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    Summary
    EudraCT Number:2011-006292-20
    Sponsor's Protocol Code Number:GS-US-312-0115
    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:2012-06-26
    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 number2011-006292-20
    A.3Full title of the trial
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of GS-1101 (CAL-101) in Combination with Bendamustine and Rituximab for Previously Treated Chronic Lymphocytic Leukemia
    Estudio de fase 3, aleatorizado, doble ciego, controlado con placebo para evaluar la eficacia y la seguridad de GS-1101 (CAL-101) en combinación con bendamustina y rituximab para la leucemia linfocítica crónica tratada previamente
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3, Randomised, Double-Blind, Placebo-Controlled Study of GS-1101 in Combination with Bendamustine and Rituximab for Previously Treated CLL
    Estudio de fase 3, aleatorizado, doble ciego, controlado con placebo de GS-1101 en combinación con bendamustina y rituximab para la leucemia LLC tratada previamente
    A.4.1Sponsor's protocol code numberGS-US-312-0115
    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 SponsorGilead Sciences, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGilead Sciences Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGilead Sciences Inc.
    B.5.2Functional name of contact pointMedical Monitor
    B.5.3 Address:
    B.5.3.1Street Address199 East Blaine Street
    B.5.3.2Town/ citySeattle, WA
    B.5.3.3Post code98102
    B.5.3.4CountryUnited States
    B.5.4Telephone number+001206256 4924
    B.5.5Fax number+001206832 2012
    B.5.6E-mailthomas.jahn@gilead.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code GS-1101
    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.3.9.1CAS number 870281-82-6
    D.3.9.2Current sponsor codeGS-1101
    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 Yes
    D.3.11.13.1Other medicinal product typeOral, small molecule inhibitor
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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 MabThera 100mg concentrate
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Products 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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMabThera
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 RoleComparator
    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 MabThera 500mg concentrate
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Products 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 No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameMabThera
    D.3.4Pharmaceutical form Concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRITUXIMAB
    D.3.9.1CAS number 174722-31-7
    D.3.9.4EV Substance CodeSUB12570MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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: 4
    D.1.2 and D.1.3IMP RoleComparator
    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 Levact
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma GmbH
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLevact
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBENDAMUSTINE HYDROCHLORIDE
    D.3.9.1CAS number 3543-75-7
    D.3.9.4EV Substance CodeSUB00696MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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: 5
    D.1.2 and D.1.3IMP RoleComparator
    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 Levact
    D.2.1.1.2Name of the Marketing Authorisation holderAstellas Pharma GmbH
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameLevact
    D.3.4Pharmaceutical form Powder for concentrate for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBENDAMUSTINE HYDROCHLORIDE
    D.3.9.1CAS number 3543-75-7
    D.3.9.4EV Substance CodeSUB00696MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 6
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.2Product code GS-1101
    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.3.9.1CAS number 870281-82-6
    D.3.9.2Current sponsor codeGS-1101
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product Yes
    D.3.11.13.1Other medicinal product typeOral, small molecule inhibitor
    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 placeboTablet
    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
    Chronic Lymphocytic Leukemia (CLL)
    Leucemia linfocítica crónica (LLC)
    E.1.1.1Medical condition in easily understood language
    Chronic Lymphocytic Leukemia (CLL)
    Leucemia linfocítica crónica (LLC)
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 15.0
    E.1.2Level PT
    E.1.2Classification code 10008958
    E.1.2Term Chronic lymphocytic leukaemia
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of the addition of GS-1101 to bendamustine/rituximab on progression-free survival (PFS) in
    subjects with previously treated chronic lymphocytic leukemia
    (CLL)
    Evaluar el efecto de la adición de GS-1101 a bendamustina/rituximab sobre la supervivencia libre de progresión (SLP) en sujetos con leucemia linfocítica crónica (LLC) tratada previamente
    E.2.2Secondary objectives of the trial
    ? To determine the effect of the addition of GS-1101 to bendamustine/rituximab on the onset, magnitude, and duration of
    tumor control
    ? To assess the effect of the addition of GS-1101 to bendamustine/rituximab on measures of subject well-being, including overall survival (OS), health-related quality of life (HRQL), and performance status
    ? To assess the effects of the addition of GS-1101 to bendamustine/rituximab on disease-associated biomarkers and to evaluate potential mechanisms of resistance to GS-1101
    ? To characterize exposure to study treatment as determined by treatment administration with each of the therapeutic agents and evaluation of GS-1101 plasma concentrations over time
    ? To describe the safety profile observed with the addition of GS-1101 to bendamustine/rituximab
    ? To estimate health resource utilization associated with the addition of GS-1101 to bendamustine/rituximab
    - Determinar el efecto de la adición de GS-1101 a bendamustina/rituximab sobre el inicio, la magnitud y la duración del control tumoral
    - Evaluar el efecto de la adición de GS-1101 a bendamustina/rituximab sobre las medidas del bienestar del sujeto, incluidas la supervivencia global (SG), la calidad de vida relacionada con la salud (CVRS) y el estado funcional
    - Evaluar los efectos de la adición de GS-1101 a bendamustina/rituximab sobre los biomarcadores asociados a la enfermedad y estudiar los posibles mecanismos de resistencia a GS-1101
    - Caracterizar la exposición al tratamiento en estudio, determinada mediante la administración del tratamiento con cada uno de los agentes terapéuticos y la evaluación de las concentraciones plasmáticas de GS-
    1101 a lo largo del tiempo
    - Describir el perfil de seguridad observado con la adición de GS-1101 a bendamustina/rituximab
    - Calcular el uso de recursos sanitarios asociado a la adición de GS-1101 a bendamustina/rituximab
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1) Male or female ?18 years of age.
