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    Summary
    EudraCT Number:2012-004092-40
    Sponsor's Protocol Code Number:CAMN107I2201
    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:2013-03-04
    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 number2012-004092-40
    A.3Full title of the trial
    A single-arm, multicenter, nilotinib treatment-free remission study in patients with BCR-ABL1 positive Chronic Myelogenous Leukemia in chronic phase who have achieved durable minimal residual disease (MRD) status on first line nilotinib treatment
    Estudio multicéntrico, de un único brazo, de remisión libre de tratamiento de nilotinib, en pacientes con leucemia mieloide crónica en fase crónica con BCR-ABL1 positivo, que han alcanzado un estado de enfermedad residual mínima (ERM) duradera con tratamiento de primera línea con nilotinib
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A clinical research study evaluating the possibility to suspend the drug nilotinib (Tasigna) in chronic myeloid leukemia (CML) patients who have very small amount of leukemia cells remaining after nilotinib (Tasigna) treatment.
    Estudio de investigación clínica para evaluar la posibilidad de suspender el medicamento nilotinib (Tasigna) en pacientes con leucemia mieloide crónica (LMC) que tienen muy poca cantidad de células leucémicas después del tratamiento con nilotinib (Tasigna).
    A.3.2Name or abbreviated title of the trial where available
    ENEST Freedom
    ENEST Freedom
    A.4.1Sponsor's protocol code numberCAMN107I2201
    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 Pharma Services AG
    B.4.2CountrySwitzerland
    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 Via Corts Catalanes, 764
    B.5.3.2Town/ cityBarcelona
    B.5.3.3Post code08013
    B.5.3.4CountrySpain
    B.5.4Telephone number+34900353036
    B.5.5Fax number+34932479903
    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 Tasigna
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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/3/06/375
    D.3 Description of the IMP
    D.3.1Product namenilotinib
    D.3.2Product code AMN107
    D.3.4Pharmaceutical form Capsule, hard
    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 INNNILOTINIB
    D.3.9.1CAS number 641571-10-0
    D.3.9.2Current sponsor codeAMN107
    D.3.9.4EV Substance CodeSUB25225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number150
    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 Yes
    D.2.1.1.1Trade name Tasigna
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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/3/06/375
    D.3 Description of the IMP
    D.3.1Product namenilotinib
    D.3.2Product code AMN107
    D.3.4Pharmaceutical form Capsule, hard
    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 INNNILOTINIB
    D.3.9.1CAS number 641571-10-0
    D.3.9.2Current sponsor codeAMN107
    D.3.9.4EV Substance CodeSUB25225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    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
    Adult patients treated with a planned dose of nilotinib 300 mg BID (or at a reduced dose level of 400 mg QD if required from the perspective of tolerance) for a minimum of 2 calendar years for newly diagnosed BCR-ABL positive Chronic Myelogenous Leukemia in chronic phase and have achieved MR 4.5 (BCR-ABL ? 0.0032% IS) at any time point before being enrolled in the study
    Pacientes adultos tratados con una dosis planeada de nilotinib de 300 mg dos veces al día (o a un nivel de dosis reducida de 400 mg 1 vez al día si es necesario desde el punto de vista de tolerancia) durante un mínimo de 2 años de calendario para diagnóstico reciente de leucemia mieloide crónica BCR-ABL positivo en fase crónica y que han logrado RM 4,5 (BCR-ABL ? 0,0032% IS) en cualquier momento antes de ser inscritos en el estudio
    E.1.1.1Medical condition in easily understood language
    Adult patients with CML who have been treated with nilotinib (Tasigna) for at least two years and who have achieved a certain level of molecular response prior to study entry.
