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    Summary
    EudraCT Number:2012-005397-63
    Sponsor's Protocol Code Number:CRAD001MES12
    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:2014-01-16
    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 number2012-005397-63
    A.3Full title of the trial
    An open-label, multi-center, expanded access study of RAD001 in patients with angiomyolipoma associated with tuberous sclerosis complex (TSC)
    Estudio abierto, multicéntrico, de acceso expandido con RAD001 para pacientes con angiomiolipomas asociados a complejo de esclerosis tuberosa
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Expanded access study of RAD001 in patient with angiomyolipoma associated with tuberous sclerosis complex (TSC)
    Estudio de acceso expandido con RAD001 en pacientes con angiomiolipoma asociado a complejo de esclerosis tuberosa (CET)
    A.4.1Sponsor's protocol code numberCRAD001MES12
    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.1.3.4CountrySpain
    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 Farmacéutica,S.A
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNovartis Farmacéutica, S.A
    B.5.2Functional name of contact pointDepartamento Médico de Oncología
    B.5.3 Address:
    B.5.3.1Street AddressGran Vía de les Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number0034900353036
    B.5.5Fax number0034932479903
    B.5.6E-maileecc.novartis@novartis.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 Yes
    D.2.1.1.1Trade name Votubia
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS EUROPHARM LIMITED
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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/3/07/449
    D.3 Description of the IMP
    D.3.1Product nameeverolimus
    D.3.2Product code RAD001
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    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.3.9.3Other 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 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Angiomyolipoma associated with either Tuberous Sclerosis Complex (TSC)
    Angiomiolipoma en pacientes con Complejo de Esclerosis Tuberosa (CET)
    E.1.1.1Medical condition in easily understood language
    Angiomyolipoma associated with either Tuberous Sclerosis Complex (TSC)
    Angiomiolipoma en pacientes con 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 16.1
    E.1.2Level PT
    E.1.2Classification code 10051810
    E.1.2Term Angiomyolipoma
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the dose-limiting safety of everolimus in patients with angiomyolipoma associated with TSC.
    Evaluar la seguridad limitante de dosis de everolimus en pacientes con angiomiolipoma asociado a CET.
    E.2.2Secondary objectives of the trial
    To evaluate the angiomyolipoma response rate on RAD001
    to evaluate safety of RAD001 in patients with angiomyolipoma associated with TSC
    Evaluar la tasa de respuesta del angiomiolipoma con everolimus.
    Evaluar la seguridad general de everolimus en pacientes con angiomiolipima asociado a CET.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female ? 18 years of age.
    2. Clinically definite diagnosis of tuberous sclerosis according to the modified Gomez criteria (Roach 1998, Hyman 2000, Table 5-1). Clinically definite diagnosis of tuberous sclerosis according to the modified Gomez criteria is defined as either of the following:
    a. Two Major Features from Table 5-1.
    b. One Major Feature plus two Minor Features from Table 5-1.
    3. Clinically definite diagnosis of renal angiomyolipoma (according to local requirements)
    4. Presence of at least one angiomyolipoma ? 3 cm in its longest diameter using CT/MRI. The choice of 3 cm reflects the vague limits between a justified wait and watch policy and the more proactive surgical intervention approaches.
    5. If female and of child-bearing potential, documentation of negative pregnancy test prior to enrollment. Sexually active pre-menopausal female patients (and female partners of male patients) must use adequate contraceptive measures, while on study and for 8 weeks after ending treatment.
    6. Written informed consent prior to any screening procedures according to local guidelines.
    1. Hombres o mujeres ? 18 años de edad.
    2. Diagnóstico clínicamente definitivo de esclerosis tuberosa según los criterios de Gómez modificados (Roach 1998, Hyman 2000, Tabla 5-1). El diagnóstico clínicamente definitivo de esclerosis tuberosa según los criterios de Gómez modificados se define como uno de los siguientes:
    a. Dos características principales de la Tabla 5-1.
    b. Una característica principal más dos características menores de la Tabla 5-1.
    3. Diagnóstico clínicamente definitivo de angiomiolipoma renal (según los requisitos locales).
    4. Presencia de al menos un angiomiolipoma ? 3 cm en su diámetro más largo mediante TC/RM. La elección de 3 cm refleja los límites imprecisos entre una espera justificada y una política de observación y los métodos de intervención quirúrgica más proactivos.
