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    Summary
    EudraCT Number:2018-001672-38
    Sponsor's Protocol Code Number:KRT-232-102
    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 number2018-001672-38
    A.3Full title of the trial
    A Two-Part, Randomized, Open-label, Multicenter, Phase 2a/2b Study of the Efficacy, Safety, and Pharmacokinetics of KRT-232 Compared to Ruxolitinib in Patients with Phlebotomy-Dependent Polycythemia Vera
    Estudio de fase IIa/IIb en dos partes, multicéntrico, aleatorizado y abierto de la eficacia, seguridad y farmacocinética de KRT-232 en comparación con ruxolitinib en pacientes con policitemia vera dependiente de flebotomía
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Two-Part, Randomized, Open-label, Multicenter, Phase 2a/2b Study of the Efficacy, Safety, and Pharmacokinetics of KRT-232 Compared to Ruxolitinib in Patients with Phlebotomy-Dependent Polycythemia Vera
    Estudio de fase IIa/IIb en dos partes, multicéntrico, aleatorizado y abierto de la eficacia, seguridad y farmacocinética de KRT-232 en comparación con ruxolitinib en pacientes con policitemia vera dependiente de flebotomía
    A.4.1Sponsor's protocol code numberKRT-232-102
    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 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 Jakavi
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameJakavi
    D.3.2Product code Ruxolitinib
    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 INNRUXOLITINIB
    D.3.9.1CAS number 1092939-17-7
    D.3.9.2Current sponsor codeRUXOLITINIB
    D.3.9.4EV Substance CodeSUB32273
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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: 3
    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
    Phlebotomy-dependent polycythemia vera. Polycythemia Vera (PV) is classified as a myeloproliferative neoplasm (MPN).
    Policitemia vera dependiente de flebotomía. La policitemia vera (PV) se clasifica como una neoplasia mieloproliferativa (NMP).
    E.1.1.1Medical condition in easily understood language
    Polycythemia vera is a slow-growing blood cancer in which your bone marrow makes too many red blood cells. These excess cells thicken your blood, slowing its flow.
    Policitemia vera es un cáncer de sangre de crecimiento lento en el que la m ósea produce demasiados glob rojos. Estos excesos de glob hacen que la sangre se espese y provocan ralentización de su flujo
    E.1.1.2Therapeutic area Diseases [C] - Cancer [C04]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level LLT
    E.1.2Classification code 10036061
    E.1.2Term Polycythemia vera
    E.1.2System Organ Class 100000004864
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Part A Primary Objectives
    -To determine the efficacy of KRT-232 in PV subjects with splenomegaly who are phlebotomy dependent
    -To determine the dose of KRT-232 in PV subjects with splenomegaly to be evaluated against ruxolitinib in Part B.

    Part B Primary Objectives

    To demonstrate superiority of KRT-232 vs. ruxolitinib in PV subjects with splenomegaly who are resistant/intolerant to hydroxyurea
    Objetivos principales de la Parte A
    Determinar la eficacia de KRT-232 en sujetos con PV con esplenomegalia que dependan de flebotomía
    Determinar la dosis de KRT-232 en sujetos con PV con esplenomegalia que se evaluará frente a ruxolitinib en la Parte B.

    Objetivos principales de la Parte B
    Demostrar la superioridad de KRT-232 frente a ruxolitinib en sujetos con PV con esplenomegalia que sean resistentes/intolerantes a hidroxiurea.
    E.2.2Secondary objectives of the trial
    Part A and Part B Secondary Objectives
    -To determine duration of response
    -To determine the response rate at Week 32 (PR + CR)
    -To determine spleen response at Week 32
    -To determine duration of response, including percentage of subjects with durable response lasting 12 weeks and beyond
    -To determine KRT-232 safety and tolerability
    -To determine changes from baseline in patient-reported outcomes
    -To determine the pharmacokinetic/ pharmacodynamic (PK/PD) profile of KRT-232
    Objetivos secundarios de la Parte A y de la Parte B
    Determinar la duración de la respuesta.