    2) Diagnosis of B-cell CLL, with diagnosis established according to International Workshop on Chronic Lymphocytic Leukemia
    (IWCLL) criteria and documented within medical records.
    3) CLL that warrants treatment (consistent with accepted IWCLL criteria for initiation of therapy)
    4) Presence of measurable lymphadenopathy (defined as the presence of ?1 nodal lesion that measures ?2.0 cm in the longest dimension [LD] and ?1.0 cm in the longest perpendicular dimension [LPD] as assessed by computed tomography [CT] or magnetic resonance imaging [MRI]).
    5) Prior treatment for CLL comprising:
    a) ?2 cycles of a regimen containing a purine analog (eg,
    fludarabine, pentostatin, cladribine) or bendamustine, and
    b) ?2 doses with a regimen containing an anti-CD20 monoclonal
    antibody (eg, rituximab, ofatumumab, GA-101)
    6) Documentation of CLL progression <36 months since the completion of the last prior therapy for CLL.
    7) Discontinuation of all therapy (including radiotherapy, chemotherapy, immunotherapy, systemic corticosteroids, or
    investigational therapy) for the treatment of CLL ?3 weeks before randomization.
    8) All acute toxic effects of any prior antitumor therapy resolved to Grade ?1 before randomization (with the exception of alopecia [Grade 1 or 2 permitted], neurotoxicity [Grade 1 or 2 permitted], or bone marrow parameters [Grades 1 or 2 permitted]).
    9) Karnofsky performance score of ?60
    10) Required baseline laboratory data (within 4 weeks prior to randomization) as shown in the protocol
    11) For female subjects of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the screening visit (Visit 1) throughout the study treatment period and for 30 days following the last dose of study drug. Note: A female subject is considered to be of childbearing potential unless she has had a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy; has medically documented ovarian failure (with serum estradiol and folliclestimulating hormone [FSH] levels within the institutional postmenopausal range and a negative serum or urine ?HCG); or is menopausal (age ?55 years with amenorrhea for ?6 months)
    12) For male subjects of childbearing potential having intercourse with females of childbearing potential, willingness to abstain from heterosexual intercourse or use a protocol-recommended method of contraception from the randomization visit (Visit 2) throughout the study treatment period and for 90 days following the last dose of study drug and to refrain from sperm donation from randomization (Visit 2) throughout the study treatment period and for 90 days following the last dose of study drug. Note: A male subject is considered able to father a child unless he has had a bilateral vasectomy with documented aspermia or a bilateral orchiectomy, or has ongoing testicular suppression with a depot luteinizing hormone- releasing hormone (LH-RH) agonist (eg, goserelin acetate [Zoladex®]), leuprolide acetate [Lupron®]), or triptorelin pamoate [Trelstar®]).
    13) In the judgment of the investigator, participation in the protocol offers an acceptable benefit-to-risk ratio when considering current CLL disease status, prior treatment history, medical condition, and the potential benefits and risks of alternative treatments for CLL.
    Note: Investigators should consider whether a study subject is an appropriate candidate for bendamustine-containing therapy based
    on the number and severity of comorbid conditions; subjects with a baseline Cumulative Illness Rating Scale (CIRS) score of ?6 may be particularly appropriate candidates for this trial
    14) Willingness and ability to comply with scheduled visits, drug administration plan, imaging studies, laboratory tests, other study procedures, and study restrictions. Note: Psychological, social, familial, or geographical factors that might preclude adequate study participation should be considered.
