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    Summary
    EudraCT Number:2018-001671-21
    Sponsor's Protocol Code Number:KRT-232-101
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-23
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedSpain - AEMPS
    A.2EudraCT number2018-001671-21
    A.3Full title of the trial
    An Open-Label, Phase 2a/2b Study of KRT-232 in Subjects With Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (Post–PV-MF), Or Post–Essential Thrombocythemia MF (Post–ET-MF) Who Have Failed Ruxolitinib
    Estudio en fase IIa/IIb abierto de KRT-232 en pacientes con mielofibrosis primaria (MFP), mielofibrosis post-policitemia vera (MF-post-PV) o mielofibrosis post-trombocitemia esencial (MF-post-TE) que no han respondido al tratamiento con ruxolitinib
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study of KRT-232 in Subjects with Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (Post–PV-MF), Or Post–Essential Thrombocythemia MF (Post–ET-MF) Who Have Failed Ruxolitinib
    Estudio de KRT-232 en pacientes con mielofibrosis primaria (MFP), mielofibrosis post-policitemia vera (MF-post-PV) o mielofibrosis post-trombocitemia esencial (MF-post-TE) que no han respondido al tratamiento con ruxolitinib
    A.4.1Sponsor's protocol code numberKRT-232-101
    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 SponsorKartos Therapeutics, 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 supportKartos Therapeutics, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKartos Therapeutics, Inc.
    B.5.2Functional name of contact pointMedical Director
    B.5.3 Address:
    B.5.3.1Street Address275 Shoreline Drive
    B.5.3.2Town/ cityRedwood City, California
    B.5.3.3Post code94065
    B.5.3.4CountryUnited States
    B.5.6E-mailtjahn@kartosthera.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 nameKRT-232
    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 INN-
    D.3.9.2Current sponsor codeKRT-232
    D.3.9.3Other descriptive nameAMG-232
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number15
    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 nameKRT-232
    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 INN-
    D.3.9.2Current sponsor codeKRT-232
    D.3.9.3Other descriptive nameAMG-232
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number60
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Primary Myelofibrosis (PMF), Post–Polycythemia Vera MF (Post–PV-MF), Or Post–Essential Thrombocythemia MF(Post–ET-MF)
    Mielofibrosis primaria (MFP), mielofibrosis post-policitemia vera (MF-post-PV) o mielofibrosis post-trombocitemia esencial (MF-post-TE)
    E.1.1.1Medical condition in easily understood language
    A disorder of the bone marrow
    Una enfermedad de la médula ósea
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level PT
    E.1.2Classification code 10077161
    E.1.2Term Primary myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10074689
    E.1.2Term Post polycythemia vera myelofibrosis
    E.1.2System Organ Class 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10074690
    E.1.2Term Post essential thrombocythemia 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 Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine spleen response
    Determinar la respuesta esplénica.
    E.2.2Secondary objectives of the trial
    To determine the change in modified MPN-SAF Total Symptom Score (TSS) at Week 24 and Week 48;
    To determine the duration of spleen response (DoR-spleen);
    To determine spleen size reduction as measured by palpation;
    To determine red blood cell (RBC) transfusion usage;
    To determine the clinical response rate at Week 24;
    To determine the overall survival (OS) rate;
    To determine the leukemia free survival rate;
    To determine the safety and tolerability of KRT-232;
    To determine the pharmacokinetic/ pharmacodynamic (PK/PD) profile of KRT-232;
    Determinar el cambio en la puntuación total de los síntomas (PTS) del formulario de evaluación de síntomas de neoplasia mieloproliferativa (MPN-SAF) modificado a la semana 24 y la semana 48.
    Determinar la duración de la respuesta esplénica (DdR-bazo).
    Determinar la reducción del tamaño del bazo medido mediante palpación.
    Determinar el uso de transfusiones de glóbulos rojos.
    Determinar la tasa de respuesta clínica en la semana 24.
    Determinar la tasa de supervivencia global (SG).
    Determinar la tasa de supervivencia sin leucemia.
    Determinar la seguridad y tolerabilidad de KRT-232.
