-arm, randomized, double-blind, placebo-controlled study of the efficacy and safety of two trough-ranges of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures
    Estudio doble ciego, aleatorizado, controlado con placebo, de tres brazos de tratamiento sobre la eficacia y seguridad de dos rangos de concentración valle de everolimus como tratamiento coadyuvante en pacientes con complejo de esclerosis tuberosa (CET) que presentan crisis convulsivas de inicio parciales refractarias
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of the efficacy and safety of two trough-ranges of everolimus as adjunctive therapy in patients with tuberous sclerosis complex (TSC) who have refractory partial-onset seizures
    Estudio sobre la eficacia y seguridad de dos rangos de concentración de everolimus como tratamiento coadyuvante en pacientes con complejo de esclerosis tuberosa (CET) que presentan crisis convulsivas de inicio parciales refractarias.
    A.4.1Sponsor's protocol code numberCRAD001M2304
    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 SponsorNovartis Farmacéutica, S.A.
    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 supportNovartis Farmaceutica S.A.
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmaceutica S.A.
    B.5.2Functional name of contact pointJavier Malpesa
    B.5.3 Address:
    B.5.3.1Street AddressGran Via de las Cortes Catalanas, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.4Telephone number0034933064464
    B.5.5Fax number0034 93 3064290
    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/3/10/764
    D.3 Description of the IMP
    D.3.1Product nameEverolimus
    D.3.2Product code RAD001
    D.3.4Pharmaceutical form Dispersible tablet
    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 INNeverolimus
    D.3.9.1CAS number 159351-69-6
    D.3.9.2Current sponsor codeRAD001
    D.3.9.3Other descriptive nameEVEROLIMUS
    D.3.9.4EV Substance CodeSUB02065MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number2
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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 placeboDispersible 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
    Refractory partial-onset seizures associated with tuberous sclerosis complex (TSC)
    Crisis convulsivas de inicio parciales refractarias asociadas a complejo de esclerosis tuberosa (CET)
    E.1.1.1Medical condition in easily understood language
    Refractory partial-onset seizures associated with tuberous sclerosis complex (TSC)
    Crisis convulsivas de inicio parciales refractarias asociadas a complejo de esclerosis tuberosa (CET)
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    E.1.2Level PT
    E.1.2Classification code 10045138
    E.1.2Term Tuberous sclerosis
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare the reduction in frequency of partial-onset seizures on each of two trough ranges of everolimus (3-7 ng/mL and 9-15 ng/mL) versus placebo in patients with TSC who are taking one to three AEDs
    Comparar la reducción en la frecuencia de crisis convulsivas de inicio parciales en cada uno de los dos rangos de concentración valle de everolimus (3-7 ng/ml y 9-15 ng/ml) frente a placebo en pacientes con CET que toman de uno a tres FAE.
    E.2.2Secondary objectives of the trial
    Please refer to the protocol for all secondary objectives
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female between the ages of 2 and 65 years
    2. Clinically definite diagnosis of TSC per modified Gomez criteria
    3. Diagnosis of partial-onset epilepsy according to the classification of the International League Against Epilepsy (1989) and revised in 2009.
    4. Uncontrolled partial-onset seizures; must meet the following:
    a. At least 16 reported quantifiable partial-onset seizures over the Baseline period with no continuous 21-day seizure-free period between Visit 1 (Screening Visit) and Visit 2 (Randomization visit), as per data captured in daily seizure diaries.
    b. Prior history of failure to control partial-onset seizures despite having been treated with two or more sequential regimens of single or combined antiepileptic drugs.
    c. Prior or concurrent use of vagal nerve stimulator (VNS) is allowed. If the patient is using VNS, device stimulator parameters must remain constant throughout the study.
    d. Prior epilepsy surgery is allowed if performed at least 12 months before study entry.
    5. Must be receiving one, two, or three AEDs at a stable dose for at least 4 weeks at the start of the 8-week prospective Baseline phase, remain on the same regimen throughout the Baseline phase, and intend to continue the same regimen throughout the 18-week double blind Core phase (rescue medications are permitted).