    15) Evidence of a personally signed informed consent indicating that the subject is aware of the neoplastic nature of the disease and has been informed of the procedures to be followed, the experimental nature of the therapy, alternatives, potential benefits, possible side effects, potential risks and discomforts, and other pertinent aspects of study participation.
    1) Sujetos de ambos sexos ?18 años de edad.
    2) Diagnóstico de LLC de linfocitos B, confirmado de acuerdo a los criterios del IWCLL (International Workshop on Chronic Lymphocytic Leukemia, Grupo Internacional sobre Leucemia Linfocítica Crónica) y
    documentado en la historia clínica.
    3) LLC para la que el tratamiento está justificado (que cumpla los criterios aceptados del IWCLL para el inicio del tratamiento).
    4) Presencia de linfadenopatía medible (definida por la presencia de ?1
    lesión ganglionar de ?2,0 cm de diámetro máximo [DM] y ?1,0 cm de diámetro perpendicular máximo [DPM] y evaluada mediante tomografía computarizada [TC] o resonancia magnética [RM]).
    5) Tratamiento previo para la LLC consistente en:
    a) ?2 ciclos de un régimen con un análogo de la purina (p.ej., fludarabina, pentostatina, cladribina) o bendamustina y
    b) ?2 dosis con un régimen con un anticuerpo monoclonal anti-CD20
    (p.ej., rituximab, ofatumumab o GA-101).
    6) Progresión de la LLC documentada, en <36 meses desde la finalización del último tratamiento previo para la LLC.
    7) Retirada de todos los tratamientos (radioterapia, quimioterapia, inmunoterapia, corticoesteroides sistémicos o tratamiento en fase de investigación) para la LLC ?3 semanas antes de la aleatorización.
    8) Todos los efectos tóxicos inmediatos de cualquier tratamiento antineoplásico previo se resolvieron hasta el grado ?1 antes de la
    aleatorización (a excepción de alopecia [grados 1 y 2 permitidos], neurotoxicidad [grados 1 y 2 permitidos] o parámetros medulares [grados 1 y 2 permitidos]).
    9) Puntuación funcional de Karnofsky ?60.
    10) Los datos analíticos basales requeridos (en las 4 semanas previas a la aleatorización) según el protocolo.
    11) En las mujeres en edad fértil, voluntad de abstenerse de mantener relaciones sexuales heterosexuales o utilizar un método anticonceptivo recomendado en el protocolo, desde la visita de selección (visita 1),
    durante la totalidad del periodo de tratamiento del estudio, y hasta 30
    días después de la última dosis del fármaco del estudio. Nota: se considera que una mujer es fértil a menos que se haya sometido a una histerectomía, ligadura de trompas bilateral u ovariectomía bilateral;
    presente insuficiencia ovárica demostrada médicamente (con valores de estradiol sérico y hormona foliculoestimulante [FSH] dentro del intervalo posmenopáusico de la institución y ?-HCG negativa en suero u orina) o sea menopáusica (edad ? 55 años con amenorrea durante ? 6 meses).
    12) En los varones en edad fértil que mantengan relaciones sexuales con mujeres en edad fértil, voluntad de abstenerse de practicar relaciones sexuales o usar un método anticonceptivo recomendado en el protocolo, desde la visita de aleatorización (visita 2), durante la totalidad del periodo de tratamiento del estudio, y hasta 90 días después de la última dosis del fármaco del estudio, así como no donar esperma desde la
    aleatorización (visita 2), durante la totalidad del periodo de tratamiento del estudio, y hasta 90 días después de la última dosis del fármaco del estudio. Nota: se considera que un varón es capaz de tener un hijo a menos que se haya sometido a una vasectomía bilateral con aspermia documentada, a una orquiectomía bilateral o a una supresión
    testicular continua con un agonista de la luliberina (LHRH) (p.ej., acetato de goserelina [Zoladex®]), acetato de leuprorelina
    [Lupron®]) o pamoato de triptorelina [Trelstar®]).
    13) A juicio del investigador, la participación en el estudio de conformidad con el protocolo ofrece una relación riesgo-beneficio aceptable, cuando se consideran el estado actual de la LLC, los tratamientos previos, la enfermedad y los posibles riesgos y beneficios de los tratamientos alternativos para la LLC. Nota: los investigadores deben valorar si un sujeto del estudio es un candidato adecuado para un tratamiento con bendamustina, en función del número y la gravedad de las enfermedades concomitantes; los sujetos con una puntuación basal en el índice CIRS (Cumulative Illness Rating Scale, índice acumulativo de enfermedad) ?6 serían candidatos especialmente adecuados para
    este ensayo.