    5. En caso de mujer en edad fértil, documentación de una prueba de embarazo negativa antes de su inclusión. Las pacientes premenopáusicas sexualmente activas (y las parejas de pacientes varones) deben utilizar métodos anticonceptivos adecuados durante el estudio y durante las 8 semanas posteriores a la finalización del tratamiento.
    6. Consentimiento informado por escrito antes de realizar cualquier procedimiento de selección según las pautas locales.
    E.4Principal exclusion criteria
    1. Patients with angiomyolipoma which, in the opinion of the investigator, requires surgery at the time of study inclusion
    2. Angiomyolipoma-related bleeding or embolization during the 6 months prior to study inclusion
    3. History of myocardial infarction, angina or stroke related to atherosclerosis.
    4. Known impaired lung function (e.g. FEV1 or DLco ? 70% of predicted)
    5. Significant hematological or hepatic abnormality (i.e., transaminase levels > 2.5 × upper limit of normal (ULN), serum bilirubin > 1.5 × ULN, hemoglobin < 9g/dL, platelets < 80,000/mm3, or absolute neutrophil count < 1,000/mm3).
    6. Ongoing or active infection at the date of enrollment
    7. Patients with a known history of HIV seropositivity.
    8. Prior history of organ transplantation.
    9. Recent surgery (involving entry into a body cavity or requiring sutures) within the 2 months prior to study inclusion.
    10. Patient with a known hypersensitivity to RAD001 or other rapamycin analogs (sirolimus temsirolimus), or its excipients
    11. Use of an investigational drug within the 30 days prior to study inclusion
    12. Uncontrolled hyperlipidemia: Fasting serum cholesterol > 300 mg/dL (or > 7.75 mmol/L), AND fasting triglycerides > 2.5 × ULN.
    13. Uncontrolled diabetes mellitus as defined by fasting serum glucose > 1.5 × ULN.
    14. Patients with bleeding diathesis or on oral anti-vitamin K medication (except low dose warfarin).
    15. Serum creatinine > 1.5 x ULN
    16. Any severe and/or uncontrolled medical conditions which could cause unacceptable safety risks:
    a. uncontrolled hypercholesterolemia/hypertriglyceridemia

    b. Impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of study drug (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome).
    17. For the purpose of MRI assessments:
    a. Ferromagnetic metal implants other than those approved as safe for use in MR scanner (e.g., braces, some types of aneurysm clips, shrapnel)
    b. Patients suffering from uncontrollable claustrophobia or physically unable to fit into the machine (e.g., obesity, etc).
    Note: patients with vagal nerve stimulators are permitted to have CT assessments of angiomyolipoma unless local or national regulations do not permit this.
    18. Inability to attend scheduled clinic visits and noncompliace with scheduled clinic visits required for toxicity management
    19. Female patients who are pregnant or breast feeding, women of child-bearing potential, unless they are using effective methods of contraception during the study and for 8 weeks after ending treatment and sexually active males unless they use a condom during the study and for 8 weeks after the end of treatment.

    20. Prior randomization to either arm of study CRAD001M2302
    1. Pacientes con angiomiolipoma que requieran cirugía en el momento de la incñusión en el estudiosegún el criterio del investigador.
    2. Pacientes con angiomiolipoma hemorrágico o embolización en el angiomiolipoma durante los 6 meses anteriores a la inclusion en el estudio.
    3. Antecedentes de infarto de miocardio, angina, derrame cerebral relacionado con aterosclerosis.
    4. Deterioro conocido de la función pulmonar ( (p.ej., FEV1 o DLco ? 70% del valor teórico).
    5. Anomalía hematológica o hepática significativa (es decir, niveles de transaminasa > 2,5 × límite superior normal (LSN), bilirrubina sérica > 1,5 × LSN, hemoglobina < 9 g/dl, plaquetas < 80 000/mm3 o recuento absoluto de neutrófilos < 1000/mm3).
    6. Infección en curso o activa en el momento de la inclusión en el estudio
    7. Pacientes con antecedentes conocidos de VIH seropositivo.
    8. Antecedentes de trasplante de órganos.
    9. Intervención quirúrgica reciente (que conlleve una entrada en una cavidad corporal o que precise suturas) durante los 2 meses anteriores a la inclusion en el estudio.
    10. Pacientes con hipersensibilidad conocida a everolimus o a otros análogos de la rapamicina (sirolimus, temsirolimus) o sus excipientes.
