Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   41039   clinical trials with a EudraCT protocol, of which   6717   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).


    Phase 1 trials conducted solely in adults and that are not part of an agreed PIP are not public in the EU CTR (refer to European Guidance 2008/C 168/02   Art. 3 par. 2 and   Commission Guideline 2012/C 302/03,   Art. 5) .
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Print Download

    Summary
    EudraCT Number:2016-005214-21
    Sponsor's Protocol Code Number:RuNiC.
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2017-05-29
    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 number2016-005214-21
    A.3Full title of the trial
    Phase Ib/II clinical trial of ruxolitinib in combination with nilotinib and prednisona for myelofibrosis: RuNiC study
    Ensayo Clínico fase Ib/II de ruxolitinib en combinación con nilotinib y prednisona para mielofibrosis: Estudio RuNiC
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial of ruxolitinib in combination with nilotinib and prednisona for myelofibrosis: RuNiC study
    Ensayo Clínico de ruxolitinib en combinación con nilotinib y prednisona para mielofibrosis: Estudio RuNiC
    A.3.2Name or abbreviated title of the trial where available
    RuNiC
    RuNiC
    A.4.1Sponsor's protocol code numberRuNiC.
    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 Sponsor Grupo Español de Enfermedades Mieloproliferativas GEMFIN
    B.1.3.4CountrySpain
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportGrupo Español de Enfermedades Mieloproliferativas Crónicas Filadelfia Negativas, GEMFIN
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationDynamic Solutions S.L
    B.5.2Functional name of contact pointDepartamento de Ensayos Clínicos
    B.5.3 Address:
    B.5.3.1Street AddressC/ Azcona, 31
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28028
    B.5.3.4CountrySpain
    B.5.4Telephone number34914561125
    B.5.5Fax number34914561126
    B.5.6E-maila.tello@dynasolutions.com
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Jakavi
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical 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.3.9.3Other descriptive nameRUXOLITINIB
    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: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Tasigna
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical form Capsule
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNNILOTINIB
    D.3.9.1CAS number 641571-10-0
    D.3.9.4EV Substance CodeSUB25225
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number300
    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 Yes
    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 nameprednisone
    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 INNPREDNISONE
    D.3.9.1CAS number 53-03-2
    D.3.9.3Other descriptive namePREDNISONE
    D.3.9.4EV Substance CodeSUB10020MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typenot less then
    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: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Jakavi
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical 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.3.9.3Other descriptive nameRUXOLITINIB
    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 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: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Jakavi
    D.2.1.1.2Name of the Marketing Authorisation holderNovartis Europharm Limited
    D.2.1.2Country which granted the Marketing AuthorisationSpain
    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.3.4Pharmaceutical 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.3.9.3Other descriptive nameRUXOLITINIB
    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 number20
    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
    Myeloproliferative Diseases
    Enfermedades mieloproliferativas
    E.1.1.1Medical condition in easily understood language
    Myelofibrosis
    Mielofibrosis
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10074691
    E.1.2Term Post polycythaemia vera myelofibrosis
    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
    The primary objective of the study is to determine the maximum tolerated dose (MTD) and the recommended phase III dose (RP3D) of ruxolitinib when administered in combination with nilotinib 300mg twice a day (BID) and prednisone 50mg every other day (EOD).
    El objetivo principal del estudio es determinar la dosis máxima tolerada (DMT) y la dosis recomendada para la fase III (DRF3) de ruxolitinib cuando se administra en combinación con 300 mg de nilotinib dos veces al día y 50 mg de prednisona en días alternos.
    E.2.2Secondary objectives of the trial
    The secondary objectives of the study are the follows:
     To evaluate the safety profile of ruxolitinib, nilotinib and prednisone administered in combination.
     To evaluate the clinical activity of ruxolitinib, nilotinib and prednisone administered in combination.
    Los objetivos secundarios del estudio son los siguientes:
     Evaluar el perfil de seguridad de ruxolitinib, nilotinib y prednisona administrados conjuntamente.