    Determinar el perfil de farmacocinética/farmacodinámica (FC/FD) de KRT-232.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adults >18 years of age
    2. Palpable splenomegaly at least 5 cm below left costal margin
    3. Confirmed diagnosis of PMF, post–PV-MF, or post–ET-MF according to the World Health Organization (WHO) criteria
    4. High-risk, intermediate-2 risk, or intermediate-1 risk, defined by Dynamic International Prognostic System (DIPSS)
    5. ECOG performance status of 0 to 2
    6. Adequate hematological, hepatic, and renal organ function (as per protocol definition and within 14 days prior to the first dose of KRT-232)
    7. Females of childbearing potential and males who have partners of childbearing potential must agree to use an effective contraception method during the study. In addition, males must continue to use contraception for 3 months after the last dose of study drug and females must continue to use contraception for 1 week after the last dose of study drug.
    Subjects in Part A must meet the following ruxolitinib treatment failure criteria in order to be eligible for the study:
    Ruxolitinib treatment failure in Part A must meet either criterion (a) or (b) below:
    a) Either a lack of spleen response defined as receiving at least 12 weeks of ruxolitinib treatment and having both of the following:
    • Persistent splenomegaly, by physical exam, that is palpable ≥ 5 cm below the lower costal margin (LCM)
    • and TSS of >10 on the MPN-SAF TSS 2.0 or patients with a single symptom score of >5 or two symptoms of >3, including only the symptoms of left upper quadrant pain, bone pain, itching, or night sweats
    b) Or progressive disease any time while on ruxolitinib treatment as defined by any one of
    the following:
    • Spleen volume increase by ≥ 25% from the nadir as assessed by MRI or CT
    • Appearance of new splenomegaly that is palpable at least 5 cm below the LCM
    • A ≥ 100% increase in palpable distance, below the LCM, for baseline splenomegaly of 5 to 10 cm
    • A ≥ 50% increase in palpable distance, below the LCM, for baseline splenomegaly of > 10 cm
    Subjects in Part B must meet the following ruxolitinib treatment failure criteria in order to
    be eligible for the study.
    Ruxolitinib treatment failure in Part B must meet either criterion (a) or (b) below:
    a) Either a lack of spleen response defined as receiving at least 12 weeks of ruxolitinib treatment and having at least one of the following:
    • For subjects that have a MRI or CT to assess ruxolitinib treatment, failure to have a least ≥ 35% reduction in spleen volume
    • A Baseline splenomegaly prior to ruxolitinib treatment that is palpable at 5 to 10 cm, below the LCM, but remains palpable
    • A Baseline splenomegaly prior to ruxolitinib treatment that is palpable > 10 cm, below the LCM, but does not decrease by at least 50%
    • A Baseline splenomegaly prior to ruxolitinib treatment that is palpable < 5 cm, below the LCM, is not eligible to be considered as a ruxolitinib treatment failure
    b) Or progressive disease any time while on ruxolitinib treatment as defined by any one of
    the following:
    • Spleen volume increase by ≥ 25% from the nadir as assessed by MRI or CT
    • Appearance of new splenomegaly that is palpable at least 5 cm below the LCM
    • A ≥100% increase in palpable distance, below the LCM, for baseline splenomegaly of 5 to 10 cm
    • A ≥ 50% increase in palpable distance, below the LCM, for baseline splenomegaly of > 10 cm
    1. Adultos >18 años.
    2. Esplenomegalia palpable al menos 5 cm por debajo del reborde costal izquierdo.
    3. Diagnóstico confirmado de MFP, MF-post-PV y MF-post-TE, según la evaluación del médico responsable del tratamiento de acuerdo con los criterios de la Organización Mundial de la Salud (OMS)
    4. Riesgo alto, riesgo intermedio 2 o riesgo intermedio 1, definidos mediante el sistema dinámico de pronóstico internacional (Dynamic International Prognostic System, DIPSS)
    5. Estado funcional ECOG de 0 a 2.
    6. Función orgánica hematológica, hepática y renal adecuada (según la definición del protocolo y en los 14 días previos a la primera dosis de KRT-232).
    7. Las mujeres en edad fértil y los hombres cuyas parejas estén en edad fértil deben estar de acuerdo en utilizar un método anticonceptivo eficaz durante el estudio. Además, los hombres deberán seguir utilizando métodos anticonceptivos durante 3 meses después de la última dosis de fármaco del estudio y las mujeres deberán continuar utilizando métodos anticonceptivos durante una semana después de la última dosis de fármaco del estudio.