    14) Voluntad y capacidad de cumplir con las visitas programadas, el plan de administración del fármaco, las pruebas de diagnóstico por la imagen, los análisis clínicos, otros procedimientos del estudio y las restricciones del estudio. Nota: deben tenerse en cuenta los factores psicológicos,
    sociales, familiares o geográficos que puedan impedir la adecuada participación en el estudio.
    15) Existencia de un consentimiento informado firmado personalmente que
    indique que el sujeto conoce la naturaleza neoplásica de la enfermedad y ha sido informado de los procedimientos a seguir, del carácter experimental del tratamiento, las alternativas, los posibles efectos beneficiosos, los posibles efectos adversos, los posibles riesgos y molestias, y otros aspectos pertinentes de la participación en el estudio.
    E.4Principal exclusion criteria
    1) Known histological transformation from CLL to an aggressive
    lymphoma (ie, Richter transformation). Note: Biopsy
    documentation of the absence or presence of transformation is not required.
    2) Known presence of intermediate- or high-grade myelodysplastic
    syndrome (ie, subjects are excluded who have ?5 bone marrow
    blasts; karotypic abnormalities other than normal, Y deletion, 5q
    deletion, or 20q deletion; or ?2 lineages of cytopenias due to
    myelodysplasia).
    3) History of a non-CLL malignancy except for the following:
    adequately treated local basal cell or squamous cell carcinoma of
    the skin, cervical carcinoma in situ, superficial bladder cancer,
    asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for ?1 year prior to randomization, other adequately treated Stage 1 or 2 cancer currently in complete remission, or any other cancer that has been in complete remission for ?5 years.
    4) Evidence of ongoing systemic bacterial, fungal, or viral infection at the time of randomization (Visit 2). Note: Subjects with localized
    fungal infections of skin or nails are eligible. Subjects may be
    receiving prophylactic antiviral or antibacterial therapies at the
    discretion of the investigator. For subjects who are at substantial
    risk of an infection (eg, influenza) that may be prevented by
    immunization, consideration should be given to providing the
    vaccine prior to initiation of protocol therapy
    5) Ongoing drug-induced liver injury, chronic active hepatitis C
    (HCV), chronic active hepatitis B (HBV), alcoholic liver disease,
    non-alcoholic steatohepatitis, primary biliary cirrhosis, ongoing
    extrahepatic obstruction caused by cholelithiasis, cirrhosis of the
    liver, or portal hypertension.
    6) Ongoing drug-induced pneumonitis.
    7) Ongoing inflammatory bowel disease.
    8) Ongoing alcohol or drug addiction.
    9) Pregnancy or breastfeeding.
    10) History of prior allogeneic bone marrow progenitor cell or solid
    organ transplantation
    11) Ongoing immunosuppressive therapy, including systemic
    corticosteroids for treatment of CLL. Note: Subjects may use
    topical, enteric, or inhaled corticosteroids as therapy for comorbid
    conditions and systemic steroids for autoimmune anemia and/or
    thrombocytopenia. Ongoing use of low-dose systemic
    corticosteroids (?5 mg/day of methylprednisolone or equivalent)
    for rheumatologic conditions is permitted. During study participation, subjects may receive systemic or other corticosteroids as pretreatment for rituximab infusions or as
    needed for treatment-emergent comorbid conditions.
    12) In a subject with a history of prior bendamustine therapy, a time interval from the last dose of bendamustine to the subsequent CLL progression of <6 months.
    13) History of prior therapy with any inhibitor of AKT, Bruton tyrosine kinase (BTK), Janus kinase (JAK), mammalian target of rapamycin (mTOR), phosphatidylinositol 3-kinase (PI3K) (including
    GS-1101), or spleen tyrosine kinase (SYK).
    14) History of anaphylaxis in association with previous administration of monoclonal antibodies
    15) Concurrent participation in another therapeutic clinical trial.
    16) Prior or ongoing clinically significant illness, medical condition,
    surgical history, physical finding, electrocardiogram (ECG) finding,
    or laboratory abnormality that, in the investigator?s opinion, could
    adversely affect the safety of the subject or impair the assessment of study results.
    1) Transformación histológica conocida de la LLC en un linfoma agresivo (esto es, transformación de Richter). Nota: no se requiere documentación mediante biopsia de la ausencia o presencia de transformación.