    6. If female of child bearing potential, documentation of negative pregnancy test at time of informed consent and must use highly effective contraception during the study and for 8 weeks after stopping treatment
    7. Sexually active males must use a condom during intercourse while taking study drug, and for 30 days after stopping study treatment
    8. Hepatic, renal and blood laboratory values within the following range at both screening and randomization:
    a. AST and ALT levels < 2.5 x ULN
    b. serum bilirubin <1.5 × ULN (this limit does not apply to patients with an elevated indirect bilirubin, if they have Gilbert?s Syndrome)
    c. serum creatinine < 1.5 x ULN
    d. hemoglobin ? 9 g/dL
    e. platelets ? 80,000/mm3
    f. absolute neutrophil count ? 1,000/mm3
    9. Written informed consent. Subjects or their legal guardians must have the ability to comprehend the informed consent form and be willing to provide informed consent.
    10. Patient or caregiver must be able to reliably record seizures and keep a daily diary and recall adverse events.
    1. Hombre o mujer entre 2 y 65 años de edad. (Se aleatorizará un número mínimo de pacientes pediátricos según los grupos de edad siguientes: 2 a <6 años (12 pacientes), 6 a <12 años (20 pacientes) y 12 a <18 años (20 pacientes)).
    2. Diagnóstico clínicamente definitivo de CET según los criterios modificados de Gómez.
    3. Diagnóstico de epilepsia de inicio parcial según la clasificación de la International League Against Epilepsy revisada en 2009.
    4. Crisis convulsivas de inicio parciales no controladas, deben cumplirse los criterios siguientes:
    a. Al menos 16 crisis convulsivas de inicio parciales cuantificables (no en accesos ni innumerables) (definidas como crisis convulsivas parciales simples con signos motrices, crisis convulsivas parciales complejas o crisis convulsivas parciales complejas con generalización secundaria, o una combinación de estos tipos de criterios de inclusión), durante el periodo basal (56 días, 8 semanas) sin ningún periodo continuado de 21 días sin crisis convulsivas entre la visita 1 (visita de selección) y la visita 2 (visita de aleatorización), según los datos reflejados en los diarios de crisis convulsivas diarias.
    b. Antecedentes de incapacidad para controlar las crisis convulsivas de inicio parciales a pesar de haber recibido tratamiento con dos o más regímenes secuenciales de fármacos antiepilépticos solos o combinados.
    c. Se permite el uso anterior o concurrente de un estimulador del nervio vago (ENV). Si el paciente utiliza ENV, deben conservarse los parámetros del estimulador de forma constante a lo largo del estudio.
    d. Se permite cirugía anterior para la epilepsia si se ha realizado al menos 12 meses antes de la inclusión del paciente en el estudio.
    5. Debe estar recibiendo uno, dos o tres FAE en una dosis estable durante al menos las 4 semanas anteriores al inicio de la fase basal prospectiva de 8 semanas, mantenerse dicho régimen durante la fase basal y tener intención de continuarlo a lo largo de la fase principal doble ciego de 18 semanas (se permite medicación de rescate).
    6. Las mujeres en edad fértil deben aportar documentación de la prueba de embarazo negativa en el momento del consentimiento informado. Las mujeres en edad fértil, definidas como toda mujer fisiológicamente capaz de quedarse embarazada, deben utilizar un método anticonceptivo altamente eficaz durante el estudio y durante las 8 semanas posteriores a la finalización del tratamiento. Un método anticonceptivo altamente eficaz se define como:
    ? Abstinencia total: cuando esté en consonancia con el estilo de vida habitual y preferido de la sujeto. [La abstinencia periódica (p. ej., calendario, ovulación, métodos sintotérmicos o postovulación) y el coitus interruptus no son métodos anticonceptivos aceptables].
    ? Esterilización: cuando se haya realizado ooforectomía bilateral (con o sin histerectomía) o ligadura de trompas por lo menos seis semanas antes de tomar el tratamiento del estudio. En caso de ooforectomía sola, cuando se haya confirmado el estado reproductor de la mujer mediante una evaluación de seguimiento del nivel hormonal
    ? Esterilización de la pareja masculina (con la correspondiente documentación posterior a la vasectomía sobre la ausencia de esperma en la eyaculación). [El el caso de mujeres del estudio, el varón a quien se le haya realizado una vasectomía deberá ser la única pareja de la sujeto del estudio].
    ? El uso de una combinación de cualquiera de estas dos (a+b o a+c o b+c):
    a. Métodos anticonceptivos orales, inyectados o implantes hormonales.
    b. Colocación de un dispositivo intrauterino (DIU) o un sistema intrauterino (SIU).
    c. Métodos anticonceptivos de barrera: Preservativo o capuchón oclusivo (diafragma o capuchón cervical) con espuma/gel/película/crema espermicida/supositorio vaginal.