    Determinar la tasa de respuesta en la semana 32 (RP + RC)
    Determinar la respuesta del bazo en la semana 32
    Determinar la duración de la respuesta, incluido el porcentaje de sujetos con respuesta duradera que dure 12 semanas y más
    Determinar la seguridad y tolerabilidad e KRT-232
    Determinar los cambios desde el inicio en los resultados notificados por el paciente
    Determinar el perfil farmacocinético/farmacodinámico (FC/FD) de KRT-232
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adults > 18 years of age
    2. Documentation that the patient has met the revised 2016 World Health Organization (WHO) criteria for the diagnosis of PV
    3. Subjects must be phlebotomy dependent. The definition of phlebotomy dependent is:
    • Hematocrit is 40–45% with two phlebotomies or more spaced at least 4 weeks apart within 24 weeks before Screening
    or
    • Hematocrit level is higher than 45% with at least one phlebotomy within 16 weeks before Screening
    4. In Part A, subjects with splenomegaly (defined as spleen volume ≥450 cubic centimeters cm3) and without splenomegaly by MRI (or CT) are eligible. In Part B, only subjects with splenomegaly by MRI or CT are eligible.
    5. Previous treatment with hydroxyurea (HU) (Part A and B), or interferon (Part A only). If previously treated with HU, subject must be resistant to/intolerant of HU according to the following criteria:
    HU resistance is defined as a dose ≥2 g/day or a maximum tolerated dose <2 g/day for a minimum of 12 weeks, resulting in need for phlebotomy to maintain hematocrit <45% or platelet count >400 x109 /L and white blood cell (WBC) count >10 x 109 /L

    HU intolerance is defined as:
    • ANC <1.0 x109/L or platelet count <100 x109/L or hemoglobin <100 g/L (i.e., 10 g/dL) at the lowest dose of HU required to achieve a response (hematocrit <45% without phlebotomy and/or all 3 of a platelet count ≤ 400 x109/L, a WBC count ≤10 x109/L, and a nonpalpable spleen)
    or
    • Presence of leg ulcers or other unacceptable HU-related nonhematologic toxicities (such as mucocutaneous manifestations, gastrointestinal symptoms, pneumonitis, or fever at any dose of HU), defined as:
    Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 grade 3–4 adverse event (AE) or
    >1 week of CTCAE version 5.0 grade 2 AE or Permanent discontinuation of HU or Interruption of HU until toxicity resolved or Hospitalization due to HU toxicity
    6. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
    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. Effective birth control includes (a) combined, estrogen and progestogen containing, hormonal contraception (oral, intravaginal, transdermal); (b) progestogen-only hormonal contraception (oral, injectable, implantable); (c) intrauterine device; (d) intrauterine hormone-releasing system; (e) bilateral tubal occlusion; (f) vasectomised partner; and (g) sexual abstinence.
    1. Adultos >18 años de edad.
    2. Documentación de que el paciente ha cumplido con los criterios revisados de la Organización Mundial de la Salud (OMS) 2016 para el diagnóstico de PV.
    3. Los sujetos deben ser dependientes de flebotomía La definición de dependiente de flebotomía es:
    • El nivel de hematocrito está entre el 40 y el 45 % con dos flebotomías o más con una separación de al menos 4 semanas entre ellas, en las 24 semanas previas a la selección
    o
    • El nivel de hematocrito es superior al 45 % con al menos una flebotomía en las 16 semanas previas a la selección
    4. En la Parte A, los sujetos con esplenomegalia (definida por un volumen del bazo de ≥450 centímetros cúbicos cm3) y sin esplenomegalia según lo visto mediante RM (o TAC) son aptos. En la Parte B, solo son aptos los sujetos con esplenomegalia según lo visto mediante RM o TAC.
    5. Tratamiento previo con hidroxiurea (HU) (Parte A y B) o interferón (solo en la Parte A). Si se le ha tratado previamente con HU, el sujeto debe ser resistente/intolerante a HU de acuerdo con los siguientes criterios:
    La resistencia a la HU se define como una dosis ≥2 g/día o una dosis máxima tolerable <2 g/día durante un mínimo de 12 semanas, que provoca la necesidad de flebotomía para mantener el nivel de hematocrito <45 % o el recuento de plaquetas >400x109 /l y el recuento leucocitario (LEU) >10 x 109 /l.

