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    Summary
    EudraCT Number:2014-001048-40
    Sponsor's Protocol Code Number:B1371013
    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:2015-08-31
    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 number2014-001048-40
    A.3Full title of the trial
    A phase 2, double-blind, randomized safety and efficacy study of Glasdegib (PF-04449913) versus placebo in patients with Myelofibrosis previously treated with ruxolitinib.
    Estudio de fase II, doble ciego, aleatorizado sobre la seguridad y la eficacia de Glasdegib (PF 04449913) frente a placebo en pacientes con Mielofibrosis previamente tratada con Ruxolitinib
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to test the safety and efficacy of Glasdegib (PF-04449913) versus placebo in patients with Myelofibrosis.
    Ensayo para probar la seguridad y eficacia de Glasdegib (PF-04449913) frente a placebo en pacientes con mielofibrosis
    A.3.2Name or abbreviated title of the trial where available
    Glasdegib (PF-04449913)
    A.4.1Sponsor's protocol code numberB1371013
    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 SponsorPfizer Inc. 235 East 42nd Street, New York, 10017
    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 supportPfizer Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc
    B.5.2Functional name of contact pointClinical Trials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018007181021
    B.5.5Fax number0013037391119
    B.5.6E-mailclinicaltrials.govcallcentre@pfizer.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.3.1Product nameGlasdegib
    D.3.2Product code PF-04449913
    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 INNN/A
    D.3.9.2Current sponsor codePF-04449913
    D.3.9.4EV Substance CodeSUB31245
    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: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameGlasdegib
    D.3.2Product code PF-04449913
    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 INNN/A
    D.3.9.2Current sponsor codePF-04449913
    D.3.9.4EV Substance CodeSUB31245
    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.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
    Myelofibrosis
    Mielofibrosis
    E.1.1.1Medical condition in easily understood language
    A bone marrow disorder that disrupts a body's normal production of blood cells.
    Un trastorno de la médula ósea que interrumpe la producción normal de células sanguíneas del cuerpo.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10028537
    E.1.2Term Myelofibrosis
    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
    Lead-in Cohort
    - To assess the safety and tolerability of PF-04449913 in patients with primary or secondary MF who have been previously treated with ?1 JAKi.

    Randomized Cohort
    -To compare the effect of PF-04449913 vs. placebo on SVR in patients with primary or secondary MF who have been previously treated with ruxolitinib.
    Cohorte de preinclusión
    -Evaluar la seguridad y la tolerabilidad de PF 04449913 en pacientes con MF primaria o secundaria que hayan sido tratados previamente con >= 1 JAKi.

    Cohorte aleatorizada
    -Comparar el efecto de PF 04449913 frente a placebo en la RVB en pacientes con MF primaria o secundaria que hayan sido tratados previamente con ruxolitinib.
    E.2.2Secondary objectives of the trial
    Lead-in Cohort

    - To assess the effect of PF-04449913 on spleen volume reduction (SVR) in patients with primary or secondary MF who have been previously treated with >=1 JAKi.
    - To assess the effect of PF-04449913 on patient reported MF symptoms in patients with primary or secondary MF who have been previously treated with >=1 JAKi.
    - To assess the effect of PF-04449913 on hematologic improvement (peripheral blood) in patients with primary or secondary MF who have been previously treated with >=1 JAKi.
    - To characterize the pharmacokinetics (PK) of PF-04449913.

    Randomized Cohort

    - To compare the symptomatic efficacy of PF-04449913 vs. placebo on patient reported MF symptoms in patients with primary or secondary MF who have been previously treated with ruxolitinib;
    Please refer to Section 2.2.2 of the Protocol for the additional Randomized Cohort Secondary objectives.
    Cohorte de preinclusión
    -Evaluar el efecto de PF 04449913 en la reducción del volumen del bazo (RVB) en pacientes con MF primaria o secundaria que hayan sido tratados previamente con ? 1 JAKi.
    -Evaluar el efecto de PF 04449913 en los síntomas de la MF notificados por los pacientes, en pacientes con MF primaria o secundaria que hayan sido tratados previamente con ? 1 JAKi.
    -Evaluar el efecto de PF-04449913 en la mejora hematológica (sangre periférica) en pacientes con MF primaria o secundaria que hayan sido tratados previamente con ? 1 JAKi.
    -Caracterizar la farmacocinética (FC) de
    PF-04449913.