    En caso de que la mujer utilice un método anticonceptivo oral, deberán haberlo tomado de forma estable antes de recibir el tratamiento del estudio.
    7. Los hombres sexualmente activos deben utilizar preservativos durante el coito mientras estén recibiendo el fármaco del estudio y durante los 30 días posteriores al final del tratamiento.
    8. Valores de laboratorio hepáticos, renales y sanguíneos dentro de los intervalos siguientes en la selección y la aleatorización:
    ? Niveles de AST y ALT < 2,5 x LSN.
    ? Bilirrubina sérica <1,5 × LSN (este límite no se aplica a pacientes con un nivel elevado de bilirrubina indirecta si padecen el síndrome de Gilbert).
    ? Creatinina sérica < 1,5 x LSN.
    ? Hemoglobina ? 9 g/dL.
    ? Plaquetas ? 80.000/mm3.
    ? Recuento de neutrófilos absoluto ? 1.000/mm3
    9. Consentimiento informado por escrito. Los sujetos o sus tutores legales deben comprender el formulario de consentimiento informado y estar dispuestos a proporcionar el consentimiento informado.
    10. El paciente o el cuidador deben ser capaces de registrar de forma fidedigna las crisis convulsivas, de llevar un diario cada día y de recordar los acontecimientos adversos.
    E.4Principal exclusion criteria
    1. Patients with seizures secondary to metabolic, toxic, infectious or psychogenic disorder or drug abuse or current seizures related to an acute medical illness
    2. Presence of only non-motor simple partial seizures
    3. Patients with TSC who have SEGA in need of immediate surgical intervention
    4. Patients who suffer from active infantile spasms
    5. Within 52 weeks prior to study therapy, an episode of status epilepticus as defined in the
    6. Patients with history of seizure clusters (where individual seizures cannot be accurately counted
    according to the judgment of the investigator) occurring within 26 weeks prior to study entry
    7. Patients with non-TSC related progressive encephalopathy
    8. Patients with a history of Lennox-Gastaut Syndrome
    9. Patients with coexisting malignancies within the 3 years prior to randomization, except for adequately treated carcinoma of the cervix or basal or squamous cell carcinomas of the skin. 10. Patients with any severe and/or uncontrolled medical conditions at randomization such as:
    a. Symptomatic congestive heart failure of New York Heart Association Class III or IV, history of left ventricular ejection fraction (LVEF) <50%, QTc interval >460ms, congenital QT syndrome, unstable angina pectoris, myocardial infarction within 6 months of study entry, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease
    b. Significant symptomatic deterioration of lung function
    c. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of everolimus (e.g., ulcerative disease, malabsorption syndrome or small bowel resection)
    d. liver disease such as cirrhosis, decompensated liver disease, and chronic hepatitis
    e. Uncontrolled diabetes as defined by fasting serum glucose > 1.5 × ULN
    f. Active skin, mucosa, ocular or GI disorders of Grade > 1.
    g. Active (acute or chronic) or uncontrolled severe infections
    h. A known history of HIV seropositivity or other active viral infections
    11. Patients with an active, bleeding diathesis.
    12. Patient with uncontrolled hyperlipidemia: fasting serum cholesterol > 300 mg/dL OR >7.75 mmol/L AND fasting triglycerides > 2.5 x ULN.
    13. Patients who have had a major surgery or significant traumatic injury within 4 weeks of study entry.
    14. Patients with a prior history of organ transplant.
    15. Patients receiving more than 3 antiepileptic drugs at any time in the baseline phase or at randomization or who change the dose of the AEDs during 4 weeks before screening or during the baseline period.
    16. Patients being treated with felbamate, unless treatment has been continuous for ? 1 years.
    17. Patients currently receiving anticancer therapies or who have received anticancer therapies within 4 weeks of study entry (including chemotherapy, radiation therapy, antibody based therapy, etc.).
    18. Prior treatment with any investigational drug within the preceding 4 weeks prior to study entry. 19. Patients receiving chronic, systemic treatment with corticosteroids or another immunosuppressive agent at study entry. Topical or inhaled corticosteroids are allowed.
    20. Patients who have received prior treatment with a systemic mTOR inhibitor (sirolimus, temsirolimus, everolimus) within 24 months of study entry. Patients who have received prior treatment with a topical mTOR inhibitor (sirolimus, temsirolimus, everolimus) within 4 weeks of study entry.