    Pacientes adultos con LMC que han recibido tratamiento con nilotinib (Tasigna) durante al menos dos años y que han alcanzado un cierto nivel de respuesta molecular antes del ingreso al estudio.
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.1
    E.1.2Level LLT
    E.1.2Classification code 10054352
    E.1.2Term Chronic phase chronic myeloid leukemia
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the percentage of patients who are in Major Molecular Response (MMR) at 48 weeks after starting the treatment-free remission (TFR) phase (patients who required re-initiation of treatment will be considered as non-responders)
    Determinar el porcentaje de pacientes que se encuentren en respuesta molecular mayor (RMM) a las 48 semanas después de comenzar la fase de remisión libre de tratamiento (RLT) (los pacientes que requieren el reinicio del tratamiento serán considerados como no respondedores)
    E.2.2Secondary objectives of the trial
    1) To determine the percentage of patients who are in MR4.5 (BCR-ABL ? 0.0032% IS) at 48 weeks after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
    2) To determine the percentage of patients who are in MMR at 96, 144 and 192 weeks after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
    3) To determine the percentage of patients who are in MR4.5 at 96, 144 and 192 weeks after starting the TFR phase (patients who required re-initiation of treatment will be considered as non-responders)
    4) To determine the percentage of patients who achieve MMR within 12 weeks of re-treatment with nilotinib
    5) To estimate the duration of re-initiated treatment required to regain MMR after loss of MMR
    Additional objectives apply
    1) Determinar el porcentaje de pacientes que están en RM4.5 (BCR-ABL ? 0,0032% IS) a las 48 semanas después de comenzar la fase de RLT (los pacientes que requieren el reinicio del tratamiento serán considerados como no respondedores)
    2) Determinar el porcentaje de pacientes que están en RMM a las 96, 144 y 192 semanas después de comenzar la fase de RLT(los pacientes que requieren el reinicio del tratamiento serán considerados como no respondedores)
    3) Determinar el porcentaje de pacientes que están en RM4.5 en las semanas 96, 144 y 192 después de comenzar la fase de RLT(los pacientes que requirieron re-inicio del tratamiento se considerarán como no respondedores)
    4) Determinar el porcentaje de pacientes que alcanzan RMM dentro de las 12 semanas de re-tratamiento con nilotinib
    5) Estimar la duración del tratamiento reiniciado necesaria para recuperar la RMM después de pérdida de RMM
    Objetivos adicionales se aplican
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients eligible for inclusion in this study have to meet all of the following criteria; additional inclusion criteria may apply as per protocol:
    1) Male or female patients ?18 years of age
    2) Minimum of 2 calendar years of nilotinib treatment (300 mg BID or transiently lower dose of nilotinib from the perspective of tolerance) for BCR-ABL positive CML in documented chronic phase at the time of diagnosis
    3) Evidence of typical BCR-ABL transcripts (b3a2 or b2a2) at the time of CML diagnosis i.e. prior to first start of TKI treatment which are amenable to standardized RT-PCR quantification?
    4) Patient in MR4.5 at prescreening at Novartis designated lab
    5) ECOG performance status of 0-2
    6) Adequate end organ function as defined by:
    ? Direct bilirubin ? 1.5 x ULN
    ? SGOT(AST) and SGPT(ALT) ? 3 x ULN i.e. equivalent to ? Grade 1 NCI-CTCAE v.4.03
    ? Serum lipase ? 2 x ULN i.e. equivalent to ? Grade 2 NCI-CTCAE v.4.03
    ? Alkaline phosphatase ? 2.5 x ULN
    ? Serum creatinine < 1.5 x ULN
    7) Patients must have the following electrolyte values within normal limits or corrected to be within normal limits with supplements prior to first dose of study medication:
    ? Potassium (suggested keep to prevent issues with QT and/or rhythm abnormalities)
    ? Magnesium (suggested keep to prevent issues with QT and/or rhythm abnormalities)
    ? Total calcium (corrected for serum albumin)
    8) Patients must have normal marrow function as defined:
    ? Absolute Neutrophil Count (ANC) ? 1.5 x 109/L
    ? Hemoglobin ? 9.0 g/dL
    ? Platelets ? 100 x 109/L