    2) Presencia conocida de síndrome mielodisplásico de grado medio o alto
    (es decir, quedan excluidos sujetos con ?5 mieloblastos; anomalías cariotípicas no habituales, deleción del cromosoma Y, deleción 5q o deleción 20q; o citopenias de ?2 linajes por la mielodisplasia).
    3) Antecedentes de neoplasia distinta de LLC, a excepción de las siguientes: carcinoma basocelular o espinocelular localizados y tratados adecuadamente; carcinoma cervicouterino in situ; cáncer vesical superficial; cáncer de próstata asintomático, sin metástasis conocida, sin
    necesidad de tratamiento o que solo necesite hormonoterapia, y con PSA (antígeno próstata-específico) normal durante ?1 año antes de la aleatorización; otra neoplasia en estadio 1 o 2 tratada adecuadamente y
    actualmente en remisión completa; o cualquier otra neoplasia en remisión completa desde hace ?5 años.
    4) Signos de infección bacteriana, micótica o vírica sistémicas en curso, en
    el momento de la aleatorización (visita 2). Nota: los sujetos con micosis
    localizadas, cutáneas o ungueales, son aptos para participar en el
    estudio. Los sujetos podrán recibir tratamiento profiláctico antiviral o
    antibiótico, a criterio del investigador. En los sujetos con riesgo
    importante de padecer una infección, (p.ej., gripe) evitable mediante
    vacunación, se debe sopesar la posibilidad de administrar la vacuna
    antes de iniciar el tratamiento del protocolo.
    5) Lesión hepática en curso inducida por fármacos, hepatitis C (VHC)
    activa crónica, hepatitis B (VHB) activa crónica, hepatopatía alcohólica,
    esteatohepatitis no alcohólica, cirrosis biliar primaria, obstrucción
    extrahepática en curso por colelitiasis, cirrosis hepática o hipertensión
    portal.
    6) Neumonitis en curso inducida por fármacos.
    7) Enfermedad intestinal inflamatoria en curso.
    8) Alcoholismo o drogadicción en curso.
    9) Embarazo o lactancia.
    10) Antecedentes de trasplante alogénico de células progenitoras de la
    médula ósea o de trasplante de víscera maciza.
    11) Tratamiento inmunosupresor en curso, incluidos los corticoesteroides sistémicos para el tratamiento de la LLC. Nota: los sujetos pueden utilizar corticoesteroides tópicos, inhalados o por vía gastroentérica,
    como tratamiento para las enfermedades concomitantes, y corticoesteroides sistémicos para la anemia y/o trombocitopenia autoinmunes. Está permitido el uso continuado de corticoesteroides sistémicos en dosis bajas (?5 mg/día de metilprednisolona o
    equivalente) para el tratamiento de enfermedades reumáticas.
    Durante la participación en el estudio, los sujetos podrán recibir corticoesteroides sistémicos o de otro tipo, como pretratamiento para las infusiones de rituximab o según sea necesario para tratar las enfermedades concomitantes surgidas durante el tratamiento.
    12) En sujetos con tratamiento previo con bendamustina, un intervalo de
    tiempo <6 meses, desde la última dosis de bendamustina hasta la
    subsiguiente progresión de la LLC.
    13) Tratamiento previo con un inhibidor de la AKT, la tirosina-cinasa de
    Bruton (BTK), la cinasa Janus (JAK), la molécula diana de rapamicina
    en mamíferos (mTOR), la fosfatidilinositol-3-cinasa (PI3K) (incluido
    GS-1101) o la tirosina-cinasa esplénica (SYK).
    14) Antecedentes de anafilaxia en asociación con la administración previa
    de anticuerpos monoclonales.
    15) Participación simultánea en otro ensayo clínico terapéutico.
    16) Enfermedad clínicamente significativa previa o en curso, patología,
    antecedentes quirúrgicos, datos de la exploración física, resultados del
    electrocardiograma (ECG) o anomalía analítica que, en opinión del
    investigador, podría afectar negativamente a la seguridad del sujeto o
    alterar la evaluación de los resultados del estudio.