    La intolerancia a la HU se define como:
    • Recuento absoluto de neutrófilos (RAN) <1,0 x109/l o recuento plaquetario <100 x109/l o hemoglobina <100 g/l (es decir, 10 g/dl) a la dosis más baja de HU necesaria para lograr una respuesta (hematocrito <45 % sin flebotomía y/o los tres siguientes recuento plaquetario ≤400 x109/l, recuento de LEU ≤10 x109/l y bazo no palpable)
    o
    • Presencia de úlceras en las piernas u otras toxicidades no hematológicas inaceptables relacionadas con HU (como manifestaciones mucocutáneas, síntomas gastrointestinales, neumonía o fiebre con cualquier dosis de HU), definidas como:
    - Acontecimiento adverso (AA) de grado 3-4 según los Criterios de terminología común para acontecimientos adversos (Common Terminology Criteria for Adverse Events, CTCAE), versión 5.0 o
    - AA de grado 2 según los CTCAE versión 5.0 durante >1 semana o
    - Interrupción permanente de HU o
    - Interrupción de HU hasta que resuelva la toxicidad o
    - Hospitalización a consecuencia de una toxicidad por HU
    6. Estado funcional del Grupo Oncológico Cooperativo del Este (Eastern Cooperative Oncology Group, ECOG) de 0, 1 o 2.
    7. Las mujeres en edad fértil y los hombres que tengan parejas en edad fértil deben aceptar usar un método anticonceptivo eficaz durante el estudio. Además, los hombres deben continuar utilizando métodos anticonceptivos durante 3 meses después de la última dosis del fármaco del estudio y las mujeres deben continuar usando métodos anticonceptivos durante 1 semana después de la última dosis del fármaco del estudio. Los métodos anticonceptivos eficaces incluyen (a) los anticonceptivos hormonales combinados de estrógenos y progesterona (por vía oral, intravaginal, transdérmica); (b) los anticonceptivos hormonales solo de progesterona (por vía oral, inyectable, implantable); (c) dispositivo intrauterino; (d) sistema liberador de hormonas intrauterino; (e) ligadura de trompas bilateral; (f) pareja con vasectomía y (g) abstinencia sexual.
    E.4Principal exclusion criteria
    1. Meets the criteria for post-PV myelofibrosis, as defined by the International Working Group-
    Myeloproliferative Neoplasms Research and Treatment (IWG-MRT)
    2. >10% blasts
    3. Clinically significant thrombosis within 3 months of screening
    4. Inadequate liver or renal function:
    a. Renal impairment (estimated creatinineclearance <45 mL/min by Cockcroft Gault)
    Known history of hepatocellular disease (for example, hepatitis B or C, cirrhosis or other hepatocellular disease)
    c. Total bilirubin ≥ 2 X upper limit of laboratory normal (ULN) unless Gilbert’s Syndrome
    d. Alanine aminotransferase (ALT) > 2.5x ULN
    5. Part B only: Previous treatment with a JAK inhibitor
    6. Previous treatment with histone deacetylase (HDAC) inhibitors or BCL-2 inhibitors
    7. Patients previously treated with MDM2 antagonist therapies, p53-directed therapies, or patients receiving interferon-alpha, anagrelide,
    or ruxolitinib within 28 days or approximately 5 half-lives, or hydroxyurea within 1 day, or subjects receiving any other cytoreductive or investigational agents within 28 days or 5 half lives of initial dose. Aspirin is permitted per treatment guidelines for PV unless medically
    contraindicated.
    8. Absolute neutrophil count < 1.5 × 109/L prior to dosing on Cycle 1 Day 1
    9. Platelet count ≤150 × 109/L prior to dosing on Cycle 1 Day 1
    10. Splenic radiation within 3 months prior to first dose of KRT-232
    11. Women who are pregnant or breastfeeding
    12. History of major organ transplant
    13. 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
    14. 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.