    Additional inclusion criteria are defined in the protocol.
    1.Hombres o mujeres ? 18 años de edad

    2. Mínimo de 2 años de calendario de tratamiento con nilotinib (300 mg BID o a un nivel de dosis reducido de 400 mg QD, si es preciso desde la perspectiva de la tolerancia) para LMC con BCR-ABL positivo en fase crónica documentada en el momento del diagnóstico.

    3. La LMC en fase crónica documentada deberá cumplir todos los criterios definidos por:
    -- < 15% de blastos en sangre periférica y médula ósea,
    -- < 30% de blastos más promielocitos en sangre periférica y médula ósea,
    -- < 20% de basófilos en sangre periférica,
    -- ? 100 x 109/L (? 100,000/mm3) de plaquetas,
    -- Sin evidencia de afectación leucémica extramedular, con la excepción de hepatoesplenomegalia.

    4. Los pacientes deberán tolerar una dosis diaria total mínima de nilotinib de 400 mg.

    5. Evidencia de tránscritos típicos de BCR-ABL (b3a2 o b2a2) en el momento del diagnóstico de LMC, es decir, antes del primer inicio del tratamiento con TKI que sean susceptibles a cuantificación estandarizada con RT-PCR

    6. Pacientes en RM4.5 en la preselección en el laboratorio designado por Novartis.

    7. Estado funcional del ECOG de 0-2

    8. Función orgánica adecuada final definida con:
    -- Bilirrubina directa ? 1.5 x LSN
    -- SGOT(AST) y SGPT(ALT) ? 3 x LSN, es decir, equivalente a ? Grado 1 de los CTCAE del INC v.4.03
    -- Lipasa sérica ? 2 x LSN, es decir, equivalente a ? Grado 2 de los CTCAE del INC-v.4.03
    -- Fosfatasa alcalina ? 2.5 x LSN
    -- Creatinina sérica < 1.5 x LSN

    9. Los pacientes deberán seguir los siguientes valores de electrolitos dentro de los límites de normalidad o corregidos dentro de los límites de normalidad con suplementos antes de la primera dosis de la medicación del estudio:
    -- Potasio (se sugiere que se mantengan para evitar problemas con el QT y/o anomalías del ritmo cardíaco)
    -- Magnesio (se sugiere que se mantengan para evitar problemas con el QT y/o anomalías del ritmo cardíaco)
    -- Calcio total (corregido para albúmina sérica)

    10. Los pacientes deberán presentar función de la médula ósea normal definida con:
    -- Recuento absoluto de neutrófilos (RAN) ? 1.5 x 109/L
    -- Hemoglobina ? 9.0 g/dL
    -- Plaquetas ? 100 x 109/L