    Cohorte aleatorizada

    -Comparar la eficacia sintomática de PF-04449913 frente a placebo en los síntomas de la MF notificados por los pacientes, en pacientes con MF primaria o secundaria que hayan sido tratados previamente con ruxolitinib.

    Refieranse a la sección 2.2.2 del protocol para objetivos secundarios adicionales de la cohorte aleatorizada.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must meet all of the following inclusion criteria to be eligible for enrollment into the study:

    1. Diagnosis of primary MF (PMF) or secondary MF (PET-MF and PPV-MF) as per WHO 2008 criteria.

    2. Lead-in cohort only: Prior treatment with >=1 JAKi (must meet one of the following criteria):

    a. Previous treatment with >=1 JAKi (licensed or experimental) for a minimum duration of >=4 weeks and failure to achieve or sustain adequate symptomatic control and/or achieve or sustain an adequate reduction of splenomegaly (Investigator´s judgment);

    b. JAKi therapy discontinuation for unacceptable toxicity irrespective of the duration of therapy.

    3. Randomized cohort: At least one of the following criteria for prior ruxolitinib resistance OR intolerance must be met:

    a. Primary Resistance

    i. No reduction in spleen volume (MRI/CT) or size (manual palpation from below left inferior costal margin) following treatment with ruxolitinib for at least 12 weeks.

    b. Secondary Resistance:

    i. Increase in spleen volume (assessed by MRI/CT) from nadir by >=25% at any time following the start of ruxolitinib therapy; OR

    ii. Appearance for new splenomegaly palpable at least 5cm below the left inferior costal margin; OR

    iii. Increase in spleen size (manual palpable from below the left inferior costal margin) by >=50% from nadir (or >=100% if nadir is <5 cm) in the contect of worsening splenomegaly-related abdominal pain or other disease-related signs/symptoms at any time following the start of ruxolitinib therapy.

    c. Intolerance

    i. Anaphylaxis or Grade ¾ allergic reactions following any duration of ruxolitinib therapy; OR

    ii. In accordance with the dose modification guidelines in the ruxolitinib prescribing information, documentation in the medical record of the presence of ruxolitinib-related toxicity/toxicities that resulted in ruxolitinib discontinuation.

    4. Documentation by the Investigator that the patient has exhausted available treatment options (eg, resistant or intolerant to hydroxyurea, etc).

    5. Spleen >=5 cm below the inferior left costal margin (LCM) as measured by manual palpation.

    6. Active symptomatic MF as defined by the screening MPN-SAD patient reported instrument requiring a severity score of at least 5 on one symptom, or a severity score of >=3 on at least two of the symptoms (on a 0 to 10 sclare) (Appendix 1):

    a. Early satiety

    b. Abdominal discomfort (pressure or bloating)

    c. Inactivity (including work, home and social activities)

    d. Night sweats

    e. pruritus;

    f. Bone pain (other than arthritis or joint pains);

    g.. Pain below the ribs on the left-hand side

    h. Fatigue (associated with MF).

    i.. Shortness of breath

    7. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, 2 or 3.

    8. The following laboratory values:

    a. Absolute Neutrophil Count (ANC) >.75 x 109/L;

    b. Platelet count >50 x 109/L with no evidence of bleeding and not requiring platelet transfusions;

    c. Serum creatinine <1.5 x upper limit of normal (ULN) or estimated creatinine clearance >=60mL /min (as calculated using the standard method of institution);

    d. Serum amylase or lipase <1.5 x ULN;

    e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) values ?=3.0 x ULN (or ?=5x ULN in the case of patients with MF accompanied by hepatic extramedullary hematopoiesis, as manifested by any degree of hepatomegaly).

    f. Total bilirubin values <1.5 x ULN unless the bilirubin is principally unconjugated (in the context of hemolysis) or there is documented Gilbert´s disease.

    g. Serum electrolyte values < Grade 2 (sodium, potassium, calcium, phosphorous and magnesium), .per CTCAE v.4.03.