    E.5 End points
    E.5.1Primary end point(s)
    Progression-free survival (PFS) ? defined as the interval from randomization to the earlier of the first documentation of definitive
    disease progression or death from any cause; definitive disease progression is CLL progression based on standard criteria and
    occurring for any reason (ie, increasing lymphadenopathy,organomegaly or bone marrow involvement; decreasing platelet
    count, hemoglobin, or neutrophil count; or worsening of disease-related symptoms) other than lymphocytosis alone
    Supervivencia libre de progresión (SLP), definida como el intervalo desde la aleatorización hasta la primera documentación de progresión demostrada de la enfermedad, o muerte por cualquier causa, lo que suceda primero; por progresión demostrada de la enfermedad se entiende la progresión de la LLC, según los criterios de referencia, que ocurre por cualquier razón que no sea únicamente la linfocitosis (esto es, linfadenopatía creciente, organomegalia o afectación de la médula ósea; descenso de la cifra de trombocitos, neutrófilos o hemoglobina; o empeoramiento de los síntomas relacionados con la enfermedad).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Clinic/laboratory visits will occur every 2 weeks through Week 24 and every 6 weeks between Weeks 24 and 48. Subjects who continue on study treatment past Week 48 will have clinic visits every 12 weeks. Subjects will be assessed for safety at each clinic visit. Subjects will be assessed for CLL disease status by physical and laboratoryexaminations at each clinic visit and by CT or MRI at Weeks 12, 24, 36, and 48 and every 12 weeks thereafter through Week 120. For follow-up visits after Week 120, CT or MRI is only required at the Endof-Treatment visit.
    Las visitas clínicas/analíticas tendrán lugar cada 2 semanas hasta la semana 24 y cada 6 semanas entre las semanas 24 y 48. Los sujetos que continúen con el tratamiento del estudio después de la semana 48 realizarán visitas clínicas cada 12 semanas. Se evaluará la seguridad de los sujetos en cada visita clínica. Se evaluará el estado de la LLC de los sujetos mediante exploraciones físicas y pruebas analíticas en cada visita clínica y mediante TC o RM en las semanas 12, 24, 36 y 48 y, posteriormente, cada 12 semanas hasta la semana 120. Para las visitas de seguimiento tras la semana 120, solo se necesitará una TC o RM en la visita de fin del tratamiento.
    E.5.2Secondary end point(s)
    Tumor Control
    ? Overall response rate (ORR) ? defined as the proportion of subjects who achieve a complete response (CR) or partial response (PR)
    ? Time to response (TTR) ? defined as the interval from randomization to the first documentation of CR or PR
    ? Duration of response (DOR) ? defined as the interval from the first documentation of CR or PR to the earlier of the first documentation of definitive disease progression or death from any cause
    ? Time to treatment failure (TTF) ? defined as the interval from
    randomization to the earliest of the first documentation of definitive disease progression, the permanent cessation of study drug (GS-1101/placebo) due to an adverse event, or death from any cause
    ? Percent change in lymph node area ? defined as the percent change from baseline in the sum of the products of the greatest
    perpendicular diameters (SPD) of index lymph nodes
    ? Lymph node response rate ? defined as the proportion of subjects who achieve a ?50% decrease from baseline in the SPD of index lymph nodes
    ? Splenomegaly response rate ? defined as the proportion of subjects with baseline splenomegaly who achieve an on-study normalization or a decrease by ?50% from baseline in the pretreatment enlargement of the splenic longest vertical dimension (LVD) (by imaging) or in the pretreatment enlargement of the splenic LVD below the left costal margin (by palpation)
    ? Hepatomegaly response rate ? defined as the proportion of subjects with baseline hepatomegaly who achieve an on-study normalization or a decrease by ?50% from baseline in the pretreatment enlargement of the hepatic LVD (by imaging) or in the pretreatment enlargement of the hepatic LVD at the right midclavicular line (by percussion)
    ? Platelet response rate ? defined as the proportion of subjects with baseline thrombocytopenia (platelet count <100 x 109/L) who achieve an on-study platelet count ?100 x 109/L or demonstrate a
    ?50% increase in platelet count from baseline
    ? Hemoglobin response rate ? defined as the proportion of subjects with baseline anemia (hemoglobin <110 g/L [11.0 g/dL]) who achieve an on-study hemoglobin ?110 g/L (11.0 g/dL) or demonstrate a ?50% increase in hemoglobin from baseline
    ? Neutrophil response rate ? defined as the proportion of subjects with baseline neutropenia (absolute neutrophil count [ANC] <1 x 109/L) who achieve an ANC ?1 x 109/L or demonstrate a ?50% increase in ANC from baseline

    Patient Well-Being
    ? Overall survival (OS) ? defined as the interval from randomization
    to death from any cause
    ? Change in HRQL domain and symptom scores based on the