     Evaluar la actividad clínica de ruxolitinib, nilotinib y prednisona administrados conjuntamente.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients are included in the study if all of the following criteria are met:
    1. Patients must be 18 years or older.
    2. Patients must be diagnosed with primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PPV-MF) or post-essential thrombocythemia-myelofibrosis (PET-MF) irrespective of JAK2 mutation status, guided by the criteria outlined in the 2008 World Health Organization (WHO) criteria for PMF9 and the proposed criteria for PPV-MF and PET-MF outlined by the International Working Group for Myelofibrosis Research and Treatment (IWG-MRT)10.
    3. Patient must be classified as at least intermediate risk level 1 (1 or more prognostic factors) with at least one criteria other than age. The prognostic factors, defined by the International Working Group are11:
     Age > 65 years.
     Presence of constitutional symptoms (weight loss > 10% in the year preceding the screening visit, unexplained fever, or excessive night sweats persisting for more than 1 month).
     Marked anemia (hemoglobin < 10g/dL)*.
     Leukocytosis (history of white blood cell count > 25 x109/L).
     Circulating blasts ≥ 1%.
    *A hemoglobin value < 10 g/dL must be demonstrated during the screening for patients who are not transfusion dependent. Patients receiving regular transfusions of packed red blood cells will be considered to have hemoglobin < 10 g/dL for the purpose of evaluation of risk factors.
    4. Patient must have palpable spleen of at least 5 cm from the costal margin to the point of greatest splenic protrusion at screening.
    5. Patients must have active symptoms of MF as measured by the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS). Demonstrated as a minimum of 5 points in at least one item (scale 0-10), or two items of at least 3 points (scale 0-10).
    6. Patients naïve to JAK inhibitors treatment are eligible for treatment arm A. Patients non-responding to or relapsed after JAK inhibitors treatment must meet one of the following criteria at screening to be eligible for treatment arm B (patients with prior ruxolitinib [INC424] treatment must meet one of the criteria below after at least 12 weeks on ruxolitinib treatment):
     Patients with no improvement in spleen length and may or may not have a corresponding symptomatic improvement.
     Patients with less than a 25% spleen length reduction by palpation and may or may not have a corresponding symptomatic improvement.
     Patients that have had a 25% to 49% reduction in spleen length by palpation and without symptomatic improvement.
     Patients who have lost benefit from prior treatment with a JAK inhibitor as per investigator (i.e. increased spleen length from nadir >40% as measured by palpation and/or return of symptoms as per investigator’s assessment).
    7. Platelet counts ≥ 50 x 109/L not reached with the aid of transfusions at screening or cycle 1 day 1.
    8. Patients with absolute neutrophil count > 1 x 109/L at screening without the use of granulocyte colony-stimulating factors.
    9. Fasting plasma glucose ≤ 120 mg/dL or < 6.7 mmol/L at screening.
    10. Serum creatinine ≤ 2 x upper limit of normal (ULN) at screening.
    11. Patients with peripheral blood blast count of <5% at screening.
    12. Patients with an ECOG performance status of 0, 1, or 2 at screening.
    13. Patients must have discontinued all drugs used to treat underlying MF disease no later than 7 days prior to screening evaluation visit.
    Se incluirá en el estudio a los pacientes que cumplan todos los criterios siguientes:
    1. Los pacientes deben tener 18 años de edad o más.
    2. Los pacientes deben haber sido diagnosticados de mielofibrosis primaria (MFP), mielofibrosis post-policitemia vera (MF-PPV) o mielofibrosis post-trombocitemia esencial (MF-PTE) independientemente del estado de mutación JAK2, según los criterios enunciados en los criterios de MFP de 2008 de la Organización Mundial de la Salud (OMS)9 y los criterios propuestos para MF-PPV y MF-PTE enunciados por el Grupo Internacional de Trabajo de Investigación y Tratamiento de la Mielofibrosis (IWG-MRT, por sus siglas en inglés)10.
    3. El paciente debe estar clasificado como mínimo en un nivel de riesgo intermedio 1 (1 o más factores pronósticos) con al menos un criterio diferente de la edad. Los factores pronósticos, definidos por el Grupo Internacional de Trabajo son11:
     Edad > 65 años.
     Presencia de síntomas generales (pérdida de peso > 10 % en el año anterior a la visita de selección, fiebre por causas no conocidas o sudoración nocturna excesiva persistente durante más de 1 mes).