    Los pacientes de la parte A deben cumplir los criterios siguientes de fracaso terapéutico de ruxolitinib a fin de ser aptos para participar en este estudio:
    El fracaso terapéutico de ruxolitinib en la parte A deberá cumplir alguno de los criterios (a) o (b) que aparecen a continuación:
    a) Ausencia de respuesta esplénica definida como recibir al menos 12 semanas de tratamiento con ruxolitinib y presentar ambas de las siguientes condiciones:
    • Esplenomegalia persistente, mediante exploración física, que es palpable ≥5 cm por debajo del reborde costal inferior izquierdo (RCII).
    • y PTS de >10 en la PTS MPN-SAF 2.0 o pacientes con una única puntuación de los síntomas de >5 o dos síntomas de >3, incluidos solo los síntomas de dolor del cuadrante superior izquierdo, dolor óseo, picor o sudores nocturnos.
    b) O enfermedad progresiva en cualquier mientras durante el tratamiento con ruxolitinib según se define mediante cualquiera de los siguientes criterios:
    • Aumento del volumen esplénico en ≥25 % con respecto al volumen mínimo según la evaluación mediante RMN o TAC.
    • Aparición de una nueva esplenomegalia que sea palpable al menos 5 cm por debajo del RCII.
    • Aumento ≥100 % en la distancia palpable, por debajo del RCII, para una esplenomegalia inicial de 5 a 10 cm.
    • Aumento ≥50 % en la distancia palpable, por debajo del RCII, para una esplenomegalia inicial de >10 cm.
    Los pacientes de la parte B deben cumplir los criterios siguientes de fracaso terapéutico de ruxolitinib a fin de ser aptos para participar en este estudio:
    a) Ausencia de respuesta esplénica definida como recibir al menos 12 semanas de tratamiento con ruxolitinib y presentar al menos una de las siguientes condiciones:
    • En los pacientes que cuentan con una RMN o una TAC para evaluar el tratamiento con ruxolitinib, incapacidad para obtener al menos ≥35 % de reducción en el volumen esplénico.
    • Esplenomegalia inicial previa al tratamiento con ruxolitinib que es palpable entre 5 y 10 cm, por debajo del RCII, pero sigue siendo palpable.
    • Esplenomegalia inicial previa al tratamiento con ruxolitinib que es palpable >10 cm, por debajo del RCII, pero no disminuye en al menos el 50 %.
    • Una esplenomegalia inicial previa al tratamiento con ruxolitinib que es palpable <5 cm, por debajo del RCII, no es apta para considerarse como fracaso terapéutico de ruxolitinib.
    b) O enfermedad progresiva en cualquier mientras durante el tratamiento con ruxolitinib según se define mediante cualquiera de los siguientes criterios:
    • Aumento del volumen esplénico en ≥25 % con respecto al volumen mínimo según la evaluación mediante RMN o TAC.
    • Aparición de una nueva esplenomegalia que sea palpable al menos 5 cm por debajo del RCII.
    • Aumento ≥100 % en la distancia palpable, por debajo del RCII, para una esplenomegalia inicial de 5 a 10 cm.
    • Aumento ≥50 % en la distancia palpable, por debajo del RCII, para una esplenomegalia inicial de >10 cm.
    E.4Principal exclusion criteria
    1. Participation in another interventional clinical trial within the past 4 weeks of the first dose of KRT-232 (participation in observational studies is permitted)
    2. Recent/concurrent treatment such as a major surgery, chemotherapy, immunomodulating therapy, biologic therapy, radiation therapy, or investigational therapy within 4 weeks or approximately 5 half lives of the first dose of KRT-232
    3. Prior splenectomy
    4. Splenic irradiation within 3 months prior to the first dose of KRT-232
    5. Prior allogeneic stem-cell transplantation or eligible for allogeneic stem cell transplantation
    6. Previous treatment with histone deacetylase (HDAC) inhibitors or BCL-2 inhibitors
    7. Prior MDM2 inhibitor therapy or p53-directed therapy
    8. Women who are pregnant or breastfeeding
    9. History of major organ transplant
    10. Uncontrolled intercurrent illness including, but not limited to, acute hepatitis A; known history of human immunodeficiency virus (HIV)-positive; clinically significant cardiac disease (New York Heart Association Class III or IV); symptomatic congestive heart failure; unstable angina pectoris; ventricular
    arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements
    11. Subjects with clinically significant bacterial, fungal, parasitic, or viral infection that requires therapy. Subjects with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
    12. Other malignancy within the last 3 years, other than curatively treated basal cell or squamous cell skin cancer, carcinoma in situ of the cervix, organ-confined or treated nonmetastatic prostate cancer with normal prostate-specific antigen, in situ breast carcinoma after complete surgical resection, or superficial transitional cell bladder carcinoma
    13. Grade 2 or higher QTc prolongation (>480 milliseconds per NCI-CTCAE criteria, version 5.0)
    14. Hematopoietic growth factors (i.e., erythropoietin [Epo], granulocyte colony stimulating factor (GCSF), romiplostim) within 28 days prior to receiving the first dose of KRT-232
    15. Active or chronic bleeding within 4 weeks prior to the first dose of KRT-232
    1. Participación en otro ensayo clínico de intervención en las 4 semanas previas a la primera dosis de KRT-232 (se permite la participación en estudios observacionales).