    Functional Assessment of Cancer Therapy: Leukemia (FACT-Leu)
    ? Changes in Karnofsky performance status ? defined as the change from baseline in the performance status and the time to definitive performance status improvement or worsening; time to definitive performance status improvement (better than baseline) is the interval from randomization to the first timepoint when the performance status is consistently better than at baseline (including that timepoint as well as all the subsequent timepoints) in a subject whose last performance status score is better than at baseline; and time to definitive performance status worsening (worse than baseline) is the interval from randomization until the earliest of death or the first timepoint when the performance status is consistently worse than at baseline (including that timepoint as well as all the subsequent timepoints) in a subject whose last performance status score is worse than at baseline

    Pharmacodynamic Markers of Drug Activity and Resistance
    ? Changes from baseline in PI3K/AKT/mTOR pathway activation as
    a measure of PI3K? pathway activity
    ? Changes from baseline in the plasma concentrations of diseaseassociated chemokines and cytokines

    Exposure
    ? Study drug administration as assessed by prescribing records and compliance as assessed by quantification of used and unused drug
    ? Trough (pre-dose) and peak (1.5-hour samples) of GS-1101 plasma concentrations as assessed by a validated bioanalytical method

    Safety
    ? Overall safety profile of each study treatment regimen characterized by the type, frequency, severity, timing of onset, duration, and relationship to study therapy of any adverse events or abnormalities of laboratory tests; serious adverse events; or adverse events leading to discontinuation of study treatment

    Pharmacoeconomics
    ? Change in health status ? defined as the change from baseline in
    overall health and single-item dimension scores as assessed using
    the EuroQoL Five-Dimension (EQ-5D) utility measure
    ? Health resource measures, including resource utilization, total costs, and measures of cost per unit of benefit (eg, cost per additional progression-free month, cost per quality-adjusted life-year)
    Control tumoral
    -Tasa de respuesta global (TRG), definida como proporción de sujetos que logran una respuesta completa (RC) o una respuesta parcial (RP).
    -Tiempo hasta la respuesta (THR), definido como el intervalo entre la aleatorización y la primera documentación de RC o RP.
    -Duración de la respuesta (DR), definida como el intervalo entre la primera documentación de RC o RP, y la primera documentación de progresión demostrada de la enfermedad o muerte por cualquier causa.
    -Tiempo hasta el fracaso del tratamiento (TFT), definido como el intervalo entre la aleatorización y la primera documentación de
    progresión demostrada de la enfermedad, suspensión permanente del fármaco del estudio (GS-1101/placebo) debido a un acontecimiento adverso, o muerte por cualquier causa.
    -Cambio porcentual en la zona de los ganglios linfáticos, definido como el cambio en el porcentaje, respecto al inicio, en la suma de los productos de los diámetros máximos perpendiculares (SPD) de los
    ganglios linfáticos de referencia.
    -Tasa de respuesta de los ganglios linfáticos, definida como la proporción de sujetos que logran un descenso ?50 % respecto al inicio en la SPD de los ganglios linfáticos de referencia.
    -Tasa de respuesta de la esplenomegalia, definida como la proporción de sujetos con esplenomegalia al inicio que logran una normalización durante el estudio; o una reducción ?50 % respecto al inicio de la
    hipertrofia previa al tratamiento del diámetro longitudinal máximo (DLM) del bazo (por imagen); o una reducción de la hipertrofia previa al tratamiento del DLM del bazo por debajo del reborde costal izquierdo
    (a la palpación).
    -Tasa de respuesta de la hepatomegalia, definida como la proporción de sujetos con hepatomegalia al inicio que logran una normalización durante el estudio; o un descenso ?50 % respecto al inicio de la
    hipertrofia previa al tratamiento del DLM hepático (por imagen); o una reducción en la hipertrofia previa al tratamiento del DLM hepático a lo largo de la línea medioclavicular derecha (a la percusión).
    -Tasa de respuesta de los trombocitos, definida como la proporción de sujetos con trombocitopenia al inicio (cifra de trombocitos <100 x 109/l)
    que logran una cifra de trombocitos durante el estudio ?100 x 109/l o presentan un aumento ?50 % en la cifra de trombocitos respecto al inicio.
    -Tasa de respuesta de la hemoglobina, definida como la proporción de sujetos con anemia al inicio (hemoglobina <110 g/l [11,0 g/dl]) que logran un valor de la hemoglobina durante el estudio ?110 g/l (11,0 g/dl) o presentan un aumento ?50 % de la hemoglobina respecto al inicio.
    -Tasa de respuesta de los neutrófilos, definida como la proporción de sujetos con neutropenia al inicio (cifra absoluta de neutrófilos [CAN] <1 x 109/l) que logran una CAN ?1 x 109/l o presentan un aumento
    ?50 % en la CAN respecto al inicio.