    9. Recovery to ?= Grade 1 from all clinically significant adverse events related to prior MF therapy, including transplant related toxicities.

    10. More than 2 months out from allogenic hematopoietic stem cell transplant prior to randomization.

    11. Must be able to undergo MRI of abdomen (spleen and liver). Patients who are contra-indicated for MRI may be enrolled and evaluated by CT scan at the discretion of the Sponsor.

    12. >=18 years of age.

    13. Male subjects able to father children and female patients of childbearing potential and at risk for pregnancy must agree to use two highly effective method of contraception throughout the study and for 90 days after the last dose of assigned treatment.

    14. Serum or urine pregnancy test (for females of childbearing potential)negative at screening .

    15. Evidence of a personally signed and dated informed consent document indicating that the patient (or a legally acceptable representative) has been informed of all pertinent aspects of the study.

    16. Patients who are willing and able to comply with the scheduled visits, treatment plan, laboratory tests, and other study procedures.
    Los pacientes deben cumplir todos los criterios de inclusión para ser aptos para participar en el ensayo: 1-Diagnóstico de MF prim. (MFP) o MF sec. (PET-MF y PPV-MF) según criterios de la OMS de 2008. 2-Solo cohorte de preinclusión: Tto. previo con >=1 JAKi (debe cumplir uno de los siguientes criterios): a)Tto. previo con >=1 JAKi (autorizado o exp.) durante duración mínima de >=4 semanas y fracaso para lograr o mantener control sintomático adecuado y/o lograr o mantener reducción adecuada de la esplenomegalia (juicio del Inv.); b)Interrupción del tto. con JAKi por toxicidad inaceptable con independencia de duración del tto. 3-Cohorte aleatorizada: Debe cumplirse al menos uno de los criterios siguientes para resistencia O intolerancia anterior a ruxolitinib: a-Resistencia primaria: i)Sin reducción en vol. (RMN/TC) o tamaño del bazo (palpación manual desde debajo del margen costal inferior izq) después del tto. con ruxolitinib durante al menos 12 semanas. b- Resistencia secundaria: i)Aumento en volumen del bazo (evaluado mediante RMN/TC) respecto al nadir en >=25 % en cualquier momento después del inicio del tto. con ruxolitinib; O ii)Aparición de esplenomegalia nueva palpable al menos 5 cm por debajo del margen costal inferior izq; O ii) Aumento de tamaño del bazo (palpación manual desde debajo del margen costal inferior izq) en >=50 % con respecto al nadir (o >=100 % si el nadir es <5 cm) en el contexto de dolor abdominal relacionado con empeoramiento de la esplenomegalia u otros signos/síntomas relacionados con la enfermedad en cualquier momento después del inicio del tto. con ruxolitinib. C-Intolerancia: i)Anafilaxia o reacciones alérgicas de grado 3/4 después de cualquier duración del tto. de ruxolitinib; O ii)de acuerdo con las pautas de modificación de la dosis en la ficha técnica de ruxolitinib, documentación en historia de presencia de toxicidad(es) relacionada(s) con ruxolitinib que causaron su interrupción. 4-Documentación por Inv. que el paciente ha agotado opciones de tto. a su disposición (p.ej., resistente o intolerante a la hidroxiurea, etc.).5-Bazo >=5 cm por debajo del margen costal izq (MCI) inferior medido mediante palpación manual.6-MF sintomática activa según definición del instrumento comunicado por el paciente MPN-SAD en la selección que exige puntuación de intensidad de, al menos, 5 en un síntoma o puntuación de intensidad de >= 3 en, al menos, dos de los síntomas (en una escala del 0 al 10) (apéndice 1): a)Saciedad temprana; b) Molestias abdominales (presión o hinchazón); c)Inactividad (incl.. actividades laborales, domésticas y sociales); d)Sudores nocturnos e)Prurito; f) Dolor de huesos (distinto de artritis o dolores de articulaciones); g) Dolor bajo las costillas en el lado izq.; h)Cansancio (asociado con MF); i) Falta de aire.7-Estado funcional de 0,1,2 o 3 según escala ECOG (Eastern Cooperative Oncology Group). 8-Los siguientes valores analíticos: a)recuento absoluto de neutrófilos (RAN) >0,75×109/l; b)recuento de plaquetas >50x109/l sin evidencia de hemorragia y sin que requiera transfusiones de plaquetas; c) creatinina sérica < 1,5 × límite sup. de la normalidad (LSN) o aclaramiento de creatinina calculado >= 60 ml/min (calculado utilizando el método habitual del centro);d)amilasa o lipasa sérica <1,5xLSN; d)valores de aspartato aminotransferasa (AST) y alanina aminotransferasa (ALT) <=3,0×LSN (o <=5×LSN en pacientes con MF acompañada de hematopoyesis extramedular hepática, según se manifieste mediante cualquier grado de hepatomegalia); e)valores de bilirrubina total <1,5×LSN, a menos que la bilirrubina sea principalmente sin conjugar (en el contexto de la hemólisis) o enf. de Gilbert documentada; f) Valores de electrólitos en suero <grado 2 (Na, K, Ca, P y Mg), según CTCAE v.4.03. 9- Recuperación a <=grado 1 de todos los AA clínicamente significativos, relacionados con el tto. previo para MF, incluidas toxicidades relacionadas con trasplantes.10-Más de 2 meses desde un trasplante alogénico de células madre hematopoyéticas antes de aleatorización.11-Debe poder someterse a RMN abdominal (bazo e hígado). Los pacientes con RMN contraindicada pueden incluirse y ser evaluados mediante TC a discreción del promotor. 12->=18 años de edad.13-Pacientes hombres que puedan tener hijos y pacientes mujeres en edad fértil y en riesgo de embarazo deben acceder a utilizar 2 métodos anticonceptivos de alta eficacia durante todo el ensayo y durante 2 90 días siguientes a la administración de la última dosis del tto. asignado. 14-Resultado neg. en prueba de embarazo en suero u orina (para mujeres en edad fértil) en selección.15-Prueba de documento de consentimiento informado, firmado y fechado personalmente, que indique que se ha informado al paciente (o a su representante legal) de todos los aspectos pertinentes del ensayo.16-Los pacientes deben ser capaces de, y estar dispuestos a, cumplir con las visitas programadas, el plan de tto., las analíticas y otros procedimientos del ensayo.
    E.4Principal exclusion criteria
    Patients presenting with any of the following will not be included in the study:

    1. Prior treatment with a licensed or experimental smoothened inhibitor (SMOi).

    2. Randomized cohot only: Prior treatment with a Janua Kinase (JAK) inhibitor other than ruxolitinib.

    3. Other anti-cancer therapy up to 14 days prior to enrollment, with the exception of hydroxyurea, which can be given up to 4 days prior to enrollment.

    4. Splenic irradiation ?= 3 months prior to enrollment.


    5. History of congenital long QT syndrome, or a baseline >470 msec QTcF abnormality (average of the triplicate reading),

    6. Evidence of significant cardiac disease, for example: symptomatic cardiac heart failure (CHF, NYHA >=class 3), complete bundle branch block, significant atrial or ventricular tachyarrythmias and any unstable cardiac arrhythmias requiring medication.

    7. History of myocardial infarction or unstable angina within 6 months prior to enrollment.

    8. Uncontrolled inflammatory bowel disease, peptic ulcer disease or history of significant gastro-intestinal bleeding within 6 months of enrollment.

    9. Any condition requiring chronic use of moderate/high dose steroids (equivalent to >= 10 mg QD prednisone).

    10. Hematopoietic growth factor receptor agonists (eg, erythropoietin (Epo), granulocyte colony stimulating factor (GCSF), romiplostim, eltrombopag within 28 days of enrollment.

    11. Currently active malignancy (other than MF). Prior malignancies are allowed so long as there is no evidence of disease recurrence within the last 2 years.

    12. Prior history of chronic liver disease (eg, chronic alcoholic liver disease, autoimmune hepatitis, sclerosing cholangitis, primary biliary cirrhosis, hemachromatosis, non-alcoholic steatohepatitis [NASH]).