     Anemia pronunciada (hemoglobina < 10 g/dl)*.
     Leucocitosis (antecedentes de leucocitos > 25 x109/l).
     Blastos circulantes ≥ 1 %
    *Debe demostrarse un valor de hemoglobina < 10 g/dl durante la selección en los pacientes que no presentan dependencia transfusional. Se considerará que los pacientes que reciban transfusiones regulares de concentrados de hematíes tienen valores de hemoglobina < 10 g/dl para el propósito de evaluación de los factores de riesgo.
    4. El paciente debe presentar un bazo palpable de al menos 5 cm desde el borde costal hasta el punto de mayor protrusión en la selección.
    5. Los pacientes deben presentar síntomas activos de MF evaluados mediante la puntuación sintomática total del formulario de evaluación de los síntomas de la neoplasia mieloproliferativa (MPN-SAF TSS, por sus siglas en inglés). Demostrados como un mínimo de 5 puntos en al menos un ítem (escala 0-10) o dos ítems de al menos 3 puntos (escala 0-10).
    6. Los pacientes que no han recibido tratamiento previo con inhibidores de JAK son elegibles para el grupo A de tratamiento. Los pacientes que no han respondido o han recaído tras el tratamiento con inhibidores de JAK deben cumplir uno de los siguientes criterios en la selección para ser elegibles para el grupo B de tratamiento (los pacientes que hayan recibido tratamiento previo con ruxolitinib [INC424] deben cumplir uno de los criterios siguientes después de al menos 12 semanas de tratamiento con ruxolitinib):
     Pacientes sin mejora en la longitud del bazo y que pueden o no presentar una mejora sintomática acorde.
     Pacientes con una reducción inferior al 25 % de la longitud del bazo mediante palpación y que pueden o no presentar una mejora sintomática acorde.
     Pacientes que han tenido una reducción de entre un 25 % y un 49 % de la longitud del bazo mediante palpación y sin mejora sintomática.
     Pacientes que han dejado de beneficiarse de un tratamiento previo con un inhibidor de JAK según el criterio del investigador (es decir, aumento de la longitud del bazo respecto al nadir > 40 % medida mediante palpación y/o reaparición de los síntomas según el criterio del investigador).
    7. Recuento de plaquetas ≥ 50 x 109/l no logrado con ayuda de transfusiones en la selección o en el día 1 del ciclo 1.
    8. Pacientes con recuento absoluto de neutrófilos > 1 x 109/l en la selección sin uso de factores estimulantes de colonia de granulocitos.
    9. Glucosa plasmática en ayunas ≤ 120 mg/dl o < 6,7 mmol/l en la selección.
    10. Creatinina sérica ≤ 2 x límite superior de normalidad (LSN) en la selección.
    11. Pacientes con recuento de blastos circulantes en sangre periférica < 5 % en la selección.
    12. Pacientes con estado funcional ECOG de 0, 1 o 2 en la selección.
    13. Los pacientes deben haber dejado de tomar todos los fármacos usados para tratar la MF subyacente no más tarde de 7 días antes de la visita de evaluación de la selección.
    E.4Principal exclusion criteria
    Pregnant or nursing (lactating) women, confirmed by a positive human chorionic gonadotropin (hCG) laboratory test.
    -Women of child-bearing potential.
    -Male sterilization (at least 6 months prior to screening).
    -For female subjects on the study the vasectomized male partner should be the sole partner for that subject.

    . Previous treatment with JAK inhibitors (including ruxolitinib [INC424]) that resulted in clinically significant toxicities at the discretion of the investigator.
    Patient with clinically significant bacterial, fungal, parasitic or viral infection which require therapy at screening. Patients with acute bacterial infections requiring antibiotic use should delay screening/enrollment until the course of antibiotic therapy has been completed.
    Patients with known active hepatitis B or C or with known HIV positivity (testing is not mandatory).
    Patients with impairment of gastrointestinal function or gastrointestinal disease that may significantly alter the absorption of ruxolitinib, nilotinib and prednisone at screening (e.g. uncontrolled nausea, vomiting, diarrhea, mal-absorption syndrome, small bowel resection).