    Bienestar del paciente
    -Supervivencia global (SG), definida como el intervalo entre la aleatorización y la muerte por cualquier causa.
    -Cambio en el dominio de la CVRS y las puntuaciones de síntomas según la escala de evaluación funcional del tratamiento oncológico: Leucemia (FACT-Leu)
    -Cambios en el estado funcional de Karnofsky, definidos como el cambio del estado funcional entre el inicio y el tiempo hasta la mejora o el empeoramiento demostrados del estado funcional; el tiempo hasta la mejora demostrada del estado funcional (mejor que al inicio) es el
    intervalo entre la aleatorización y el primer momento en que el estado funcional es invariablemente mejor que al inicio (incluyendo ese momento, además de todos los momentos subsiguientes) en un sujeto
    cuya última puntuación en el estado funcional es mejor que al inicio del estudio; y el tiempo hasta el empeoramiento demostrado del estado funcional (peor que al inicio) es el intervalo entre la aleatorización y, lo
    que suceda primero, la muerte, o el primer momento en que el estado funcional es invariablemente peor que al inicio (incluyendo ese momento, además de todos los momentos subsiguientes) en un sujeto
    cuya última puntuación en el estado funcional es peor que al inicio.
    Marcadores farmacodinámicos de la actividad del fármaco y la resistencia al mismo
    -Cambios respecto al inicio en la activación de la vía PI3K/AKT/mTOR como medida de la actividad de la vía del PI3K?.
    -Cambios respecto al inicio en las concentraciones plasmáticas de quimiocinas y citocinas asociadas a la enfermedad.
    Exposición
    -Administración del fármaco del estudio, evaluada mediante el apartado del informe del paciente relativo a las prescripciones y, cumplimiento, evaluado mediante la cuantificación del fármaco utilizado y no utilizado.
    -Concentraciones plasmáticas de GS-1101 mínima (antes de la dosis) y máxima (muestras a las 1,5 horas) evaluadas por un método bioanalítico validado.

    Para el perfil de Seguridad y Farmacoeconomía consúltese el protocolo.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Clinic/laboratory visits will occur every 2 weeks through Week 24 and every 6 weeks between Weeks 24 and 48. Subjects who continue on study treatment past Week 48 will have clinic visits every 12 weeks.Subjects will be assessed for safety at each clinic visit. Subjects will be assessed for CLL disease status by physical and laboratory examinations at each clinic visit and by CT or MRI at Weeks 12, 24, 36, and 48 and every 12 weeks thereafter through Week 120. For follow-up visits after Week 120, CT or MRI is only required at the End-of-Treatment visit.
    Las visitas clínicas/analíticas tendrán lugar cada 2 semanas hasta la semana 24 y cada 6 semanas entre las semanas 24 y 48. Los sujetos que continúen con el tratamiento del estudio después de la semana 48 realizarán visitas clínicas cada 12 semanas. Se evaluará la seguridad de los sujetos en cada visita clínica. Se evaluará el estado de la LLC de los sujetos mediante exploraciones físicas y pruebas analíticas en cada visita clínica y mediante TC o RM en las semanas 12, 24, 36 y 48 y, posteriormente, cada 12 semanas hasta la semana 120. Para las visitas de seguimiento tras la semana 120, solo se necesitará una TC o RM en la visita de fin 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 No
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) 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) Yes
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA87
    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
    Belgium
    France
    Germany
    Italy
    Poland
    Russian Federation
    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
    It is expected that the final analysis of the study will take place after a minimum of 24 months of follow-up. The final analysis will be conducted after the 260th event (definitive CLL progression or death) or 36 months from the time the last subject is enrolled (whichever occurs first). Once outstanding data queries have been resolved, the database will be locked, the blind will be broken, and the final analysis of the study will be performed.
    Se prevé que el análisis final del estudio se lleve a cabo después de un mínimo de 24 meses de seguimiento. Se prevé que el análisis final tenga lugar tras el acontecimiento n.º 260 (progresión demostrada de la LLC o muerte) o 36 meses tras la inclusión del último sujeto, lo que suceda antes. Una vez resueltas las consultas pendientes sobre los datos, se cerrará la base de datos, se terminará el
    enmascaramiento y se realizará el análisis final del estudio.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months8
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months8
    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: 270
    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 state25
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 290
    F.4.2.2In the whole clinical trial 390
    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 a patient has completed/terminated their study participation, long term care for the participant will remain the responsibility of their primary treating physician.
    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 Decision2012-09-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-08-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-06-10
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
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