    15. 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
    16. Grade 2 or higher QTc prolongation (>480 milliseconds, per NCI CTCAE criteria, version 5.0)
    1. Cumple con los criterios de mielofibrosis después de la PV, según la definición del Grupo de trabajo internacional se investigación y tratamiento de las neoplasias mieloproliferativas (International Working Group-Myeloproliferative Neoplasms Research and Treatment, IWG-MRT).
    2. >10 % blastocitos.
    3. Trombosis clínicamente significativa en los 3 meses previos a la selección.
    4. Función hepática o renal inadecuada:
    a. Insuficiencia renal (aclaramiento de creatinina estimado <45 ml/min según la ecuación de Cockcroft-Gault).
    b. Antecedentes conocidos de enfermedad hepatocelular (por ejemplo, hepatitis B o C, cirrosis u otra enfermedad hepatocelular).
    c. Bilirrubina total ≥2 X límite superior de la normalidad (LSN) a menos que se trate de síndrome de Gilbert.
    d. Alanina aminotransferasa (ALT) >2,5 × LSN.
    5. Solo en la parte B: Tratamiento anterior con algún inhibidor de JAK.
    6. Tratamiento anterior con inhibidores de deacetilasa de histona (histone deacetylase, HDAC) o inhibidores de BCL-2.
    7. Pacientes a los que se haya tratado previamente con tratamientos con antagonistas de MDM2, tratamientos dirigidos a p53, o pacientes que hayan recibido interferón-alfa, anagrelida o ruxolitinib en los 28 días previos o aproximadamente 5 semividas, o hidroxiurea el día previo o los sujetos que estén recibiendo cualquier otro citorreductor o fármacos en investigación en los 28 días previos o las 5 semividas previas a la dosis inicial. Según las directrices de tratamiento para PV se permite la aspirina a menos que esté clínicamente contraindicado (Apéndice 3).
    8. Recuento absoluto de neutrófilos <1,5 × 109/l antes de la administración del día 1 del ciclo 1.
    9. Recuento plaquetario ≤150 × 109/l antes de la administración del día 1 del ciclo 1.
    10. Irradiación esplénica en los 3 meses anteriores a la primera dosis de KRT-232.
    11. Mujeres embarazadas o en periodo de lactancia.
    12. Antecedentes de trasplante de órgano importante.
    13. Enfermedad intercurrente no controlada incluidas, entre otras, hepatitis A aguda; antecedentes conocidos de positivo para virus de inmunodeficiencia humana (VIH); enfermedad cardíaca clínicamente significativa (de Clase III o IV según la Asociación del corazón de Nueva York [New York Heart Association]); insuficiencia cardíaca congestiva sintomática; angina de pecho inestable; arritmia ventricular o enfermedad psiquiátrica/situación social que pueda limitar el cumplimiento con los requisitos del estudio.
    14. Sujetos con infección bacteriana, fúngica, parasitaria o vírica clínicamente significativa que requiera tratamiento. Los sujetos con infecciones bacterianas agudas que requieran el uso de antibióticos deben retrasar la selección/inclusión hasta haber completado la tanda de tratamiento con antibióticos.
    15. Otra neoplasia maligna en los últimos 3 años, diferente del cáncer de piel basocelular o epidermoide, el carcinoma localizado de cuello cervicouterino, el cáncer de próstata confinado en el órgano o tratado y no metastásico con niveles normales de antígeno prostático específico, cáncer de mama localizado tras resección quirúrgica completa o carcinoma de células de transición de vejiga superficial.