    Patient with a concurrent malignancy or malignancy within 3 years of screening, with the exception of adequately treated basal or squamous cell carcinoma, non-melanomatous skin cancer or curatively resected cervical cancer.
    Patient who has not recovered to grade 1 or better from any AEs (except alopecia, fatigue, nausea, vomiting) related to previous antineoplastic therapy before screening procedures are initiated.
    Patients receiving the following treatments/medications:
    An enzyme-inducing anti-epileptic drug within 2 weeks prior to starting study treatment.
    Medication that has a known risk to prolong the QT interval or induce Torsades de Pointes, and the treatment cannot be discontinued or switched to a different medication prior to starting study treatment.
    Treatment with a potent systemic inhibitor or a potent systemic inducer of CYP3A4 at the time of screening and cannot be discontinued or switched to alternative medication prior to starting study treatment.
    Any regular use of drugs that interferes with coagulation or inhibits platelet function. NOTE: low doses of aspirin ≤ 150 mg/day and low molecular weight heparin are allowed.
    Patients who have had splenic irradiation within 12 months prior to screening.
    Patient has undergone the following invasive procedures:
    Major surgical procedure, open biopsy or significant traumatic injury < 14 days prior to starting study drug or has not recovered from side effects of such therapy.
    Patient has a history of cardiac dysfunction including any of the following:
    Myocardial infarction within the past 6 months documented by elevated cardiac enzymes or persistent regional wall abnormalities on assessment of left ventricular ejection fraction (LVEF) function.
    Documented congestive heart failure (New York Heart Association functional classification III-IV).
    Documented cardiomyopathy.
    Patient has active cardiac disease including any of the following:
    LVEF < 50% as determined by (MUGA) or (ECHO).
    QTc > 480 msec on screening (ECG) (QTcF, using the Fridericia formula).
    Angina pectoris that requires the use of anti-anginal medication.
    Ventricular arrhythmias except for benign premature ventricular contractions.
    Supraventricular and nodal arrhythmias requiring a pacemaker or not controlled with medication.
    Conduction abnormality requiring a pacemaker.
    Valvular disease with documented compromise in cardiac function.
    Symptomatic pericarditis.
    Concurrent uncontrolled clinical disease and/or severe that, in the opinion of the investigator, could cause unacceptable safety risks or compromise compliance with the protocol (e.g. ischemic heart disease, atherothrombotic events, peripheral arterial occlusive disease, cerebrovascular accident (CVA) / stenosis symptomatic carotid) or uncontrolled diabetes.
    . Patients with inadequate liver or renal function at screening as demonstrated by (not related with MF):
    Encephalopathy grade 1 or more, as per West Haven Criteria.
    Total bilirubin ≥ 3 x ULN and subsequent determination of direct bilirubin ≥ 2 x ULN.
    Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 3 x ULN.
    MDRD-estimated glomerular filtration rate (eGFR) < 30 mL/min/1,73m2 or on dialysis.
    Patients who currently are willing candidates for a stem cell transplantation at the time of the screening assessments.
    Patients under ongoing treatment with another investigational medication or having been treated with an investigational medication within 7 days.
    Patients who are unable to comprehend or are unwilling to sign an informed consent form.
    Patients with active alcohol or drug addiction
    Patients with any concurrent condition that, in the investigator’s opinion, would jeopardize the safety of the patient or compliance with the protocol.
    Mujeres embarazadas o en periodo de lactancia, confirmado por las pruebas de (hCG).
    Mujeres fértiles, definidas como todas las mujeres fisiológicamente capaces de quedarse embarazadas, a menos que utilicen métodos anticonceptivos muy eficaces durante la administración del tratamiento y durante las 4 semanas posteriores a la administración de la última dosis de la medicación del estudio.
    Esterilización en hombres (al menos 6 meses antes de la selección). En el caso de las mujeres que participen en el estudio, la pareja masculina que se ha sometido a una vasectomía debe ser la única pareja de la paciente.
    Tratamiento previo con inhibidores de JAK (incluyendo ruxolitinib [INC424]) que produjo toxicidades clínicamente significativas .
    Paciente con infecciones bacterianas, fúngicas, parasitarias o víricas clínicamente s que requieren tratamiento en el periodo de selección. En pacientes con infecciones bacterianas agudas que requieran el uso de antibióticos se debe aplazar la selección/inclusión hasta que haya finalizado el tratamiento.