    13. Active, uncontrolled bacterial, fungal or viral infection, including hepatitis B (HBV), hepatitis C (HCV), known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS)-related illness.

    14. Active graft versus host disease (GVHD) with other than grade 1 skin involvement or GVHD requiring immunosuppressive treatment.

    15. Uncontrolled disseminated intravascular coagulation.

    16. Current (including their administration within 3-days prior to study entry) use or anticipated need for food or drugs that are strong CYP3A4 inhibitors. Please refer to Appendix 8 for a list of strong CYP3A4 inhibitors.


    17. Current use or anticipated requirement for drugs that are known strong CYP3A4/5 inducers.

    18. Patients who are investigational site staff members directly involved in the conduct of the trial and their family members, site staff members otherwise supervised by the Investigator, or patients who are Pfizer employees directly involved in the conduct of the trial.

    19. Participation in other clinical trials with investigational agents (Phases 1-4) within 28 days prior to first dose of study treatment.

    20. Other severe acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior as judged by the treating physician or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study.

    21. Pregnant female patients; breastfeeding female patients; male subjects able to father children and female patients of childbearing potential who are unwilling or unable to use two highly effective methods of contraception as outlined in this protocol for the duration of the study and for 90 days after the last dose of investigational product or longer, based upon the compound´s half-life characteristics.
    Los pacientes que presenten cualquiera de las siguientes características no serán incluidos en el estudio:
    1.Tratamiento anterior con un inhibidor de Smoothened (SMOi), autorizado o experimental.
    2.Solo la cohorte aleatorizada: Tratamiento anterior con un inhibidor de la quinasa Janus (JAK) distinto a ruxolitinib.
    3.Otro tratamiento anticanceroso hasta 14 días antes de la inclusión, a excepción de hidroxiurea, que se puede administrar hasta 4 días antes de la inclusión.
    4.Irradiación esplénica ?= 3 meses antes de la inclusión.
    5.Antecedentes de síndrome congénito de QT largo, o una anomalía de QTcF > 470 ms (media de la lectura por triplicado).
    6.Evidencia de cardiopatía significativa, por ejemplo: insuficiencia cardíaca sintomática (NYHA >=clase 3), bloqueo completo de una rama, taquicardias auriculares o ventriculares significativas y cualquier arritmia cardíaca inestable que requiera medicación.
    7.Antecedentes de infarto de miocardio o angina inestable en los 6 meses anteriores a la inclusión.
    8.Enfermedad inflamatoria intestinal no controlada, enfermedad de úlcera péptica o antecedente de hemorragia gastrointestinal en los 6 meses anteriores a la inclusión.
    9.Cualquier afección que requiera el uso crónico de esteroides de dosis moderada/alta (equivalente a >= 10 mg 1 v/d de prednisona).
    10.Agonistas de los receptores del factor de crecimiento hematopoyético (p. ej., eritropoyetina (Epo), factor estimulante de las colonias de granulocitos (GCSF), romiplostim y eltrombopag en los 28 días anteriores a la inclusión.
    11.Neoplasias malignas actualmente activas (distintas de la MF). Se permiten las neoplasias malignas anteriores siempre que no haya pruebas de recidiva de la enfermedad en los 2 años anteriores
    12.Antecedentes previos de enfermedad hepática crónica (p. ej., enfermedad hepática alcohólica crónica, hepatitis autoinmune, colangitis esclerosante, cirrosis biliar primaria, hemacromatosis, esteatohepatitis no alcohólica (NASH).
    13.Infección bacteriana, fúngica o vírica activa sin controlar, incluidas la hepatitis B (VHB), hepatitis C (VHC), virus de la inmunodeficiencia humana (VIH) conocido o enfermedad relacionada con el síndrome de la inmunodeficiencia adquirida (SIDA).