    21. Patients with a known hypersensitivity to everolimus or other rapamycinanalogues
    (sirolimus, temsirolimus) or to its excipients.
    22. Patients with a history of non-compliance to medical regimens or who are considered potentially unreliable or will not be able to complete the entire study
    23. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test.
    24. Score of 4 or 5 on the Suicidal Ideation item within 2 years of Screening, or any ?yes? on the Suicidal Behavior item of the Columbia-Suicide Severity Rating Scale at Screening.
    1. Pacientes con crisis convulsivas secundarias a un trastorno metabólico, tóxico, infeccioso o psicogénico, por abuso de sustancias o por una dolencia médica aguda.
    2. Presencia de solo crisis convulsivas parciales simples no motoras.
    3. Pacientes con CET que tienen SEGA que precisen intervención quirúrgica inmediata.
    4. Pacientes que sufren espasmos infantiles activos.
    5. En las 52 semanas anteriores al tratamiento de estudio, un episodio de estado epiléptico definido como:
    6. Pacientes con antecedentes de crisis convulsivas en accesos (en donde no se pueden contabilizar correctamente las crisis convulsivas individuales según el criterio del investigador) en las 26 semanas anteriores a la inclusión del paciente en el estudio.
    7. Pacientes con encefalopatía progresiva no relacionada con el CET.
    8. Pacientes con un antecedente de síndrome de Lennox-Gastaut.
    9. Pacientes con tumores malignos coexistentes en los 3 años previos a la aleatorización, excepto en el caso de carcinoma de cuello uterino, o carcinomas espinocelulares o basales tratados de manera adecuada.
    10. Pacientes con alguna enfermedad grave o/y no controlada en la aleatorización, como:
    a) Insuficiencia cardíaca congestiva sintomática clase III o IV de la New York Heart Association, antecedentes de fracción de eyección ventricular izquierda (FEVI) < 50%, intervalo QTc > 460ms, síndrome QT congénito, angina de pecho inestable, infarto de miocardio en los 6 meses de la inclusión en el estudio, arritmia cardíaca grave y no controlada o cualquier otra enfermedad cardiaca clínicamente significativa.
    b) Deterioro sintomático importante de la función pulmonar.
    c) Alteraciones de la función gastrointestinal o enfermedad gastrointestinal que pueden alterar significativamente la absorción de everolimus.
    d) Enfermedades hepáticas como la cirrosis, enfermedad hepática descompensada y hepatitis crónica.
    e) Diabetes no controlada definida según la glucosa sérica en ayunas > 1,5 × LSN.
    f) Trastornos activos de la piel, las mucosas, los ojos o GI de grado > 1.
    g) Infecciones graves no controladas o activas (agudas o crónicas).
    h) Antecedentes conocidos de VIH seropositivo u otras infecciones víricas activas.
    11. Pacientes con diátesis hemorrágica activa.
    12. Pacientes con hiperlipidemia no controlada: colesterol sérico en ayunas > 300 mg/dl O >7,75 mmol/l Y triglicéridos en ayunas > 2,5 x LSN.
    13. Pacientes a los que se les haya realizado una cirugía mayor o hayan tenido alguna lesión traumática importante en las 4 semanas anteriores a su inclusión en el estudio.
    14. Pacientes con antecedentes de trasplante de órganos.
    15. Pacientes que hayan recibido más de 3 fármacos antiepilépticos en cualquier momento de la fase basal o de la aleatorización o que hayan cambiado la dosis del FAE durante las 4 semanas anteriores a la selección o durante el periodo basal.
    16. Pacientes que hayan sido tratados con felbamato, a menos que el tratamiento haya sido continuado durante ? 1 año.
    17. Pacientes que estén recibiendo tratamiento contra el cáncer o que lo hayan recibido 4 semanas antes de su inclusión en el estudio (incluida la quimioterapia, radioterapia, tratamiento basado en anticuerpos, etc.).
    18. Tratamiento previo con cualquier fármaco en investigación durante las 4 semanas anteriores a la inclusión del paciente en el estudio.
    19. Pacientes que reciban tratamiento crónico, sistémico con corticosteroides o algún otro agente inmunosupresor en el momento de la inclusión del paciente en el estudio. Se permiten corticoides inhalados o por vía tópica.