    11. Voluntad y capacidad para cumplir con las visitas programadas, planes de tratamiento, análisis de laboratorio y otros procedimientos del estudio.
    E.4Principal exclusion criteria
    Patients eligible for this study must not meet any of the following criteria:
    1) Previous treatment with BCR-ABL inhibitors other than nilotinib for more than a total cumulative duration of 4 weeks
    2) Previous treatment with alpha-interferon of any duration
    3) Previous anticancer agents for CML other than nilotinib except for cytoreduction after CML diagnosis until up to 4 weeks after first dose of nilotinib
    4) Known second chronic phase of CML after previous progression to AP/BC
    5) Poorly controlled diabetes mellitus (defined as HbA1c > 9%)
    6) Impaired cardiac function as defined in the protocol
    7) History of acute pancreatitis within 1 year of study entry or past medical history of chronic pancreatitis
    8) Known presence of significant congenital or acquired bleeding disorder unrelated to cancer
    9) History of another active malignancy within 5 years prior to study entry with the exception of previous or concomitant basal cell skin cancer and previous carcinoma in situ treated curatively
    10) Treatment with other investigational agents (defined as not used in accordance with the approved indication) within 4 weeks of Day 1
    11) Patients actively receiving therapy with strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug.
    12) Patients actively receiving therapy with herbal medicines that are strong CYP3A4 inhibitors and/or inducers, and the treatment cannot be either discontinued or switched to a different medication prior to starting study drug. These herbal medicines may include Echinacea, (including E. purpurea, E. angustifolia and E. pallida), Piperine, Artemisinin, St. John?s Wort, and Ginkgo.
    13) Patients who are currently receiving treatment with any medications that have the potential to prolong the QT interval and the treatment cannot be either safely discontinued or switched to a different medication prior to starting study drug. (Please see http://www.torsades.org/medical-pros/drug-lists/printable-drug-list.cfm for a list of agents that prolong the QT interval)
    14) Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of study drug (e.g. ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small bowel resection, or gastric bypass surgery)
    15) 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.
    16) Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, unless they are using highly effective methods of contraception during the study and for 30 days after the final dose of nilotinib. Highly effective contraception is defined in the protocol.
    Additional exclusion criteria are defined in the protocol.
    1. Tratamiento previo con inhibidores de BCR-ABL que no sean nilotinib, durante más de una duración total acumulada de 4 semanas
    2. Tratamiento previo con interferón-alfa de cualquier duración
    3. Agentes antineoplásicos previos para LMC que no sea nilotinib, excepto citorreducción después del diagnóstico de LMC hasta 4 semanas después de la primera dosis de nilotinib
    4. Segunda fase crónica conocida de LMC después de progresión previa a LMC FA/CB
    5. Diabetes mellitus insuficientemente controlada (definida como HbA1c > 9%)
    6. Deterioro de la función cardíaca que incluya algo de lo siguiente:
    -- LVEF < 45% o por debajo del límite inferior del rango de normalidad del centro (lo que sea mayor)
    -- Incapacidad para determinar el intervalo QT en el ECG
    -- Bloqueo completo de rama izquierda
    -- Bloqueo de rama derecha más hemibloqueo posterior o anterior izquierdo
    -- Uso de un marcapasos ventricular
    -- Síndrome congénito de intervalo QT prolongado o antecedentes familiares conocidos de síndrome de QT prolongado
    -- Antecedentes de o presencia de taquiarritmias auriculares o ventriculares clínicamente significativas
    -- Bradicardia en reposo clínicamente significativa
    -- QTc > 450 ms de promedio en los tres ECGs basales en serie (utilizando la fórmula QTcF). Si QTcF > 450 ms y electrolitos fuera de los rangos de normalidad, los electrolitos deberían corregirse y, posteriormente, se volverá a analizar el QTc del paciente
    -- Antecedentes o signos clínicos de infarto de miocardio dentro de 1 año del inicio del estudio
    -- Antecedentes de angina inestable dentro de 1 año del inicio del estudio
    -- Otra enfermedad cardíaca clínicamente significativa (por ejemplo, insuficiencia cardíaca congestiva, cardiomiopatía o hipertensión incontrolada)
    7.Enfermedad clínica concurrente incontrolada y/o severa que, a criterio del investigador, pudiese causar riesgos de seguridad inaceptables o comprometer el cumplimiento con el protocolo (por ejemplo, diabetes incontrolada, infección incontrolada
    8. Antecedentes de pancreatitis aguda dentro de 1 año antes del inicio del estudio o antecedentes clínicos previos de pancreatitis crónica
    9. Presencia conocida de una alteración hemorrágica adquirida o congénita significativa no relacionada con el cáncer
    10. Antecedentes de otra enfermedad maligna activa dentro de los 5 años antes de entrar en el estudio con la excepción de cáncer cutáneo de células basales concomitante o previo y carcinoma previo in situ tratado curativamente
    11. Pacientes que no se han recuperado de la cirugía previa
    12. Tratamiento con otro agente en investigación (definido como no utilizado de acuerdo con la indicación aprobada) dentro de las 4 semanas del día 1
    13. Pacientes que reciban terapia activamente con inhibidores y/o inductores potentes de CYP3A4, y que el tratamiento no pueda ser suspendido o cambiado por una medicación distinta antes de iniciar el estudio. Véase Suplemento 1 para una lista de estas medicaciones. Puede no tratarse de una lista completa
    14. Pacientes que reciban terapia activamente con medicinas herbales que sean inhibidores y/o inductores potentes de CYP3A4 y que el tratamiento no pueda ser suspendido o cambiado por una medicación distinta antes de iniciar el estudio. Estas medicaciones herbales pueden incluir Echinacea, (incluyendo E. purpurea, E. angustifolia y E. pallida), Piperina, Artemisinina, Hierba de San Juan y Ginkgo