    2. Tratamiento reciente/concurrente como cirugía mayor, quimioterapia, tratamiento inmunomodulador, tratamiento biológico, radioterapia o tratamiento en investigación en las 4 semanas o aproximadamente 5 semividas previas a la primera dosis de KRT-232.
    3. Esplenectomía previa
    4. Irradiación esplénica en los 3 meses previos a la primera dosis de KRT-232.
    5. Trasplante alógeno de células madre previo o apto para trasplante alógeno de células madre.
    6. Tratamiento previo con inhibidores de la histona desacetilasa (HDAC) o inhibidores de BCL-2.
    7. Tratamiento previo con inhibidores de MDM2 o tratamiento dirigido a p53.
    8. Mujeres embarazadas o en periodo de lactancia
    9. Antecedentes de trasplante de órgano principal.
    10. Enfermedad intercurrente no controlada incluida, entre otras, la hepatitis A aguda; antecedentes conocidos de resultado positivo en la prueba del virus de la inmunodeficiencia humana (VIH); cardiopatía clínicamente significativa (clase III o IV de la New York Heart Association); insuficiencia cardíaca congestiva sintomática; angina de pecho inestable; arritmia ventricular o enfermedad psiquiátrica/situaciones sociales que puedan limitar el cumplimiento con los requisitos del estudio.
    11. Pacientes con infección bacteriana, fúngica, parasitaria o vírica clínicamente significativa que requieran tratamiento. Los pacientes con infecciones bacterianas agudas que requieran el uso de antibióticos deberán retrasar la selección/inclusión en el estudio hasta que se haya completado el ciclo de tratamiento antibiótico.
    12. Otras neoplasias malignas en los 3 años previos, distintas a cánceres basocelulares o espinocelulares tratados con intención curativa, carcinoma de cuello uterino in situ, cáncer de próstata confinado al órgano o no metastásico tratado con antígeno específico de próstata normal, carcinoma de mama in situ tras una resección quirúrgica completa o carcinoma superficial de vejiga de células transicionales.
    13. Prolongación del intervalo QTc de grado 2 o superior (>480 milisegundos según los criterios NCI-CTCAE, versión 5.0).
    14. Factores de crecimiento hematopoyéticos (es decir, eritropoyetina [Epo], factor estimulante de colonias de granulocitos [GCSF], romiplostim) en los 28 días previos a recibir la primera de dosis de KRT-232.
    15. Hemorragia activa o crónica en las 4 semanas previas a la primera dosis de KRT-232.
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of subjects achieving a >35% spleen volume reduction from Baseline to Week 24, as assessed by magnetic resonance imaging (MRI) or computed tomography (CT) scan
    Duración de una reducción ≥35 % o más con respecto al inicio del estudio en el volumen esplénico mediado mediante imagen de resonancia magnética (RMN)o escáner de tomografía computerizada (TAC)
    E.5.1.1Timepoint(s) of evaluation of this end point
    The Primary Endpoint will be assessed 24 weeks after each subject is enrolled.
    El primer criterio de valoración será evaluado 24 semanas después de que cada sujeto sea incluido.
    E.5.2Secondary end point(s)
    Proportion of subjects who have a 50% reduction from baseline to Week 24 and Week 48 in the total symptom score as measured by the modified MPN-SAF v2.0.