    20. Pacientes que hayan recibido tratamiento previo con un inhibidor de mTOR sistémico (sirolimus, temsirolimus, everolimus) durante los 24 meses anteriores a la inclusión del paciente en el estudio. Pacientes que hayan recibido tratamiento previo con un inhibidor de mTOR tópico (sirolimus, temsirolimus, everolimus) durante las 4 semanas anteriores a la inclusión del paciente en el estudio.
    21. Pacientes con hipersensibilidad conocida al everolimus, a otros análogos de rapamicina (sirolimus, temsirolimus) o a sus excipientes.
    22. Pacientes con antecedentes de incumplimiento de regímenes médicos, que hayan sido considerados posiblemente poco fiables o que no vayan a ser capaces de finalizar el estudio en su totalidad
    23. Mujeres embarazadas o en periodo de lactancia, donde el embarazo se define como el estado de una mujer después de la concepción y hasta que finalice la gestación, confirmado por un resultado positivo de hCG en la analítica.
    24. Puntuación de 4 o 5 en el ítem de pensamiento suicida durante los 2 años anteriores a la selección o cualquier respuesta afirmativa sobre comportamiento suicida en la Escala de la evaluación de tendencias suicidas de la Universidad de Columbia en la selección.
    E.5 End points
    E.5.1Primary end point(s)
    EMA: Response rate
    FDA: Percentage reduction in partial onset seizure frequency
    EMA: Tasa de respuesta
    FDA: Porcentaje de reducción en la frecuencia de las crisis de inicio parcial.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Baseline, Week 6 to Week 12 (during maintenance period of core study)
    E.5.2Secondary end point(s)
    1. Seizure free rate
    2. Proportion of patients with at least a 25% reduction in partial onset seizure frequency
    3. Categorical variable of six levels of reduction from baseline in partial-onset seizure frequency
    4. Frequency of seizure free days
    5. Treatment duration
    6. Overall Quality of Life global scores
    7. Sub-test scores for neurocognitive, neurodevelopmental, and neurobehavioral tests
    8. Percentage reduction in seizure frequency/frequency of selected adverse events
    9. Pre-dose concentrations of antiepileptic drugs (AEDs) alone and post-baseline (AEDs plus everolimus)
    10. 50% response rate from Baseline by time interval over the extension phase
    11. Seizure free days in partial onsent seizure by time interval over the extension phase
    12. Frequency of adverse events
    13. Frequency of abnormal laboratory values
    14. Frequency of Columbia Suicide Severity Rating Scale (C-SSRS) outcomes
    15. Frequency of serious adverve events (SAEs) referring to a positive suicidal evaluation
    E.5.2.1Timepoint(s) of evaluation of this end point
    1&2&4: Week 6 to 18 of treatment (during maintenance of core phase)
    3.Baseline, Week 6 to 18 (during maintenance of core phase)
    5.Randomization to Week 18 of treatment
    6.Baseline, Week 18, End of Treatment*
    7.Baseline, End of Core (18 weeks), Every 6 months during Extension, End of Treatment Extension*
    8.Baseline,end of study (if patient completes range from 74 to 142 weeks)
    9.Baseline,Week 5
    10&11:Start of Extension (Week 18) to End of Treatment Extension*
    12.to 15.:Baseline to End of Treatment Extension*

    *(time when patient completes or leaves study.Range from 74 to 142 weeks)
    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 No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarkers analysis
    Análisis de biomarcadores
    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. 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 trial3
    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 EEA64
    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
    Korea, Republic of
    Russian Federation
    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
    Please refer to section 4.1.4 of the protocol
    Por favor refiérase a la sección 4.1.4 del protocolo
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days0
    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: 2
    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. of subjects for this age range: 20
    F.1.1.6Adolescents (12-17 years) Yes
    F. of subjects for this age range: 20
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 285
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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. of subjects incapable of giving consent
    Subjects or their legal guardians must have the ability to comprehend the informed consent form and be willing to provide informed consent. For more details please see inclusion criterion 9.
    Los sujetos o sus representantes legales deben tener la capacidad de comprender el formulario de consentimiento informado y estar dispuesto a dar su consentimiento informado. Para más detalles, véase el criterio de inclusión 9.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state20
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 170
    F.4.2.2In the whole clinical trial 345
    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 the Extension phase is completed, should the Core study results be positive, everolimus will continue to be provided free of charge until the drug is approved and commercialized for use in TSC-associated refractory partial onset seizures, or until the patient stops receiving everolimus for any reason, whichever occurs first.
    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 Decision2013-02-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-01-11
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-10-25
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