    15. Pacientes que actualmente estén recibiendo tratamiento con algunas medicaciones que tengan potencial de prolongar el intervalo QT y que el tratamiento no pueda ser suspendido de forma segura o cambiado a una medicación distinta antes de iniciar el estudio. (Por favor, véase, http://torsades.org/medical-pros/drug-lists/printable-drug-list.cfm para una lista de agentes que prolongan el intervalo QT)
    16.Deterioro de la función gastrointestinal (GI) o enfermedad GI que pueda alterar significativamente la absorción de la medicación del estudio (por ejemplo, enfermedades ulcerosas, náuseas incontroladas, vómitos, diarrea, síndrome de mala absorción, resección del intestino delgado o cirugía de bypass gástrico)
    17.Pacientes embarazadas o en periodo de lactancia, donde el embarazo se define como el estado de una mujer después de la concepción y hasta el final de la gestación, confirmado con un test de laboratorio hCG positivo.
    18.Mujeres físicamente fértiles, definidas como todas las mujeres fisiológicamente capaces de quedarse embarazadas, excepto en el caso de que utilicen métodos anticonceptivos eficaces durante el estudio y durante los 30 días después de la dosis final de nilotinib.
    E.5 End points
    E.5.1Primary end point(s)
    BCR-ABL ? 0.1% IS (MMR or MR3) at 48 weeks after starting the treatment-free remission (TFR) phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase.
    BCR-ABL ? 0,1% IS (RMM o RM3) a las 48 semanas después de comenzar la fase de remisión libre de tratamiento (RLT) sin pérdida de RMM y no re-iniciar el tratamiento de nilotinib en las primeras 48 semanas después de comenzar la fase de RLT.
    E.5.1.1Timepoint(s) of evaluation of this end point
    48 weeks after starting the TFR phase
    48 semanas despues de iniciar la fase de RLT
    E.5.2Secondary end point(s)
    1) BCR-ABL ? 0.0032% IS (MR4.5) at 48 weeks after starting the treatment-free remission (TFR) phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 48 weeks after starting the TFR phase.
    2) BCR-ABL ? 0.1% IS (MMR) at 96, 144 and 192 weeks after starting the TFR phase with no loss of MMR and no re-initiation of nilotinib therapy in the first 96, 144 and 192 weeks after starting the TFR phase
    3) BCR-ABL ? 0.0032% IS (MR4.5) at 96, 144 and 192 after starting the TFR phase with no loss of MR4.5 and no re-initiation of nilotinib therapy in the first 96, 144 and 192 weeks after starting the TFR phase
    4) BCR-ABL < 0.1% at least at one assessment within 12 weeks after re-start of nilotinib treatment
    5) Duration of re-initiated treatment required to regain MMR is defined as time from date of start of re-initiation of treatment after loss of MMR to the date of first achievement of MMR
    1) BCR-ABL ? 0,0032% IS (RM4.5) a las 48 semanas después de comenzar la fase de tratamiento libre de remisión sin pérdida de RM4.5 y no re-iniciar el tratamiento nilotinib en las primeras 48 semanas después de comenzar la fase de la TLR.
    2) BCR-ABL ? 0,1% IS (RMM) en las semanas 96, 144 y 192 después de comenzar la fase de TLR sin pérdida de RMM y no re-iniciar el tratamiento nilotinib en las primeras semanas 96, 144 y 192 después de comenzar la fase de TLR.
    3) BCR-ABL ? 0,0032% IS (RM4.5) a 96, 144 y 192 después de comenzar la fase de TLR sin pérdida de RM4.5 y no re-inicio de la terapia con nilotinib en las primeras semanas 96, 144 y 192 después de iniciar la fase de TLR.
    4) BCR-ABL <0,1% al menos en una evaluación a las 12 semanas después de volver a comenzar el tratamiento nilotinib
    5) Duración del tratamiento re-iniciado necesario para recuperar la RMM se define como el tiempo desde la fecha de inicio del tratamiento re-iniciado después de la pérdida de RMM hasta la fecha de primer logro de RMM
    E.5.2.1Timepoint(s) of evaluation of this end point
    1) 48 weeks after starting the TFR phase
    2 and 3) 96, 144 and 192 weeks after starting the TFR phase
    4) within 12 weeks after re-start of nilotinib treatment
    5) after re-initation of treatment
    1) 48 semanas después de comenzar la fase de TLR.
    2 y 3) semana 96, 144 y 192 después de comenzar la fase de TLR
    4) a las 12 semanas después de volver a iniciar el tratamiento con nilotinib
    5) después de la re-Iniciación del tratamiento
    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 No
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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 concerned15
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA102
    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
    Argentina
    Austria
    Belgium
    China
    Colombia
    Denmark
    France
    Germany
    Greece
    Ireland
    Italy
    Japan
    Poland
    Spain
    Sweden
    United Kingdom
    United States
    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
    The end of the trail occours 192 weeks later the last pacient last visit will be included in the phase RLT of nilotinib.
    El final del estudio (EOS) ocurre 192 semanas después de que el último paciente entre en la fase de RLT de nilotinib. En este momento, todos los pacientes habrán completado la fase de RLT o completado el tratamiento con nilotinib o suspendido el estudio prematuramente.
    Todos los pacientes que aún reciban tratamiento en el momento del final del estudio, o si el estudio se suspende prematuramente, pasarán a nilotinib prescrito.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months0
    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 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: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 55
    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.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 175
    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)
    standard of care
    cuidado estándar
    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 Decision2013-02-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-02-12
    P. End of Trial
    P.End of Trial StatusOngoing
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