    Prolongación de QTc de grado 2 o superior (>480 milisegundos, según los criterios del NCI-CTCAE, versión 5.0)
    E.5 End points
    E.5.1Primary end point(s)
    Part A
    Proportion of subjects with splenomegaly achieving a response at Week 32, with response defined as
    having achieved both of the following:
    - The absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32, with no more than one phlebotomy eligibility occurring postrandomization and prior to the Week 8 visit
    A reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 32 Selection of KRT-232 dose in PV subjects with splenomegaly that has an overall response rate of >40% in Part A
    Part B
    Proportion of subjects with splenomegaly achieving a response at Week 32, with response defined as
    having achieved both of the following:
    • The absence of phlebotomy eligibility beginning at the Week 8 visit and continuing through Week 32, with no more than one phlebotomy eligibility occurring postrandomization and prior to the Week 8 visit
    • A reduction in spleen volume as assessed by MRI (or CT) ≥ 35% from baseline at Week 32
    Parte A
    Proporción de sujetos con esplenomegalia que logran una respuesta en la semana 32, con respuesta definida como haber logrado ambos criterios siguientes:
    • La ausencia de aptitud de la flebotomía empezando en la visita de la semana 8 y que continúa hasta la semana 32, sin más de una aptitud de flebotomía tras la aleatorización y antes de la visita de la semana 8.
    Una reducción en el volumen del bazo según la evaluación por RM (o TAC) ≥35 % a partir del valor inicial en la semana 32.
    Selección de la dosis de KRT-232 en sujetos con PV con esplenomegalia que tenga una tasa de respuesta global de ≥40 % en la Parte A.

    Parte B
    Proporción de sujetos con esplenomegalia que logran una respuesta en la semana 32, con respuesta definida como haber logrado ambos criterios siguientes:
    • La ausencia de aptitud de la flebotomía empezando en la visita de la semana 8 y que continúa hasta la semana 32, sin más de una aptitud de flebotomía tras la aleatorización y antes de la visita de la semana 8.
    • Una reducción en el volumen del bazo según la evaluación por RM (o TAC) ≥35 % a partir del valor inicial en la semana 32.
    E.5.1.1Timepoint(s) of evaluation of this end point
    up to 32 weeks
    Hasta 32 semanas
    E.5.2Secondary end point(s)
    • To estimate the duration of both the absence of phlebotomy eligibility and reduction in spleen volume (for subjects with baseline splenomegaly)
    • To estimate the proportion of subjects achieving a durable phlebotomy independence
    • Response per Modified European Leukemia Network (ELN) Criteria
    • Time to disease progression per Modified European Leukemia Net (ELN) Criteria
    • 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
    • Changes from baseline in patient-reported outcomes
    •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)
    • Estimar la duración de la ausencia de aptitud de flebotomía y la reducción del volumen del bazo (para los sujetos con esplenomegalia inicial).
    • Estimar la proporción de sujetos que logran una independencia duradera de la flebotomía.
    Response per Modified European Leukemia Network (ELN) Criteria.
    • Tiempo hasta la progresión de la enfermedad según los Criterios modificados de la Red europea de leucemia (ELN).
    • Los análisis de los criterios de valoración de la seguridad incluirán las siguientes mediciones o evaluaciones: exploraciones físicas, análisis clínicos, acontecimientos adversos (AA), AA graves (AAG), ECG y constantes vitals.
    • Cambios desde el inicio en los resultados notificados por el paciente.
    • Los parámetros de FC de KRT-232 y del metabolito acil glucurónido, incluyen, entre otros, la concentración máxima observada (Cmáx), la concentración mínima observada (Cmín), el área bajo la curva de concentración plasmática-tiempo (ABC) y la semivida de eliminación terminal (t1/2z).
    E.5.2.1Timepoint(s) of evaluation of this end point
    Duration of trial
    Duración del ensayo
    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 Yes
    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 Yes
    E.8.1.6Cross over Yes
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial5
    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 concerned7
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA45
    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
    La última visita del último paciente, lo que podría ser la llamada telefónica de seguimiento de supervivencia 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 years5
    E.8.9.2In all countries concerned by the trial months4
    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: 95
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 200
    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.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state32
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 170
    F.4.2.2In the whole clinical trial 295
    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.
    El estudio se considerará completo 2 años después de inscribir al último sujeto, en cuyo momento se evaluará para inscribirlos en 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 Opinion2018-11-23
    P. End of Trial
    P.End of Trial StatusOngoing
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