    Duration of a ≥35% or more reduction from Baseline in spleen volume as measured by MRI (or by CT for applicable subjects)
    Reduction in spleen size from Baseline to each visit at which spleen is palpated, including the proportion of subjects who have a ≥50% decrease
    • RBC transfusions (average number of RBC units per patient-month)
    • RBC transfusion independence at Week 24 (proportion of patients who were transfusion-independent at Week 24, defined as absence of RBC transfusions and no hemoglobin <8 g/dL in the previous 12 weeks)
    Complete remission (CR) and partial remission (PR) defined according to International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) and modified European LeukemiaNet (ELN) criteria
    Overall survival is defined as the interval from randomization to death from any cause
    Leukemia-free survival is defined as the interval from randomization to the date of first documented leukemia transformation or death from any cause
    Analyses of the safety endpoints will include the following measurements or assessments: physical
    examinations, laboratory tests, adverse events (AEs), serious AEs (SAEs), ECGs, vital signs
    KRT-232 and acyl glucuronide metabolite (M1) PK parameters, including but not limited to, maximum observed concentration (Cmax), minimum observed concentration (Cmin), area under the plasma concentration-time curve (AUC), and terminal elimination half-life (t1/2z)
    Proporción de pacientes con una reducción del 50 % desde el inicio del estudio a la semana 24 y la semana 48 en la puntuación total de los síntomas según se mide mediante el formulario MPN-SAF v2.0.
    La proporción de pacientes que consigan una reducción de volumen esplénico >35 % con respecto al inicio del estudio hasta la semana 24, según la evaluación mediante resonancia magnética nuclear (RMN) o tomografía computarizada (TAC).
    Reducción del tamaño esplénico desde el inicio del estudio hasta cada visita en la que se realiza una palpación del bazo, incluida la proporción de pacientes con una disminución ≥50 %.
    • Transfusiones de glóbulos rojos (número medio de unidades de glóbulos rojos por paciente y mes).
    • Independencia de transfusiones de glóbulos rojos a la semana 24 (proporción de pacientes que eran independientes de las transfusiones a la semana 24, definido como ausencia de transfusiones de glóbulos tojos y sin niveles de hemoglobina <8 g/dl en las 12 semanas previas).
    Remisión completa (RC) y remisión parcial (RP) definidas según los criterios modificados del grupo de trabajo internacional de investigación y tratamiento de las neoplasias mieloproliferativas (International Working Group-Myeloproliferative Neoplasms Research and Treatment , IWG-MRT) y de la Red Europea de Leucemia (European LeukemiaNet, ELN).
    La supervivencia global se define como el intervalo desde la aleatorización a la muerte por cualquier causa.
    La supervivencia sin leucemia se define como el intervalo desde la aleatorización a la fecha de la primera transformación documentada de la leucemia o de muerte por cualquier causa.
    Los análisis de los criterios de valoración de la seguridad incluirán las siguientes medidas o evaluaciones: exploraciones físicas, pruebas analíticas, acontecimientos adversos (AA), AA graves (AAG), ECG, constantes vitales.
    Parámetros FC de KRT-232 y su metabolito acil glucurónido (M1), incluidos entre otros, concentración máxima observada (Cmáx), concentración mínima observada (Cmín), área bajo la curva de concentración en plasma frente al tiempo (AUC) y semivida de eliminación terminal (t1/2z).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 24, Week 48 and duration of study. Please refer to protocol for full details.
    Semana 24, Semana 48 y duración del estudio. Por favor , consulte el protocolo para los detalles completos.
    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 No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    E.8.2.4Number of treatment arms in the trial4
    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 EEA35
    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
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Poland
    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
    LVLS which could be long term survival follow-up phone call
    UVUP que podrá ser una llamada telefónica para superviviencia a largo plazo.
    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 months0
    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 months9
    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: 50
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 140
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    due to anticipated age of patients it's possible a Legally authorised representative may consent for patients.
    Debido a la edad esperada de los pacientes es posibles que un Representante Legal Autorizado consienta por los pacientes
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state26
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 116
    F.4.2.2In the whole clinical trial 190
    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)
    The study will be considered complete 2 years after the last subject is enrolled, at which time subjects will be evaluated for eligibility for a rollover study.
    Se considerará completado el estudio dos años después de que el último paciente sea incluido, en ese momento los pacientes serán evaluados para seleccionaros para un estudio de continuación.
    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 Decision2018-12-28
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-12-14
    P. End of Trial
    P.End of Trial StatusOngoing
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