    14.Enfermedad de injerto contra huésped (EICH) activa con afectación de la piel distinta a un grado 1 o EICH que requiera tratamiento inmunodepresor.
    15.Coagulación intravascular diseminada no controlada.
    16.Uso actual (incluida su administración en los 3 días anteriores a la entrada en el estudio) o necesidad prevista de comida o fármacos que sean potentes inhibidores de CYP3A4. Consulte el apéndice 8 para ver un listado de inhibidores potentes.
    17.Uso actual o previsión de la necesidad de fármacos que se sepa que son potentes inductores de CYP3A4/5.

    18.Pacientes que sean miembros del personal del centro de investigación directamente implicados en la realización del ensayo, así como sus familiares, miembros del personal del centro supervisados de alguna otra manera por el investigador o empleados de Pfizer directamente implicados en la realización del ensayo.
    19.Participación en otros ensayos clínicos con agentes en investigación (fases I-IV) en los 28 días anteriores a la primera dosis del tratamiento del estudio.
    20.Otras afecciones de grado intenso, agudas o crónicas, médicas o psiquiátricas, incluidos el comportamiento o las ideas suicidas recientes (en el último año) o activas a juicio del médico responsable del tratamiento, o las anomalías analíticas que puedan aumentar el riesgo asociado con la participación en el estudio o con la administración del producto en investigación, o que puedan interferir en la interpretación de los resultados del estudio y, a juicio del investigador, hagan que el paciente no sea apto para incorporarse a este estudio.
    21.Pacientes embarazadas; pacientes en periodo de lactancia; hombres y mujeres en edad fértil que no desean o no pueden usar dos métodos anticonceptivos de elevada eficacia tal como se describe en este protocolo durante todo el estudio y durante 90 días después de la última dosis del producto en investigación o más, basándose en las características de la semivida del compuesto.
    E.5 End points
    E.5.1Primary end point(s)
    Lead-in Cohort

    -Adverse events (AEs) as characterized by: type, frequency, severity (as graded by National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] v.4.03), timing, seriousness and relationship to study therapy.
    -Laboratory abnormalities as characterized by: type, frequency, severity (as graded by NCI CTCAE v.4.03) and timing.

    Randomized Cohort
    -Proportion of patients achieving SVR ?=35% at Week 24 as measured by MRI (or CT in patients unable to tolerate an MRI).
    Cohorte de preinclusión
    -Acontecimientos adversos (AA) caracterizados por: tipo, frecuencia, intensidad (calificada de acuerdo con la versión 4.03 de los Criterios de terminología común para acontecimientos adversos del Instituto Nacional del Cáncer [CTCAE del NCI]), momento de aparición, gravedad y relación con el tratamiento del estudio.
    -Anomalías analíticas caracterizadas por: tipo, frecuencia, intensidad (calificada según los CTCAE del NCI, v.4.03) y el momento de aparición.
    Cohorte aleatorizada
    -Proporción de pacientes que logran una RVB ?= 35 % en la semana 24, medida mediante RMN (o TC, en pacientes que no pueden tolerar una RMN).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Primary endpoint will be reached at Week 24
    Los criterios de valoración primarios se alcazarán en la semana 24
    E.5.2Secondary end point(s)
    Lead-in Cohort
    - Proportion of patients achieving SVR ???35% at Week 24 as measured by MRI (or computed tomography (CT) in patients unable to tolerate an MRI);
    - Proportion of patients achieving ???50% reduction in total symptom score (TSS) at Week 24, as measured by the Myeloproliferative Neoplasms Symptom Assessment Diary (MPN-SAD);
    - Overall total symptom score (TSS) as measured by MPN-SAD;
    - Proportion of patients with improvement in peripheral blood counts, as defined by the Revised IWG-MRT Response Criteria13 (Appendix 6);
    - Pharmacokinetic parameters of PF-04449913, including but not limited to Cmax, Tmax, AUC and Cavg.