    Pacientes con hepatitis B o C activa o con infección por VIH conocida
    Pacientes con deterioro de la función gastrointestinal o enfermedad gastrointestinal que pueda alterar significativamente la absorción de ruxolitinib, nilotinib y prednisona en el periodo de selección
    Paciente con una neoplasia maligna concurrente o durante los 3 años anteriores al periodo de selección, con la excepción de carcinoma de células basales o escamosas convenientemente tratado, cáncer de piel no melanomatoso o cáncer cervical extirpado con intención curativa.
    Paciente en el que no se haya producido la recuperación de acontecimientos adversos. Pacientes que reciban los siguientes tratamientos:
    Un fármaco antiepiléptico que sea inductor enzimático en las 2 semanas anteriores al inicio del tratamiento del estudio.
    Medicamento con riesgo conocido de prolongación del intervalo QT o de inducción de Torsades de Pointes, no pudiendo suspender ese tratamiento ni sustituirlo por otra medicación antes de iniciar el tratamiento del estudio.
    Tratamiento con un inhibidor sistémico o con un inductor sistémico de CYP3A4 en el momento de la selección, no pudiendo suspenderse ese tratamiento ni sustituirlo por otra medicación antes de iniciar el tratamiento del estudio.
    Cualquier uso habitual de fármacos que interfieran con la coagulación o inhiban la función plaquetaria. Se permiten dosis bajas de aspirina, ≤ 150 mg/día, y heparina de bajo peso molecular.
    Pacientes que hayan recibido irradiación esplénica en los 12 meses previos a la selección.
    El paciente se ha sometido a los siguientes procedimientos invasivos:
    Intervención quirúrgica mayor, biopsia abierta o lesión traumática significativa < 14 días antes de iniciar el tratamiento del estudio.
    Paciente con antecedentes de disfunción cardíaca
    insuficiencia cardíaca congestiva (clase III-IV segun clasificación de la New York Heart Association).
    Cardiomiopatía documentada.
    Paciente con cardiopatía activa, incluyendo cualquiera de las siguientes:
    FEVI < 50 % determinada mediante (MUGA) o (ECO).
    QTc > 480 ms en el (ECG) realizado en el periodo de selección (QTcF, usando la fórmula de Fridericia).
    Angina de pecho que requiere el uso de medicación antianginosa.
    Arritmias ventriculares excepto contracciones ventriculares prematuras benignas.
    Arritmias supraventriculares y nodales que requieran marcapasos o que no sean controladas con medicación.
    Anomalías de la conducción que precisen marcapasos.
    Valvulopatía con compromiso documentado de la función cardíaca.
    Pericarditis sintomática.
    Enfermedad clínica concurrente no controlada y/o grave que, según el criterio del investigador, pueda causar riesgos de seguridad inaceptables o comprometer el cumplimiento del protocolo
    Pacientes con función hepática o renal inadecuada (no relacionada con la MF) en el periodo de selección demostrada mediante:
    Encefalopatía de grado ≥ 1,según los criterios de West Haven.
    Bilirrubina total ≤ 3 x LSN y determinación posterior de bilirrubina directa ≥ 2 x LSN.
    Alanina-aminotransferasa (ALT) o aspartato-aminotransferasa (AST) > 3 x LSN.
    Tasa de filtración glomerular estimada (TFGe) mediante la fórmula MDRD < 30 ml/min/1,73m2 o en diálisis.
    Pacientes que en la actualidad sean candidatos para trasplante de células madre en el momento de las evaluaciones de selección.
    Pacientes en tratamiento con otro medicamento en fase de investigación o que hayan sido tratados con otro medicamento en fase de investigación en los 7 días previos.
    Pacientes que no sean capaces de comprender o que no estén dispuestos a firmar el formulario de consentimiento informado.
    Pacientes con alcoholismo o drogadicción activas
    Pacientes con cualquier enfermedad concomitante que ponga en peligro la seguridad del paciente o el cumplimiento del protocolo.
    E.5 End points
    E.5.1Primary end point(s)
    The primary measure is the occurrence of DLTs.