    11. Uso de un fármaco en investigación durante los 30 días anteriores a la inclusión en el estudio.
    12. Hiperlipidemia no controlada: colesterol sérico en ayunas > 300 mg/dl (o > 7,75 mmol/l) Y triglicéridos en ayunas > 2,5 × LSN.
    13. Diabetes mellitus no controlada definida como glucosa sérica en ayunas > 1,5 × LSN.
    14. Pacientes con diátesis hemorrágica o con medicación antivitamina K oral (salvo dosis bajas de warfarina).
    15. Creatinina sérica > 1,5 x LSN.
    16. Cualquier enfermedad grave y/o no controlada que pueda conllevar riesgos de seguridad no aceptables:
    a. Hipercolesterolemia/hipertrigliceridemia no controlada.
    b. Alteraciones de la función gastrointestinal o enfermedad gastrointestinal que pueden alterar significativamente la absorción del fármaco del estudio (p. ej., enfermedad ulcerosa, náuseas no controladas, diarrea, síndrome de mala absorción).
    17. Para las evaluaciones de RM:
    c. Implantes con metales ferromagnéticos salvo aquellos que se haya aprobado que son seguros para la RM (p.ej., aparatos dentales, algunos tipos de clips de aneurisma, metralla).
    d. Pacientes que padecen claustrofobia no controlable o incapacidad física para meterse dentro de la máquina (p.ej., obesidad, etc.).
    Nota: a los pacientes con estimuladores del nervio vago se les permite realizar las evaluaciones con TC del angiomiolipoma, salvo que no esté permitido según la regulación local o nacional.
    18. Incapacidad para acudir a las visitas clínicas programadas e incumplimiento con las visitas clínicas programadas necesarias para el control de la toxicidad.
    19. Pacientes embarazadas o en periodo de lactancia, mujeres en edad fértil, salvo que estén utilizando métodos anticonceptivos efectivos durante el estudio y durante las 8 semanas posteriores a la finalización del tratamiento y varones sexualmente activos, salvo que estén utilizando preservativos durante el estudio y durante las 8 semanas posteriores a la finalización del tratamiento
    20. Haber sido previamente aleatorizado a cualesquiera de los brazos del estudio CRAD001M2302.
    E.5 End points
    E.5.1Primary end point(s)
    Grade 3 and Grade 4, Serious Adverse Events, and AEs that cause a change in study drug dosing. Frequency of laboratory values (hematology / chemistry) that are new or worsening based on the common toxicity criteria grade (NCI-CTCAE v. 4.03)
    Acontecimientos adversos graves de grado 3 y 4 y los AA que causen un cambio en la administración de la dosis del fármaco del estudio. Frecuencia de los valores de laboratorio (hematología/ bioquímica) que sean nuevos o hayan empeorado basándose en los grados de los criterios comunes de toxicidad (CTCAE v. 4.03 del NCI).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Until the drug becomes commercially available for angiomyolipoma associated to TSC in Spain or up to 1 year after FPFV , whichever occurs first.
    Hasta que se comercialice el fármaco para angiomiolipoma asociado a CET en España o hasta 1 año después de la PVPP, aquello que ocurra primero.
    E.5.2Secondary end point(s)
    To evaluate Angiomyolipomas volume changes during the trial by CT scan /MRI from baseline visit
    Adverse Events and Serious Adverses Events of any grade
    Evaluar los cambios de volumen de los angiomiolipomas durante el ensayo mediante TC /RM respecto a la visita basal

    Acontecimientos adversos y acontecimientos adversos de caulquier grado graves
    E.5.2.1Timepoint(s) of evaluation of this end point
    Until the drug becomes commercially available for angiomyolipoma associated to TSC in Spain or up to 1 year after FPFV , whichever occurs first.
    Hasta que se comercialice el fármaco para angiomiolipoma asociado a CET en España o hasta 1 año después de la PVPP, aquello que ocurra primero.
    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 No
    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 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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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 No
    E.8.2.3Other No
    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 concerned14
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    until the drug becomes commercially available for angiomyolipoma associated to TSC in Spain or up to 1 year after FPFV , whichever occurs first.
    Hasta que se comercialice el fármaco para angiomiolipoma asociado a CET en España o hasta 1 año después de la PVPP, aquello que ocurra primero.
    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 months12
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    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) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 25
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 5
    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 state30
    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)
    None
    Ninguno
    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 Decision2013-04-19
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-02-15
    P. End of Trial
    P.End of Trial StatusCompleted
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