    Randomized Cohort
    - Proportion of patients achieving >= 50% reduction in TSS at Week 24, as measured by the MPN-SAD;
    - Overall TSS at Week 24, as measured by MPN-SAD;
    - Proportion of patients with improvement in peripheral blood counts, as defined by the Revised IWG-MRT Response Criteria13 (Appendix 6);
    - Patient Reported Outcome (PRO) of health-related quality of life as measured by the European Organisation for Research and Treatment of Cancer (EORTC QLQ-30), Health status as measured by the EuroQol EQ-5D Self-Report Questionnaire (EQ-5D-5L) and Patient Global Impression of Change (PGIC);
    - Duration of spleen volume response;
    - OS;
    - Adverse Events as characterized by: type, frequency, severity (as graded by NCI CTCAE v.4.03), timing , seriousness and relationship to study therapy;
    - Laboratory abnormalities as characterized by: type, frequency, severity (as graded by NCI CTCAE v.4.03) and timing;
    - Pharmacokinetic parameters of PF-04449913, including but not limited to Cmax, Tmax, AUC and Cavg;
    - Psychometric validation of the MPN-SAD.
    Cohorte de preinclusión
    -Proporción de pacientes que logran una RVB? =35 % en la semana 24, medida mediante RMN (o tomografía computarizada [TC], en pacientes que no toleran una RMN).
    Proporción de pacientes que logran una reducción >= 50 % de la puntuación total de los síntomas (PTS) en la semana 24, medida según el Diario de evaluación de los síntomas de la neoplasia mieloproliferativa (MPN SAD).
    -Puntuación total de los síntomas (PTS) general, medida según el MPN-SAD.
    -Proporción de pacientes con mejora en los recuentos en sangre periférica, según se define en los Criterios de respuesta revisados del IWG-MRT13 (apéndice 6).
    -Parámetros farmacocinéticos de PF-04449913, incluidos, entre otros, la Cmáx, el Tmáx, el ABC y la Cavg.
    Cohorte aleatorizada
    -Proporción de pacientes que logran una reducción >= 50 % en la PTS en la semana 24, medida según el MPN-SAD.
    -PTS general en la semana 24 medida según el MPN-SAD.
    -Proporción de pacientes con mejora en los recuentos en sangre periférica, según se define en los Criterios de respuesta revisados del IWG-MRT13 (apéndice 6).
    -Resultados notificados por los pacientes (PRO) de la calidad de vida relacionada con la salud, medida por la Organización europea para la investigación y el tratamiento del cáncer (EORTC QLQ-30), el estado de salud medido por el Cuestionario de autocumplimentación EuroQol EQ-5D (EQ-5D-5L) y la Impresión global del cambio por parte de los pacientes (PGIC).
    -Duración de la respuesta en el volumen del bazo.
    -SG.
    -Acontecimientos adversos caracterizados por: tipo, frecuencia, intensidad (calificada según los CTCAE del NCI v.4.03), el momento de la aparición, la gravedad y la relación con el tratamiento del estudio.
    -Anomalías analíticas caracterizadas por: tipo, frecuencia, intensidad (calificada según los CTCAE del NCI, v.4.03) y el momento de aparición.
    -Parámetros farmacocinéticos de PF-04449913, incluidos, entre otros, la Cmáx, el Tmáx, el ABC y la Cavg.
    -Validación psicométrica del MPN-SAD.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Primary endpoint will be reached at Week 24
    Los criterios de valoración primarios se alcazarán en la semana 24
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Tolerability
    Tolerabilidad
    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 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 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 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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA56
    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
    Austria
    Belgium
    France
    Germany
    Israel
    Italy
    Japan
    Netherlands
    Spain
    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
    End of Study in a Member State of the EU is defined as the time at which it is deemed that sufficient patients have been recruited and completed the study as stated in the regulatory application and ethics application in the Member State. Poor recruitment by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State.

    End of Study in all other participating countries is defined as Last Patient Last Visit.
    Se define fin de estudio en un Estado miembro (EM) de la UE como el momento en el que se considera que se han reclutado un num suficiente de pacientes y han completado el estudio, según se indica en la solicitud a las autoridades reguladoras y al CEIC del EM. Un reclutamiento insuficiente no es motivo de finalización prematura, se considera una conclusión normal del estudio en dicho EM. El fin de estudio en todos los países participantes se define como la última visita del último paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months4
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months8
    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: 88
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 133
    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 state24
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 157
    F.4.2.2In the whole clinical trial 221
    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)
    N/A
    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 Decision2015-10-26
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-05
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-01-31
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