    A DLT is defined as an AE or abnormal laboratory value assessed as unrelated to disease, disease progression, inter-current illness, or concomitant medications that occurs within the first 28 days (cycle 1 day 1 to cycle 1 day 28) of treatment with ruxolitinib, nilotinib and prednisone and meets any of the DLT criteria
    La variable principal es la aparición de TLD.
    Una TLD se define como un AA o un valor analítico anómalo considerado como no relacionado con la enfermedad, progresión de la enfermedad, enfermedad o medicación concomitantes, que se produzca en los primeros 28 días (del día 1 al día 28 del ciclo 1) del tratamiento con ruxolitinib, nilotinib y prednisona y que cumpla los siguientes criterios
    E.5.1.1Timepoint(s) of evaluation of this end point
    AE that occurs within the first 28 days (cycle 1 day 1 to cycle 1 day 28) of treatment with ruxolitinib, nilotinib and prednisone .
    Análisis de AA que se produzcan en los primeros 28 días (del día 1 al día 28 del ciclo 1) del tratamiento con ruxolitinib, nilotinib y prednisona .
    E.5.2Secondary end point(s)
    Safety data will be collected by monitoring the frequency, duration and severity of AEs graded by the Common Terminology Criteria for Adverse Events (CTCAE) of the National Cancer Institute (version 4.0; Appendix 3), performing physical examinations, and evaluating changes in vital signs, Eastern Cooperative Oncology Group (ECOG) performance status, laboratory values and ECGs throughout the study.
    • All grade AEs, grade 3 and 4 AEs, and SAEs.
    • Physical examination.
    • Change in vital signs and ECOG performance status.
    • Laboratory values (serum chemistry and hematology).
    • Cardiac function as assessed by ECGs.
    5.3.2.2 SECONDARY EFFICACY ENDPOINTS
    The secondary efficacy measures are as follows:
    • The percentage of patients with at least 50% reduction in palpable spleen length at 24 and 48 weeks.
    • The percentage of patients who have a ≥ 50% reduction from baseline to 12, 24 and 48 weeks in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) (
    Las variables secundarias de eficacia son las siguientes:
     Porcentaje de pacientes con una reducción de al menos el 50 % en la longitud del bazo palpable en las semanas 24 y 48.
     Porcentaje de pacientes con una reducción de ≥ 50 % respecto a la valoración basal en MPN-SAF TSS en las semanas 12, 24 y 48.

    Los datos de seguridad se recogerán a través de la monitorización de la frecuencia, la duración y la intensidad de los AA según la versión 4.0 de los criterios CTCAE del National Cancer Institute, mediante la realización de exploraciones físicas y evaluando cambios en constantes vitales, estado funcional del ECOG, valores analíticos y ECG a lo largo del estudio.

     Los AA de cualquier grado, los AA de grado 3 y 4, y los acontecimientos adversos graves (AAG).
     Exploración física.
     Cambio en las constantes vitales y el estado funcional del ECOG.
     Valores analíticos (bioquímica sérica y hematología).
     Función cardíaca evaluada mediante ECG.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The percentage of patients with at least 50% reduction in palpable spleen length at 24 and 48 weeks.
    • The percentage of patients who have a ≥ 50% reduction from baseline to 12, 24 and 48 weeks in the Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) (
    Porcentaje de pacientes con una reducción de al menos el 50 % en la longitud del bazo palpable en las semanas 24 y 48.
     Porcentaje de pacientes con una reducción de ≥ 50 % respecto a la valoración basal en MPN-SAF TSS en las semanas 12, 24 y 48.
    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 No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other Yes
    E.7.1.3.1Other trial type description
    Phase Ib/II
    Fase Ib/II
    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 No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Determinación de la Dosis Máxima Tolerada
    Determination of the maximum tolerated dose (MTD)
    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 concerned8
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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
    LVLS
    Ultima visita del ultimo paciente
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    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: 44
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 12
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state44
    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)
    None
    Ninguna
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-07-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-06-28
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    For support, visit the EMA Service Desk , log in using your EMA account and open a ticket specifying "EU CTR" in your request.
    If you do not have an account, please visit the EMA Account management page page click on "Create an EMA account" and follow the instructions.
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2021 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA